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Sample records for antimalarial drug artemisinin

  1. Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable antimalarial drugs.

    Science.gov (United States)

    Hale, Victoria; Keasling, Jay D; Renninger, Neil; Diagana, Thierry T

    2007-12-01

    Despite considerable efforts by multiple governmental and nongovernmental organizations to increase access to artemisinin-based combination therapies (ACTs), these life-saving antimalarial drugs remain largely unaffordable to the most vulnerable populations. The cost of artemisinin derivatives, ACTs' crucial active ingredients, contributes significantly to the high price of these therapies. With a grant from the Bill and Melinda Gates Foundation, a partnership between Amyris Biotechnologies, the Institute for OneWorld Health, and the University of California, Berkeley is using synthetic biology to help reduce the cost of artemisinin. This article presents a description of the technological platform the partnership--called the Artemisinin Project--is developing to manufacture a low-cost, semi-synthetic artemisinin through a fermentation process. By making life-saving ACTs affordable to the people who most need them, the Artemisinin Project hopes to show that the power of biotechnology can be harnessed to provide solutions to global health problems.

  2. Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin

    Energy Technology Data Exchange (ETDEWEB)

    Phukon, Pinkee [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Radhapyari, Keisham [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India); Konwar, Bolin Kumar [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Nagaland University (Central), Lumami, Zunheboto, Nagaland 798627 (India); Khan, Raju, E-mail: khan.raju@gmail.com [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India)

    2014-04-01

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate–gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate–gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01–0.08 μg mL{sup −1}) with sensitivity of 0.26 μA μg mL{sup −1}. The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035 μg mL{sup −1} and 0.0036 μg mL{sup −1} in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. - Highlights: • Extraction of PHA from indigenously isolated Pseudomonas aeruginosa BPC2 • Developed PHA/AuNPs/HRP/ITO based biosensor without the use of chemical cross linker • Detection of antimalarial drug artemisinin using the nanocomposite based biosensor.

  3. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

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    Maria P. Crespo-Ortiz

    2012-01-01

    Full Text Available Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

  4. Establishment of an in vitro screening model for neurodegeneration induced by antimalarial drugs of the artemisinin-type..

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    Schmuck, G; Haynes, R K

    2000-01-01

    The establishment of an in vitro screening model for neurodegeneration inducing antimalarial drugs was conducted in stepwise fashion. Firstly, the in vivo selective neurotoxic potency of artemisinin was tested in neuronal cells in vitro in relation to the cytotoxic potency in other organ cell cultures such as liver and kidney or versus glial cells. Secondly, a comparison between different parts of the brain (cortex vs. brain stem) was performed and in the last step, a fast and sensitive screening endpoint was identified. In summary, non-neuronal cell lines such as hepatocytes (HEP-G2), liver epithelial cells (IAR), proximal tubular cells (LLC-PK(1)) and glial cells from the rat (C6) and human (GO-G-IJKT) displayed only moderate sensitivity to artemisinin and its derivatives. The same was found in undifferentiated neuronal cell lines from the mouse (N-18) and from human (Kelly), whereas during differentiation, these cells became much more sensitive. Primary astrocytes from the rat also were not specifically involved. In the comparison of primary neuronal cell cultures from the cortex and brain stem of the rat, the brain stem was found to be more sensitive than the cortex. The neurotoxic potential was determined by cytoskeleton elements (neurofilaments), which were degradated in vitro by diverse neurodegenerative compounds. In comparison of dog and rat primary brain stem cultures, the dog cells were found to be more sensitive to artemisinin than the rat cells. In addition to the primary brain stem cell cultures it was shown that the sprouting assay, which determines persistent delayed neurotoxic effects, is also useful for screening antimalarial drugs. To other compounds, artemether and artesunate, showed that use of the sprouting assay followed by primary brain stem cultures of the rat will be a good strategy to select candidate compounds.

  5. Stable production of the antimalarial drug artemisinin in the moss Physcomitrella patens

    DEFF Research Database (Denmark)

    Binti Khairul Ikram, Nur Kusaira; Kashkooli, Arman Beyraghdar; Peramuna, Anantha Vithakshana

    2017-01-01

    study shows that P. patens can be a sustainable and efficient production platform of artemisinin that without further modifications allow for industrial scale production. A stable supply of artemisinin will lower the price of artemisinin-based treatments, hence become more affordable to the lower income...

  6. Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs

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    Vreeke Ed

    2007-07-01

    Full Text Available Abstract Background Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs, the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. Methods The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe. From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Results Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1–1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum. There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania. Conclusion Additional studies are required to build a more robust methodology, and to assess current consumptions

  7. Assessment of global reporting of adverse drug reactions for anti-malarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

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    Van Erps Jan

    2011-03-01

    Full Text Available Abstract Background In spite of enhanced control efforts, malaria remains a major public health problem causing close to a million deaths annually. With support from several donors, large amounts of artemisinin-based combination therapy (ACT are being deployed in endemic countries raising safety concerns as little is known about the use of ACT in several of the settings where they are deployed. This project was undertaken to profile the provenance of the pharmacovigilance reporting of all anti-malarials, including ACT to the WHO adverse drug reaction (ADR database (Vigibase™ over the past 40 years. Methods The WHO Programme for International Drug Monitoring, the Uppsala Monitoring Centre (UMC provided anonymized extracts of Vigibase™ covering the period 1968-2008. All countries in the programme were clustered according to their malaria control phase and income status. The number of individual case safety reports (ICSRs of anti-malarials was analyzed according to those clusters. Results From 1968 to 2008, 21,312 ICSRs suspecting anti-malarials were received from 64 countries. Low-income countries, that are also malaria-endemic (categorized as priority 1 countries submitted only 1.2% of the ICSRs. Only 60 out of 21,312 ICSRs were related to ACT, 51 of which were coming from four sub-Saharan African countries. Although very few ICSRs involved artemisinin-based compounds, many of the adverse events reported were potentially serious. Conclusions This paper illustrates the low reporting of ADRs to anti-malarials in general and ACT in particular. Most reports were submitted by non-endemic and/or high-income countries. Given the current mix of large donor funding, the insufficient information on safety of these drugs, increasing availability of ACT and artemisinin-based monotherapies in public and private sector channels, associated potential for inappropriate use and finally a pipeline of more than 10 new novel anti-malarials in various stages of

  8. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity.

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    Lucchi, Naomi W; Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-12-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.

  9. Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin

    OpenAIRE

    Steyn, Minette; N’Da, David D.; Breytenbach, Jaco C; Smith, Peter J.; Meredith, Sandra; Breytenbach, Wilma J.

    2011-01-01

    Objectives The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains. Methods The ethers were synthesized in a one-step process by coupling ethylene glycol moieties of various chain lengths to carbon C-10 of artemisinin. The aqueous solubility and log D values w...

  10. Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT

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    Ringsted Frank M

    2011-08-01

    Full Text Available Abstract Background Artemether-lumefantrine (ALu replaced sulphadoxine-pymimethamine (SP as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results All surveyed drug shops illicitly sold SP and quinine (QN, and legally amodiaquine (AQ. Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%, QN (11% and ACT (2%. Conclusions In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp

  11. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

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    Jerapan Krungkrai

    2016-05-01

    Full Text Available Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  12. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai; Sudaratana Rochanakij Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu(Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  13. Antimalarial qinghaosu/artemisinin:The therapy worthy of a Nobel Prize

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  14. Substandard artemisinin-based antimalarial medicines in licensed retail pharmaceutical outlets in Ghana

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    M. El-Duah & K. Ofori-Kwakye

    2012-09-01

    Full Text Available Background & objectives: The artemisinin-based antimalarial medicines are first line medicines in the treatmentof severe and uncomplicated falciparum malaria. Numerous brands of these medicines manufactured in variouscountries are available in the Ghanaian market. The study was aimed at evaluating the authenticity and qualityof selected brands of artemisinin-based antimalarial medicines marketed in Ghana.Methods: In all, 14 artemisinin-based antimalarial medicines were purchased from pharmacies (P and licensedchemical shops (LCSs in the Kumasi metropolis, Ghana. Simple field tests based on colorimetry and thin layerchromatography were employed in determining the authenticity of the samples. Important quality assessmenttests, namely uniformity of mass, crushing strength, disintegration time, and the percentage content of activepharmaceutical ingredients (APIs were determined.Results: All the brands tested contained the stipulated APIs. Artesunate tablet AT2 failed the uniformity of masstest while artesunate tablets AT3 & AT4 as well as amodiaquine tablets AM4 & AM6 failed the crushing strengthtest. All the six artemether-lumefantrine tablet brands passed the uniformity of mass, crushing strength anddisintegration tests. Only artemether-lumefantrine tablet brand AL1 contained the correct amount of the drugs.The other 13 artemisinin products contained either a lower (underdose or higher (overdose amount of thespecified drug. Artesunate monotherapy tablets were readily available in pharmacies and licensed chemicalshops.Interpretation & conclusion: All the artemisinin-based medicines tested (except AL1 were of substandardquality. The results demonstrate the need for continuous monitoring and evaluation of the quality of artemisininbased antimalarials in the Ghanaian market. Also, the practice of artemisinin antimalarial monotherapy is prevalentin Ghana. Determined efforts should, therefore, be made to eradicate the practice to prevent the development

  15. A global subsidy for antimalarial drugs.

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    Gelband, Hellen; Seiter, Andreas

    2007-12-01

    In 2004, the Institute of Medicine concluded that a global high-level subsidy was the best way to make effective antimalarial drugs--currently, artemisinin-combination therapies (ACTs)--widely available at affordable prices and at the same time substantially delay the emergence and spread of artemisinin-resistant strains of falciparum malaria. The subsidy would be available to manufacturers of all ACTs meeting pre-specified efficacy, safety, and quality criteria. Buyers would pay very low prices, allowing drugs to flow through existing channels, with the aim of reaching consumers at a similar price to chloroquine, the most frequently used (although no longer effective) malaria drug. Unsubsidized artemisinin monotherapies would be more expensive than subsidized ACTs (co-formulations), thereby largely eliminating their use through market forces. Conditions favoring the emergence of artemisinin-resistant malaria would be greatly reduced. The global high-level subsidy is a powerful idea that is moving from economic concept to pragmatic reality.

  16. Expanding the Antimalarial Drug Arsenal—Now, But How?

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    Rajeev K. Mehlotra

    2011-04-01

    Full Text Available The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii repurposing drugs that are currently used to treat other infections or diseases; (iii chemically modifying existing antimalarial compounds; (iv exploring natural sources; (v large-scale screening of diverse chemical libraries; and (vi through parasite genome-based (“targeted” discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum, and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs, and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now and “long term” (5. Next generation of

  17. Facile oxidation of leucomethylene blue and dihydroflavins by artemisinins: relationship with flavoenzyme function and antimalarial mechanism of action.

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    Haynes, Richard K; Chan, Wing-Chi; Wong, Ho-Ning; Li, Ka-Yan; Wu, Wai-Keung; Fan, Kit-Man; Sung, Herman H Y; Williams, Ian D; Prosperi, Davide; Melato, Sergio; Coghi, Paolo; Monti, Diego

    2010-08-02

    The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite. The reduced flavin adenine dinucleotide cofactor FADH(2) initiates reduction to leucomethylene blue (LMB), which is oxidised by oxygen to generate reactive oxygen species (ROS) and MB. MB then acts as a subversive substrate for NADPH normally required to regenerate FADH(2) for enzyme function. The synergism between MB and the peroxidic antimalarial artemisinin derivative artesunate suggests that artemisinins have a complementary mode of action. We find that artemisinins are transformed by LMB generated from MB and ascorbic acid (AA) or N-benzyldihydronicotinamide (BNAH) in situ in aqueous buffer at physiological pH into single electron transfer (SET) rearrangement products or two-electron reduction products, the latter of which dominates with BNAH. Neither AA nor BNAH alone affects the artemisinins. The AA-MB SET reactions are enhanced under aerobic conditions, and the major products obtained here are structurally closely related to one such product already reported to form in an intracellular medium. A ketyl arising via SET with the artemisinin is invoked to explain their formation. Dihydroflavins generated from riboflavin (RF) and FAD by pretreatment with sodium dithionite are rapidly oxidised by artemisinin to the parent flavins. When catalytic amounts of RF, FAD, and other flavins are reduced in situ by excess BNAH or NAD(P)H in the presence of the artemisinins in the aqueous buffer, they are rapidly oxidised to the parent flavins with concomitant formation of two-electron reduction products from the artemisinins; regeneration of the reduced flavin by excess reductant maintains a catalytic cycle until the artemisinin is consumed. In preliminary experiments, we show that NADPH consumption in yeast GR with redox behaviour similar to that of parasite GR is

  18. Otimização do processo de extração e isolamento do antimalárico artemisinina a partir de Artemisia annua L. Optimization of the extraction and isolation of the antimalarial drug artemisinin from Artemisia annua L.

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    Rodney Alexandre Ferreira Rodrigues

    2006-04-01

    Full Text Available Malaria is still one of the major diseases in the world, causing physical and economic problems in tropical regions. Artemisinin (Qinghaosu, a natural compound identified in Artemisia annua L. , is an effective drug mainly against cerebral malaria. The action of this drug is immediate and parasitaemia in the treatment of drug-resistant malaria is rapidily reduced, justifying the industrial production of artemisinin. This article focuses on the industrial production of this potent antimalarial drug, including strategies for enhancing yield using inexpensive and easy steps.

  19. Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin.

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    Steyn, Minette; N'Da, David D; Breytenbach, Jaco C; Smith, Peter J; Meredith, Sandra; Breytenbach, Wilma J

    2011-02-01

    The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains.   The ethers were synthesized in a one-step process by coupling ethylene glycol moieties of various chain lengths to carbon C-10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine-sensitive (D10) and moderately chloroquine-resistant (Dd2) strains of P. falciparum. The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8, featuring three ethylene oxide units, was the most active of all the synthesized ethers. The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water-soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water-soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  20. Artemisinin combination therapies price disparity between government and private health sectors and its implication on antimalarial drug consumption pattern in Morogoro Urban District, Tanzania

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    Malisa Allen

    2012-03-01

    Full Text Available Abstract Background Universal access to effective treatments is a goal of the Roll Back Malaria Partnership. However, despite official commitments and substantial increases in financing, this objective remains elusive, as development assistance continue to be routed largely through government channels, leaving the much needed highly effective treatments inaccessible or unaffordable to those seeking services in the private sector. Methods To quantify the effect of price disparity between the government and private health systems, this study have audited 92 government and private Drug Selling Units (DSUs in Morogoro urban district in Tanzania to determine the levels, trend and consumption pattern of antimalarial drugs in the two health systems. A combination of observation, interviews and questionnaire administered to the service providers of the randomly selected DSUs were used to collect data. Results ALU was the most selling antimalarial drug in the government health system at a subsidized price of 300 TShs (0.18 US$. By contrast, ALU that was available in the private sector (coartem was being sold at a price of about 10,000 TShs (5.9 US$, the price that was by far unaffordable, prompting people to resort to cheap but failed drugs. As a result, metakelfin (the phased out drug was the most selling drug in the private health system at a price ranging from 500 to 2,000 TShs (0.29–1.18 US$. Conclusions In order for the prompt diagnosis and treatment with effective drugs intervention to have big impact on malaria in mostly low socioeconomic malaria-endemic areas of Africa, inequities in affordability and access to effective treatment must be eliminated. For this to be ensued, subsidized drugs should be made available in both government and private health sectors to promote a universal access to effective safe and affordable life saving antimalarial drugs.

  1. Quantifying the pharmacology of antimalarial drug combination therapy

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    Hastings, Ian M.; Hodel, Eva Maria; Kay, Katherine

    2016-01-01

    Most current antimalarial drugs are combinations of an artemisinin plus a ‘partner’ drug from another class, and are known as artemisinin-based combination therapies (ACTs). They are the frontline drugs in treating human malaria infections. They also have a public-health role as an essential component of recent, comprehensive scale-ups of malaria interventions and containment efforts conceived as part of longer term malaria elimination efforts. Recent reports that resistance has arisen to artemisinins has caused considerable concern. We investigate the likely impact of artemisinin resistance by quantifying the contribution artemisinins make to the overall therapeutic capacity of ACTs. We achieve this using a simple, easily understood, algebraic approach and by more sophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the two approaches gave consistent results. Surprisingly, the artemisinin component typically makes a negligible contribution (≪0.0001%) to the therapeutic capacity of the most widely used ACTs and only starts to make a significant contribution to therapeutic outcome once resistance has started to evolve to the partner drugs. The main threat to antimalarial drug effectiveness and control comes from resistance evolving to the partner drugs. We therefore argue that public health policies be re-focussed to maximise the likely long-term effectiveness of the partner drugs. PMID:27604175

  2. Anticancer properties of distinct antimalarial drug classes.

    Directory of Open Access Journals (Sweden)

    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  3. Mechanism of artemisinin resistance for malaria PfATP6 L263 mutations and discovering potential antimalarials: An integrated computational approach

    Science.gov (United States)

    Nagasundaram, N.; George Priya Doss, C.; Chakraborty, Chiranjib; Karthick, V.; Thirumal Kumar, D.; Balaji, V.; Siva, R.; Lu, Aiping; Ge, Zhang; Zhu, Hailong

    2016-07-01

    Artemisinin resistance in Plasmodium falciparum threatens global efforts in the elimination or eradication of malaria. Several studies have associated mutations in the PfATP6 gene in conjunction with artemisinin resistance, but the underlying molecular mechanism of the resistance remains unexplored. Associated mutations act as a biomarker to measure the artemisinin efficacy. In the proposed work, we have analyzed the binding affinity and efficacy between PfATP6 and artemisinin in the presence of L263D, L263E and L263K mutations. Furthermore, we performed virtual screening to identify potential compounds to inhibit the PfATP6 mutant proteins. In this study, we observed that artemisinin binding affinity with PfATP6 gets affected by L263D, L263E and L263K mutations. This in silico elucidation of artemisinin resistance enhanced the identification of novel compounds (CID: 10595058 and 10625452) which showed good binding affinity and efficacy with L263D, L263E and L263K mutant proteins in molecular docking and molecular dynamics simulations studies. Owing to the high propensity of the parasite to drug resistance the need for new antimalarial drugs will persist until the malarial parasites are eventually eradicated. The two compounds identified in this study can be tested in in vitro and in vivo experiments as possible candidates for the designing of new potential antimalarial drugs.

  4. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  5. Isoprenoid drugs, biofuels, and chemicals--artemisinin, farnesene, and beyond.

    Science.gov (United States)

    George, Kevin W; Alonso-Gutierrez, Jorge; Keasling, Jay D; Lee, Taek Soon

    2015-01-01

    Isoprenoids have been identified and used as natural pharmaceuticals, fragrances, solvents, and, more recently, advanced biofuels. Although isoprenoids are most commonly found in plants, researchers have successfully engineered both the eukaryotic and prokaryotic isoprenoid biosynthetic pathways to produce these valuable chemicals in microorganisms at high yields. The microbial synthesis of the precursor to artemisinin--an important antimalarial drug produced from the sweet wormwood Artemisia annua--serves as perhaps the most successful example of this approach. Through advances in synthetic biology and metabolic engineering, microbial-derived semisynthetic artemisinin may soon replace plant-derived artemisinin as the primary source of this valuable pharmaceutical. The richness and diversity of isoprenoid structures also make them ideal candidates for advanced biofuels that may act as "drop-in" replacements for gasoline, diesel, and jet fuel. Indeed, the sesquiterpenes farnesene and bisabolene, monoterpenes pinene and limonene, and hemiterpenes isopentenol and isopentanol have been evaluated as fuels or fuel precursors. As in the artemisinin project, these isoprenoids have been produced microbially through synthetic biology and metabolic engineering efforts. Here, we provide a brief review of the numerous isoprenoid compounds that have found use as pharmaceuticals, flavors, commodity chemicals, and, most importantly, advanced biofuels. In each case, we highlight the metabolic engineering strategies that were used to produce these compounds successfully in microbial hosts. In addition, we present a current outlook on microbial isoprenoid production, with an eye towards the many challenges that must be addressed to achieve higher yields and industrial-scale production.

  6. Herbicidal properties of antimalarial drugs.

    Science.gov (United States)

    Corral, Maxime G; Leroux, Julie; Stubbs, Keith A; Mylne, Joshua S

    2017-03-31

    The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true; many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules.

  7. Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs.

    Science.gov (United States)

    An, Jie; Minie, Mark; Sasaki, Tomikazu; Woodward, Joshua J; Elkon, Keith B

    2017-01-14

    The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.

  8. New approaches in antimalarial drug discovery and development: a review

    Directory of Open Access Journals (Sweden)

    Anna Caroline C Aguiar

    2012-11-01

    Full Text Available Malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. This problem has since been aggravated by a decreased sensitivity of Plasmodium vivax to chloroquine. This review discusses strategies for evaluating the antimalarial activity of new compounds in vitro and in animal models ranging from conventional tests to the latest high-throughput screening technologies. Antimalarial discovery approaches include the following: the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking. Using these approaches, thousands of new drugs with known molecular specificity and active against P. falciparum have been selected. The inhibition of haemozoin formation in vitro, an indirect test that does not require P. falciparum cultures, has been described and this test is believed to improve antimalarial drug discovery. Clinical trials conducted with new funds from international agencies and the participation of several industries committed to the eradication of malaria should accelerate the discovery of drugs that are as effective as artemisinin derivatives, thus providing new hope for the control of malaria.

  9. Prediction of potential antimalarial targets of artemisinin based on protein information from whole genome of Plasmodium falciparum

    Institute of Scientific and Technical Information of China (English)

    HAN LiPing; HUANG Qiang; NAN Peng; ZHONG Yang

    2009-01-01

    On the basis of the genomic data and protein pathway information about Plasmodium falciparum clone 3D7 from the NCBI taxonomy database and the KEGG database,eight key protein enzymes in the signal pathways were selected to perform molecular docking with artemisinin.The binding modes obtained from the molecular docking suggested that purine nucleoside phosphorylase (pfPNP),peptide deformylase (pfPDF),and ribose 5-phosphate isomerase (pfRpiA) may be involved in the antimalarial mode of action of artemisinin.Artemisinin exhibited its antimalarial activity probably by interfering with the metabolic pathways of purine,pyrimidine,methionine,glyoxylate and dicarboxylate,or pentose phosphate.

  10. Acquired resistance of malarial parasites against artemisinin-based drugs: social and economic impacts.

    Science.gov (United States)

    Porter-Kelley, Johanna M; Cofie, Joann; Jean, Sophonie; Brooks, Mark E; Lassiter, Mia; Mayer, Dc Ghislaine

    2010-01-01

    Malaria, a disease of poverty and high morbidity and mortality in the tropical world, has led to a worldwide search for control measures. To that end, good antimalarial chemotherapies have been difficult to find in the global market and those that seem to be most effective are rapidly becoming ineffective due to the emergence and spread of drug resistance. Artemisinin, a very effective yet expensive antimalarial, has quickly become the recommended drug of choice when all other possibilities fail. However, for all its promise as the next great antimalarial, the outlook is bleak. Resistance is developing to artemisinin while another effective antimalarial is not in sight. Malaria endemic areas which are mostly in developing countries must deal with the multifaceted process of changing and implementing new national malaria treatment guidelines. This requires complex interactions between several sectors of the affected society which in some cases take place within the context of political instability. Moreover, the cost associated with preventing and containing the spread of antimalarial resistance is detrimental to economic progress. This review addresses the impact of artemisinin resistance on the socioeconomic structure of malaria endemic countries.

  11. Molecular surveillance of antimalarial drug resistance related genes in Plasmodium falciparum isolates from Eritrea.

    Science.gov (United States)

    Menegon, Michela; Nurahmed, Abduselam M; Talha, Albadawi A; Nour, Bakri Y M; Severini, Carlo

    2016-05-01

    The introduction of artemisinin-based combination therapy has led to extraordinary results in malaria control, however the recent emergence of partial resistance to artemisinin therapy in Southeast Asia jeopardizes these successes. This study aimed at investigating resistance to the antimalarial drugs by evaluating the polymorphisms in the PfK13, Pfcrt and Pfmdr1 genes in Plasmodium falciparum isolates obtained from patients in Eritrea.

  12. Anti-Inflammatory and Immunoregulatory Functions of Artemisinin and Its Derivatives

    Directory of Open Access Journals (Sweden)

    Chenchen Shi

    2015-01-01

    Full Text Available Artemisinin and its derivatives are widely used in the world as the first-line antimalarial drug. Recently, growing evidences reveal that artemisinin and its derivatives also possess potent anti-inflammatory and immunoregulatory properties. Meanwhile, researchers around the world are still exploring the unknown bioactivities of artemisinin derivatives. In this review, we provide a comprehensive discussion on recent advances of artemisinin derivatives affecting inflammation and autoimmunity, the underlying molecular mechanisms, and also drug development of artemisinins beyond antimalarial functions.

  13. A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Cleydson Breno R. Santos

    2013-12-01

    Full Text Available The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs and molecular docking were used to investigate the interaction between ligands and the receptor (heme. Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE, the charge on the O11 oxygen atom (QO11, the torsion angle O1-O2-Fe-N2 (D2 and the maximum rate of R/Sanderson Electronegativity (RTe+. These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

  14. Evaluation of the Quality of Artemisinin-Based Antimalarial Medicines Distributed in Ghana and Togo

    Directory of Open Access Journals (Sweden)

    Dorcas Osei-Safo

    2014-01-01

    Full Text Available This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation—basic (colorimetric tests for establishing the identity of the requisite active pharmaceutical ingredients (APIs, semi-quantitative TLC assay for the identification and estimation of API content, and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally manufactured (77.3% and imported medicines (77.5% were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7% than registered medicines (70.8%. Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.

  15. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance.

    Science.gov (United States)

    Wongsrichanalai, C; Sibley, C H

    2013-10-01

    Following a decade-long scale up of malaria control through vector control interventions, the introduction of rapid diagnostic tests and highly efficacious Artemisinin-based Combination Therapy (ACT) along with other measures, global malaria incidence declined significantly. The recent development of artemisinin resistance on the Cambodia-Thailand border, however, is of great concern. This review encompasses the background of artemisinin resistance in Plasmodium falciparum, its situation, especially in the Greater Mekong Sub-region (GMS), and the responses taken to overcome this resistance. The difficulties in defining resistance are presented, particularly the necessity of measuring the clinical response to artemisinins using the slow parasite-clearance phenotype. Efforts to understand the molecular basis of artemisinin resistance and the search for molecular markers are reviewed. The markers, once identified, can be applied as an efficient tool for resistance surveillance. Despite the limitation of current surveillance methods, it is important to continue vigilance for artemisinin resistance. The therapeutic efficacy "in vivo study" network for monitoring antimalarial resistance in the GMS has been strengthened. GMS countries are working together in response to artemisinin resistance and aim to eliminate all P. falciparum parasites. These efforts are crucial since a resurgence of malaria due to drug and/or insecticide resistance, program cuts, lack of political support and donor fatigue could set back malaria control success in the sub-region and threaten malaria control and elimination if resistance spreads to other regions.

  16. Access to Artemisinin-Combination Therapy (ACT) and other Anti-Malarials: National Policy and Markets in Sierra Leone

    Science.gov (United States)

    Amuasi, John H.; Diap, Graciela; Nguah, Samuel Blay; Karikari, Patrick; Boakye, Isaac; Jambai, Amara; Lahai, Wani Kumba; Louie, Karly S.; Kiechel, Jean-Rene

    2012-01-01

    Malaria remains the leading burden of disease in post-conflict Sierra Leone. To overcome the challenge of anti-malarial drug resistance and improve effective treatment, Sierra Leone adopted artemisinin-combination therapy artesunate-amodiaquine (AS+AQ) as first-line treatment for uncomplicated P. falciparum malaria. Other national policy anti-malarials include artemether-lumefantrine (AL) as an alternative to AS+AQ, quinine and artemether for treatment of complicated malaria; and sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp). This study was conducted to evaluate access to national policy recommended anti-malarials. A cross-sectional survey of 127 medicine outlets (public, private and NGO) was conducted in urban and rural areas. The availability on the day of the survey, median prices, and affordability policy and available non-policy anti-malarials were calculated. Anti-malarials were stocked in 79% of all outlets surveyed. AS+AQ was widely available in public medicine outlets; AL was only available in the private and NGO sectors. Quinine was available in nearly two-thirds of public and NGO outlets and over one-third of private outlets. SP was widely available in all outlets. Non-policy anti-malarials were predominantly available in the private outlets. AS+AQ in the public sector was widely offered for free. Among the anti-malarials sold at a cost, the same median price of a course of AS+AQ (US$1.56), quinine tablets (US$0.63), were found in both the public and private sectors. Quinine injection had a median cost of US$0.31 in the public sector and US$0.47 in the private sector, while SP had a median cost of US$0.31 in the public sector compared to US$ 0.63 in the private sector. Non-policy anti-malarials were more affordable than first-line AS+AQ in all sectors. A course of AS+AQ was affordable at nearly two days’ worth of wages in both the public and private sectors. PMID:23133522

  17. World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs

    Directory of Open Access Journals (Sweden)

    Olliaro Piero

    2007-09-01

    Full Text Available Abstract The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.

  18. Research Progress of Artemisinins-based Antimalarial Agents%青蒿素类抗疟制剂研究概述

    Institute of Scientific and Technical Information of China (English)

    沈硕; 刘淑芝; 杜茂波

    2015-01-01

    Artemisinin is the antimalarial active ingredient, which is discovered by Chinese scientists in 1970s. The chemical structure of artemisinin is modified or altered to obtain a series of analogues to satisfy the medication requirements. According to the physicochemical properties of medicines and actual clinical necessities, the preparations of artemisinins are developed and the common preparations include tablet, suppository, injection, etc.. With the developing of technology, researchers have conducted a large number of studies on the artemisinins nanoparticles injection, transdermal drug delivery systems, mucosal drug delivery systems and etc. This article systematically collected and discussed the recent studies on the antimalarial preparations of artemisinins in line with different administration routes.%青蒿素是我国于20世纪70年代发现的抗疟活性成分。为满足不同的用药需要,研究人员近年来对其化学结构进行了改造,获得了系列青蒿素类衍生物,并根据药物的理化性质和实际临床需求,研制出了多种青蒿素类抗疟制剂,其中常用的制剂有片剂、栓剂和注射剂等。随着制剂技术不断发展,技术人员针对青蒿素类的纳米注射剂、经皮制剂和黏膜给药制剂等新剂型进行了大量研究。本文根据不同的给药途径,对近年来青蒿素类抗疟制剂的研究情况进行系统的整理和论述。

  19. Antimalarial drug discovery: screening of Brazilian medicinal plants and purified compounds.

    Science.gov (United States)

    Krettli, Antoniana Ursine

    2009-02-01

    Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected. New active compounds need to be discovered. To find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests. For antimalarial research, screening medicinal plants is more efficient than screening randomly chosen plants. Biomonitored fractionation allows selection of new active molecules identified as potential antimalarials in multidisciplinary projects in Brazil; no new molecule is available for human testing. The advantages of projects based on ethnopharmacology are discussed.

  20. Antimalarial drug resistance in Bangladesh, 1996-2012.

    Science.gov (United States)

    Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald

    2013-12-01

    Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh.

  1. Oxidative stress in malaria and artemisinin combination therapy

    DEFF Research Database (Denmark)

    Kavishe, Reginald A.; Koenderink, Jan B.; Alifrangis, Michael

    2017-01-01

    Artemisinin-based combination therapy (ACT) has been adopted as a strategy to mitigate multidrug resistance to antimalarial monotherapies. ACT combines the rapid and effective but rather short plasma half-life antimalarial action of an artemisinin derivative with a longer acting partner drug...

  2. Artemisinin-Naphthoquine Combination (ARCO®: An Overview of the Progress

    Directory of Open Access Journals (Sweden)

    Qingyun Huang

    2010-12-01

    Full Text Available With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is a derivative of two independently developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-naphthoquine combination offers a novel advantage over existing ACTs: it can be administered as a single oral dose (or a 1-day treatment. Several therapeutic studies conducted recently indicate that a single oral dose administration of artemisinin-naphthoquine combination is equally effective and safe as the 3-day treatment with artemether-lumefantrine combination and other existing ACTs. This would make ARCO® the next generation ACT for the treatment of uncomplicated falciparum malaria.

  3. Chinese propriety medicines: an "alternative modernity?" The case of the anti-malarial substance artemisinin in East Africa.

    Science.gov (United States)

    Hsu, Elisabeth

    2009-01-01

    This article discusses various modes of "modernizing" traditional Chinese medical drugs (zhongyao [image: see text]) and transforming them into so-called Chinese propriety medicines (zhongchengyao [image: see text]) that are flooding the current neoliberal wellness markets. This article argues that the chemical procedures used in the manufacture of Chinese propriety medicines are highly culture-specific and deserve being considered as instantiations of an "alternative modernity" (e.g., Knauft 2002), rather than of "Westernization." These Western-Chinese combinations, produced in strife toward fulfilling Mao Zedong's Communist-revolutionary vision, have a potential to represent a critical alterity to Western health policies, challenging rhetoric against such combinations. However, as is also noted in this article based on ethnographic fieldwork in East Africa, their potential alterity has been corroded for at least two reasons. First, the medical rationale for dispensing these medications has been shaped by commercial demands in ways that have worked toward transforming the formerly scholarly Chinese medical tradition (as outlined by Bates 1995) into a consumer-near and popular "folk medicine" (as defined by Farquhar 1994:212). Second, the repertoire of Chinese propriety medicines is impoverished as its efficacious "alternatively modern" drugs are being redefined as "modern" biomedical drugs. The article concludes that the potentially critical alterity of any formerly scholarly traditional medicine is more likely to be lost in those fields of health care that are both highly commercialized and polarized by the biomedical imperative to distinguish between "traditional" and "modern" medicines. As example for demonstrating how contentious the issue is, qinghaosu [image: see text] (artemisinin) is put center stage. It is an anti-malarial substance which in the 1970s Chinese scientists extracted from the Chinese medical drug qinghao [image: see text] (Herba Artemisiae

  4. Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy▿†

    Science.gov (United States)

    Capela, Rita; Cabal, Ghislain G.; Rosenthal, Philip J.; Gut, Jiri; Mota, Maria M.; Moreira, Rui; Lopes, Francisca; Prudêncio, Miguel

    2011-01-01

    It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The “magic bullet” thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC50], ∼10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle. PMID:21807973

  5. Design and evaluation of primaquine-artemisinin hybrids as a multistage antimalarial strategy.

    Science.gov (United States)

    Capela, Rita; Cabal, Ghislain G; Rosenthal, Philip J; Gut, Jiri; Mota, Maria M; Moreira, Rui; Lopes, Francisca; Prudêncio, Miguel

    2011-10-01

    It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC(50)], ∼10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.

  6. Anti-malarial effect of semi-synthetic drug amitozyn.

    Science.gov (United States)

    Tcherniuk, Sergey O; Chesnokova, Olga; Oleinikov, Irina V; Potopalsky, Anatoly I; Oleinikov, Andrew V

    2015-10-29

    Malaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year. Chemotherapy continues to be a key approach in malaria prevention and treatment. Due to widespread parasite drug resistance, identification and development of new anti-malarial compounds remains an important task of malarial parasitology. The semi-synthetic drug amitozyn, obtained through alkylation of major celandine (Chelidonium majus) alkaloids with N,N'N'-triethylenethiophosphoramide (ThioTEPA), is a widely used Eastern European folk medicine for the treatment of various tumours. However, its anti-malarial effect has never been studied. The anti-malarial effects of amitozyn alone and in combination with chloroquine, pyrimethamine and artemisinin on the blood stages of P. falciparum were analysed. The cytostatic effects of amitozyn on parasites and various cancerous and non-cancerous human cells were compared and their toxic effects on unparasitized human red blood cells were analysed. Obtained results demonstrate that amitozyn effectively inhibits the growth of blood-stage parasites with IC50 9.6 ± 2, 11.3 ± 2.8 and 10.8 ± 1.8 μg/mL using CS2, 3G8 and NF54 parasite lines, respectively. The median IC50 for 14 tested human cell lines was 33-152 μg/mL. Treatment of uninfected red blood cells with a high dose of amitozyn (500 μg/mL) did not change cell morphology, demonstrating its non-toxicity for erythrocytes. The synergistic impact of the amitozyn/chloroquine combination was observed at growth inhibition levels of 10-80 %, while demonstrating a nearly additive effect at a growth inhibition level of 90 %. The combination of amitozyn with pyrimethamine has a synergistic effect at growth inhibition levels of 10-70 % and a nearly additive effect at a growth inhibition level of 90 %. The synergistic anti-malarial effect of the amitozyn/artemisinin combination was observed at growth inhibition levels of 10-40 % and a nearly

  7. Evidence for pyronaridine as a highly effective partner drug for treatment of artemisinin-resistant malaria in a rodent model.

    Science.gov (United States)

    Henrich, Philipp P; O'Brien, Connor; Sáenz, Fabián E; Cremers, Serge; Kyle, Dennis E; Fidock, David A

    2014-01-01

    The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria.

  8. Perspective for the reproduction of antimalarial drugs in Brazil

    Directory of Open Access Journals (Sweden)

    Benjamin Gilbert

    1992-01-01

    Full Text Available The appears to be no chemical manufacture of antimalarial drugs is Brazil. Technology at laboratory process level has been developed for chloroquine, mefloquine, pyrimethamine and cycloquanil, but not perfected nor scaled-up, largely for economic reasons and market uncertainty. Development of primaquine has been contracted but it will run into the same difficulty. Manufacturing capacity for sulfadoxine was registred in the SDI by Roche. A project to produce artemisinine and its derivates is under way at UNICAMP-CPQBA but is hampered by low content in the plant. Proguanil could be produced easily, but apparently no attempt has been made to do so. Quinine is imported on a large scale mostly for softdrink production. Since malarial treatment falls largely within responsability of the Government health authorities, manufacture of drugs in Brazil will depend on an assured medium-term purchase order made to a potential local manufacturer, since competition in the world market is scarcelyviable at the present moment.

  9. Resistance to antimalarial drugs: An endless world war against Plasmodium that we risk losing.

    Science.gov (United States)

    Severini, Carlo; Menegon, Michela

    2015-06-01

    The objective of this review was to describe the 'state of the art' of Plasmodium falciparum resistance to the main antimalarial drugs. A brief note on Plasmodium vivax is also included. Resistance of P. falciparum to the various antimalarials has a long history of hits and misses. During the last 60 years, the pace at which this parasite has developed resistance to antimalarial drugs has exceeded the pace at which new drugs have been developed. In the last decade, the introduction of artemisinin-based combination therapies (ACTs) as a first-line drug treatment for non-complicated P. falciparum malaria had led to extraordinary results in disease control, especially in sub-Saharan Africa. However, the emergence and spread of resistance to artemisinin in Southeast Asia jeopardise these results. In conclusion, the possible spread of artemisinin resistance in Africa should be considered as an epochal disaster. Copyright © 2015 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  10. Relationship between treatment-seeking behaviour and artemisinin drug quality in Ghana

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    Klein Eili Y

    2012-04-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is currently the recommended first-line treatment for uncomplicated malaria infections. However, a significant proportion of ACT is assumed to be of poor quality, particularly in Africa. In addition, little is known about how treatment-seeking behaviour of individuals or drug price is associated with drug quality. Methods Caregivers of children less than 5 years of age were interviewed on their knowledge of malaria and their choices for treatment. Artemisinin drugs were then purchased from sellers that caregivers preferred or had previously patronized. The active ingredients were quantified by nuclear magnetic resonance spectroscopy. Results A negative relationship was anticipated between the education level of caregivers and the quality of anti-malarial drugs purchased. However, of the 33 drugs collected from 16 different shops, only one contained less than 80% of its purported active ingredient, and most drugs were within 90% of their listed amounts. No link was found between drug quality and price. Nonetheless, while ACT is the recommended first-line treatment in Ghana, 21% of the drugs collected were artemisinin monotherapy, and 27% of the ACT was not co-formulated. Among caregivers, higher education was found to be associated with both an increased likelihood of seeking treatment in a clinic first, as opposed to visiting drug shops or using herbal remedies, and with purchasing drugs from licensed sellers. Conclusion Surprisingly, drug quality was found to be uniformly high and thus no significant relationship between price, treatment-seeking behaviour and the content of the active ingredients was observed. However, artemisinin monotherapy, which the WHO considers inappropriate therapy, was still widely available in Ghana in 2010. Monotherapy was more likely to be available in unlicensed vendors where less-educated caregivers generally shopped. This linkage between education

  11. Microbial transformation of antimalarial terpenoids.

    Science.gov (United States)

    Parshikov, Igor A; Netrusov, Alexander I; Sutherland, John B

    2012-01-01

    The fungal and bacterial transformation of terpenoids derived from plant essential oils, especially the sesquiterpenoid artemisinin from Artemisia annua, has produced several new candidate drugs for the treatment of malaria. Obtaining new derivatives of terpenoids, including artemisinin derivatives with increased antimalarial activity, is an important goal of research in microbial biotechnology and medicinal chemistry.

  12. Antimalarial drugs disrupt ion homeostasis in malarial parasites

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    Marcos L Gazarini

    2007-06-01

    Full Text Available Plasmodium chabaudi malaria parasite organelles are major elements for ion homeostasis and cellular signaling and also target for antimalarial drugs. By using confocal imaging of intraerythrocytic parasites we demonstrated that the dye acridine orange (AO is accumulated into P. chabaudi subcellular compartments. The AO could be released from the parasite organelles by collapsing the pH gradient with the K+/H+ ionophore nigericin (20 µM, or by inhibiting the H+-pump with bafilomycin (4 µM. Similarly, in isolated parasites loaded with calcium indicator Fluo 3-AM, bafilomycin caused calcium mobilization of the acidic calcium pool that could also be release with nigericin. Interestingly after complete release of the acidic compartments, addition of thapsigargin at 10 µM was still effective in releasing parasite intracellular calcium stores in parasites at trophozoite stage. The addition of antimalarial drugs chloroquine and artemisinin resulted in AO release from acidic compartments and also affected maintenance of calcium in ER store by using different drug concentrations.

  13. Counterfeit and substandard antimalarial drugs in Cambodia.

    Science.gov (United States)

    Lon, C T; Tsuyuoka, R; Phanouvong, S; Nivanna, N; Socheat, D; Sokhan, C; Blum, N; Christophel, E M; Smine, A

    2006-11-01

    Counterfeit and substandard antimalarial drugs can cause death and contribute to the growing malaria drug resistance problem, particularly in Southeast Asia. Since 2003 in Cambodia the quality of antimalarial drugs both in the public and private health sector is regularly monitored in sentinel sites. We surveyed 34% of all 498 known facilities and drug outlets in four provinces. We collected 451 drug samples; 79% of these were not registered at the Cambodia Department of Drugs and Food (DDF). Twenty-seven percent of the samples failed the thin layer chromatography and disintegration tests; all of them were unregistered products. Immediate action against counterfeit drugs was taken by the National Malaria Control Program (NMCP) and the DDF. They communicated with the Provincial Health Department about the presence of counterfeit antimalarial drugs through alert letters, a manual, annual malaria conferencing and other training occasions. Television campaigns to alert the population about counterfeit drugs were conducted. Moreover, the NMCP has been promoting the use of good quality antimalarial drugs of a blister co-packaged combination of artesunate and mefloquine in public and private sectors. Appropriate strategies need to be developed and implemented by relevant government agencies and stakeholders to strengthen drug quality assurance and control systems in the country.

  14. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    Directory of Open Access Journals (Sweden)

    Zoraima Neto

    2013-01-01

    Full Text Available Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs. Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group’s 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest.

  15. ARTEMISININ, RELATED SESQUITERPENES, AND ESSENTIAL OIL IN ARTEMISIA-ANNUA DURING A VEGETATION PERIOD IN VIETNAM

    NARCIS (Netherlands)

    WOERDENBAG, HJ; PRAS, N; CHAN, NG; BANG, BT; BOS, R; VANUDEN, W; Y, PV; BOI, NV; BATTERMAN, S; LUGT, CB

    1994-01-01

    The active principle of Artemisia annua L., artemisinin, is currently being developed to a registered antimalarial drug. For production purposes, plants with a high artemisinin content are required. We followed the development of the artemisinin content and of the biosynthetically related sesquiterp

  16. Substandard anti-malarial drugs in Burkina Faso

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    Sie Ali

    2008-05-01

    Full Text Available Abstract Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers and illicit (market and street vendors, shops sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50% chloroquine, 10/77 (13% pyrimethamine-sulphadoxine, 9/77 (12% quinine, 6/77 (8% amodiaquine, 9/77 (12% artesunate, and 4/77 (5% artemether-lumefantrine. 32/77 (42% drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6% and 27/30 (90.0% samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the

  17. Molecular Farming in Artemisia annua, a sustainable approach to improve anti-malarial drug production

    Directory of Open Access Journals (Sweden)

    Giuseppe ePulice

    2016-03-01

    Full Text Available Malaria is a parasite infection affecting millions of people worldwide. Even though progresses in prevention and treatment have been developed, 198 million cases of malaria occurred in 2013, resulting in 584000 estimated deaths. 90% of all malaria deaths occurred in Africa, mostly among children under the age of five. This article aims to review malaria’s history, epidemiology and current treatments, with a particular focus on the potential of molecular farming that use metabolic engineering in plants as effective anti-malarial solution. Malaria indeed represents an example of how a health problem on one hand, may eventually influence the proper development of a country due to the burden of the disease, and on the other hand, constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is here proposed as a sustainable alternative for the production not only of natural herbal repellents used for malaria prevention but also for the production of sustainable anti-malarial drugs like artemisinin used for primary parasite infection treatments.Artemisinin, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua plant. However, the low concentration of artemisinin in plant makes this molecule relatively expensive and difficult to meet the worldwide demand of Artemisinin Combination Therapies, especially for economically disadvantaged people in developing countries. The biosynthetic pathway of artemisinin, a process that only takes place in glandular secretory trichomes of A. annua, is relatively well elucidated, and significant efforts using plant genetic engineering have been made to increase the production of this compound. These include studies on diverse transcription factors, which all have been shown to regulate artemisinin genetic pathway and other biological processes. Therefore, genetic manipulation of these genes may be used as a cost-effective potential

  18. Chemogenomic profiling of Plasmodium falciparum as a tool to aid antimalarial drug discovery.

    Science.gov (United States)

    Pradhan, Anupam; Siwo, Geoffrey H; Singh, Naresh; Martens, Brian; Balu, Bharath; Button-Simons, Katrina A; Tan, Asako; Zhang, Min; Udenze, Kenneth O; Jiang, Rays H Y; Ferdig, Michael T; Adams, John H; Kyle, Dennis E

    2015-01-01

    The spread of Plasmodium falciparum multidrug resistance highlights the urgency to discover new targets and chemical scaffolds. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle. Chemogenomic profiling is an established tool for classification of drugs with similar mechanisms of action by comparing drug fitness profiles in a collection of mutants. Inferences of drug mechanisms of action and targets can be obtained by associations between shifts in drug fitness and specific genetic changes in the mutants. In this screen, P. falciparum, piggyBac single insertion mutants were profiled for altered responses to antimalarial drugs and metabolic inhibitors to create chemogenomic profiles. Drugs targeting the same pathway shared similar response profiles and multiple pairwise correlations of the chemogenomic profiles revealed novel insights into drugs' mechanisms of action. A mutant of the artemisinin resistance candidate gene - "K13-propeller" gene (PF3D7_1343700) exhibited increased susceptibility to artemisinin drugs and identified a cluster of 7 mutants based on similar enhanced responses to the drugs tested. Our approach of chemogenomic profiling reveals artemisinin functional activity, linked by the unexpected drug-gene relationships of these mutants, to signal transduction and cell cycle regulation pathways.

  19. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  20. Counterfeit and Substandard Antimalarial Drugs

    Science.gov (United States)

    ... Where Do You Find Them? Worldwide prevalence of counterfeit and substandard products is summarized in a Drug Quality Report matrix by the U.S. Pharmacopeia Drug Quality and Information (USP DQI) Program . ... (U.S.) issues regarding counterfeit and poor-quality drugs is provided by the ...

  1. Rational Design of Proteasome Inhibitors as Antimalarial Drugs.

    Science.gov (United States)

    Le Chapelain, Camille; Groll, Michael

    2016-05-23

    One life, two strategies: Crucial structural differences between the human and the Plasmodium falciparum proteasomes were recently identified. A combination of cryo-EM and functional characterization enabled the design of a selective antimalarial proteasome inhibitor that shows low toxicity in the host. When used with artemisinin, this ligand offers a new approach for the efficient treatment of malaria at all stages of the parasite lifecycle.

  2. Perspective for the production of antimalarial drugs in Brazil.

    Science.gov (United States)

    Gilbert, B

    1992-01-01

    There appears to be no chemical manufacture of antimalarial drugs in Brazil. Technology at the laboratory process level has been developed for chloroquine, mefloquine, pyrimethamine and cycloguanil, but not perfected nor scaled-up, largely for economic reasons and market uncertainty. Development of primaquine has been contracted but it will run into the same difficulty. Manufacturing capacity for sulfadoxine was registered in the SDI by Roche. A project to produce artemisinine and its derivatives is under way at UNICAMP-CPQBA but is hampered by low content in the plant. Proguanil could be produced easily, but apparently no attempt has been made to do so. Quinine is imported on a large scale mostly for soft-drink production. Since malarial treatment falls largely within the responsibility of the Government health authorities, manufacture of drugs in Brazil will depend on an assured medium-term purchase order made to a potential local manufacturer, since competition in the world market is scarcely viable at the present moment.

  3. Neuropsychiatric effects of antimalarial drugs

    NARCIS (Netherlands)

    M.M. van Riemsdijk

    2001-01-01

    textabstractMalaria is a serious, potentially life threatening disease, and generally endemic in the (sub) tropics. Prevention may be carried out by interrupting transmission, by vector control and by giving travellers prophylactic drugs. The use of prophylactic drugs has generally been effective fo

  4. Rational Design of Antimalarial Drugs Using Molecular Modeling and Statistical Analysis.

    Science.gov (United States)

    Santos, Cleydson Breno Rodrigues dos; Lobato, Cleison Carvalho; Braga, Francinaldo Sarges; Costa, Josivan da Silva; Favacho, Hugo Alexandre Silva; Carvalho, Jose Carlos Tavares; Macedo, Williams Jorge da Cruz; Brasil, Davi Do Socorro Barros; Silva, Carlos Henrique Tomich de Paula da; Silva Hage-Melim, Lorane Izabel da

    2015-01-01

    Artemisinin is an antimalarial compound isolated from Artemisia annua L. that is effective against Plasmodium falciparum. This paper proposes the development of new antimalarial derivatives of artemisinin from a SAR study and statistical analysis by multiple linear regression (MLR). The HF/6-31G** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. MEP maps and molecular docking were used to study the interface between ligand and receptor (heme). The Pearson correlation was used to choose the most important properties interrelated to the antimalarial activity: Hydration Energy (HE), Energy of the Complex (Ecplex), bond length (FeO1), and maximum index of R/Electronegativity of Sanderson (RTe+). After the Pearson correlation, 72 MLR models were built between antimalarial activity and molecular properties; the statistical quality of the models was evaluated by means of correlation coefficient (r), squared correlation coefficient (r(2)), explained variance (adjusted R(2)), standard error of estimate (SEE), and variance ratio (F), and only four models showed predictive ability. The selected models were used to predict the antimalarial activity of ten new artemisinin derivatives (test set) with unknown activity, and only eight of these compounds were predicted to be more potent than artemisinin, and were therefore subjected to theoretical studies of pharmacokinetic and toxicological properties. The test set showed satisfactory results for six new artemisinin compounds which is a promising factor for future synthesis and biological assays.

  5. Biological Actions of Artemisinin: Insights from Medicinal Chemistry Studies

    Directory of Open Access Journals (Sweden)

    Jian Li

    2010-03-01

    Full Text Available Artemisinins have become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although tremendous efforts have been devoted to decipher how this class of molecules works, their exact antimalarial mechanism is still an enigma. Several hypotheses have been proposed to explain their actions, including alkylation of heme by carbon-centered free radicals, interference with proteins such as the sarcoplasmic/endoplasmic calcium ATPase (SERCA, as well as damaging of normal mitochondrial functions. Besides artemisinins, other endoperoxides with various backbones have also been synthesized, some of which showed comparable or even higher antimalarial effects. It is noteworthy that among these artemisinin derivatives, some enantiomers displayed similar in vitro malaria killing efficacy. In this article, the proposed mechanisms of action of artemisinins are reviewed in light of medicinal chemistry findings characterized by efficacy-structure studies, with the hope of gaining more insight into how these potent drugs work.

  6. Increasing Access to Subsidized Artemisinin-based Combination Therapy through Accredited Drug Dispensing Outlets in Tanzania

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    Gabra Michael

    2011-06-01

    Full Text Available Abstract Background In Tanzania, many people seek malaria treatment from retail drug sellers. The National Malaria Control Program identified the accredited drug dispensing outlet (ADDO program as a private sector mechanism to supplement the distribution of subsidized artemisinin-based combination therapies (ACTs from public facilities and increase access to the first-line antimalarial in rural and underserved areas. The ADDO program strengthens private sector pharmaceutical services by improving regulatory and supervisory support, dispenser training, and record keeping practices. Methods The government's pilot program made subsidized ACTs available through ADDOs in 10 districts in the Morogoro and Ruvuma regions, covering about 2.9 million people. The program established a supply of subsidized ACTs, created a price system with a cost recovery plan, developed a plan to distribute the subsidized products to the ADDOs, trained dispensers, and strengthened the adverse drug reactions reporting system. As part of the evaluation, 448 ADDO dispensers brought their records to central locations for analysis, representing nearly 70% of ADDOs operating in the two regions. ADDO drug register data were available from July 2007-June 2008 for Morogoro and from July 2007-September 2008 for Ruvuma. This intervention was implemented from 2007-2008. Results During the pilot, over 300,000 people received treatment for malaria at the 448 ADDOs. The percentage of ADDOs that dispensed at least one course of ACT rose from 26.2% during July-September 2007 to 72.6% during April-June 2008. The number of malaria patients treated with ACTs gradually increased after the start of the pilot, while the use of non-ACT antimalarials declined; ACTs went from 3% of all antimalarials sold in July 2007 to 26% in June 2008. District-specific data showed substantial variation among the districts in ACT uptake through ADDOs, ranging from ACTs representing 10% of all antimalarial sales

  7. Radical chemistry of artemisinin

    Energy Technology Data Exchange (ETDEWEB)

    Denisov, Evgenii T; Solodova, S L; Denisova, Taisa G [Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow Region (Russian Federation)

    2010-12-29

    The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

  8. Radical chemistry of artemisinin

    Science.gov (United States)

    Denisov, Evgenii T.; Solodova, S. L.; Denisova, Taisa G.

    2010-12-01

    The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

  9. Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy

    DEFF Research Database (Denmark)

    Abdulla, Salim; Achan, Jane; Adam, Ishag

    2016-01-01

    Background: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are importa...

  10. A better resolution for integrating methods for monitoring Plasmodium falciparum resistance to antimalarial drugs.

    Science.gov (United States)

    Abdul-Ghani, Rashad; Al-Maktari, Mohamed T; Al-Shibani, Latifa A; Allam, Amal F

    2014-09-01

    Effective chemotherapy is the mainstay of malaria control. However, resistance of falciparum malaria to antimalarial drugs compromised the efforts to eliminate the disease and led to the resurgence of malaria epidemics. Three main approaches are used to monitor antimalarial drug efficacy and drug resistance; namely, in vivo trials, in vitro/ex vivo assays and molecular markers of drug resistance. Each approach has its implications of use as well as its advantages and drawbacks. Therefore, there is a need to use an integrated approach that would give the utmost effect to detect resistance as early as its emergence and to track it once spread. Such integration becomes increasingly needed in the era of artemisinin-based combination therapy as a forward action to deter resistance. The existence of regional and global networks for the standardization of methodology, provision of high quality reagents for the assessment of antimalarial drug resistance and dissemination of open-access data would help in approaching an integrated resistance surveillance system on a global scale.

  11. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  12. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

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    Lee Sue J

    2009-11-01

    Full Text Available Abstract Background Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. Methods The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. Results Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. Conclusion Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women. Patients with

  13. Hemozoin Formation as a Target for Antimalarial Drug Design

    Science.gov (United States)

    2005-02-01

    AD Award Number: DAMD17-03-1-0030 TITLE: Hemozoin Formation as a Target for Antimalarial Drug Design PRINCIPAL INVESTIGATOR: Michael K. Riscoe, Ph.D...Formation as a Target for Antimalarial Drug Design DAMD17-03-1-0030 6. A UTHOR(S) Michael K. Riscoe, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S) AND ADDRESS...Report: by Principal Investigator - Michael K. Riscoe, Ph.D. DAMD1 7-03-1-0030: "Hemozoin Formation as a Target for Antimalarial Drug Design " INTRODUCTION

  14. Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure.

    Science.gov (United States)

    Ménard, Sandie; Ben Haddou, Tanila; Ramadani, Arba Pramundita; Ariey, Frédéric; Iriart, Xavier; Beghain, Johann; Bouchier, Christiane; Witkowski, Benoit; Berry, Antoine; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise

    2015-10-01

    Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.

  15. World Antimalarial Resistance Network (WARN II: In vitro antimalarial drug susceptibility

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    Ringwald Pascal

    2007-09-01

    Full Text Available Abstract Intrinsic resistance of Plasmodium falciparum is clearly a major determinant of the clinical failure of antimalarial drugs. However, complex interactions between the host, the parasite and the drug obscure the ability to define parasite drug resistance in vivo. The in vitro antimalarial drug susceptibility assay determines ex-vivo growth of parasite in the presence of serial drug concentrations and, thus, eliminates host effects, such as drug metabolism and immunity. Although the sensitivity of the parasite to various antimalarials provided by such a test provides an important indicator of intrinsic parasite susceptibility, there are fundamental methodological issues that undermine comparison of in vitro susceptibility both between laboratories and within a single laboratory over time. A network of laboratories is proposed that will agree on the basic parameters of the in vitro test and associated measures of quality control. The aim of the network would be to establish baseline values of sensitivity to commonly used antimalarial agents from key regions of the world, and create a global database, linked to clinical, molecular and pharmacology databases, to support active surveillance to monitor temporal trends in parasite susceptibility. Such a network would facilitate the rapid detection of strains with novel antimalarial resistance profiles and investigate suitable alternative treatments with retained efficacy.

  16. CYTOTOXICITY OF ARTEMISININ-RELATED ENDOPEROXIDES TO EHRLICH ASCITES TUMOR-CELLS

    NARCIS (Netherlands)

    WOERDENBAG, HJ; MOSKAL, TA; PRAS, N; MALINGRE, TM; ELFERALY, FS; KAMPINGA, HH; KONINGS, AWT

    1993-01-01

    A series of artemisinin-related endoperoxides was tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolium (MTT) assay. Artemisinin [1] had an IC50 value of 29.8 muM. Derivatives of dihydroartemisinin [2], being developed as antimalarial drugs (artemether [3],

  17. Severe malaria not responsive to artemisinin derivatives in man returning from Angola to Vietnam.

    Science.gov (United States)

    Van Hong, Nguyen; Amambua-Ngwa, Alfred; Tuan, Nguyen Quang; Cuong, Do Duy; Giang, Nguyen Thi Huong; Van Dung, Nguyen; Tinh, Ta Thi; Van Tien, Nguyen; Phuc, Bui Quang; Duong, Tran Thanh; Rosanas-Urgell, Anna; D'Alessandro, Umberto; Van Geertruyden, Jean-Pierre; Erhart, Annette

    2014-07-01

    Resistance to artemisinin derivatives, the most potent antimalarial drugs currently used, has emerged in Southeast Asia and threatens to spread to Africa. We report a case of malaria in a man who returned to Vietnam after 3 years in Angola that did not respond to intravenous artesunate and clindamycin or an oral artemisinin-based combination.

  18. How do antimalarial drugs reach their intracellular targets?

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    Katherine eBasore

    2015-05-01

    Full Text Available Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention.

  19. Drug Discovery and Development of Antimalarial Agents: Recent Advances.

    Science.gov (United States)

    Thota, Sreekanth; Yerra, Rajeshwar

    2016-01-01

    Malaria, a deadly infectious parasitic disease, is a major issue of public health in the world today and already produces serious economic constraints in the endemic countries. Most of the malarial infections and deaths are due to Plasmodium falciparum and Plasmodium vivax species. The recent emergence of resistance necessitates the search for new antimalarial drugs, which overcome the resistance and act through new mechanisms. Although much effort has been directed towards the discovery of novel antimalarial drugs. 4-anilino quinolone triazines as potent antimalarial agents, their in silico modelling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors has been reported. This review is primarily focused on the drug discovery of the recent advances in the development of antimalarial agents and their mechanism of action.

  20. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

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    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  1. Spread of anti-malarial drug resistance: mathematical model with implications for ACT drug policies.

    Science.gov (United States)

    Pongtavornpinyo, Wirichada; Yeung, Shunmay; Hastings, Ian M; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J

    2008-11-02

    Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria

  2. PENGOBATAN MALARIA DENGAN KOMBINASI ARTEMISININ

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    Emilianan Tjitra

    2012-09-01

    Full Text Available Previous approaches in malaria treatment fail to reduce the morbidity and mortality of malaria. Widespread overuse of antimalarial treatment of clinical malaria may have contributed to increase drug resistance. Moreover, poor compliance or inadequate dosage also selects for parasite resistance. The paradigm of radical treatment using drug combinations may improve the cure rate and compliance, thereby preventing or delaying the emergence of parasites resistant to antimalarial drugs. The ideal combined antimalarial regimen in Indonesia should be safe and tolerated by all age groups, effective and rapidly acting for both P.falciparum and P.vivax malaria, short course, good compliance and acceptable, without resistance and/or cross-resistance or , not widely spread use, cost-effective and affordable. Artemisinin derivatives are the best partner drug for combination, with advantages that include: well absorbed, safe and well tolerated, rapidly converted to active metabolite, having very short half-life, broad specificity of action, and extremely potent. Current artemisinin-based combinations which are suitable for Indonesia include: amodiaquine plus artesunate given as single daily dose for 3 days (AQ3+ATS3, mefloquine plus artesunate given as single daily dose for 3 days (MQ3+ATS3, lumefantrine/benflumetol plus artemether given as twice daily dose for 3 days (COARTEMETHER, piperaquine plus dihydroartemisinin given as single daily dose for 2-3 days (PPQ2-3+DHA2-3, and piperaquine plus artemisinin given as single daily dose for 2 days (PPQ2+ATM2. Given the imbalance between rapid development of parasite resistance and slow availability of new effective antimalarial drugs, research and development of antimalarial drugs must be encouraged.

  3. PENGOBATAN MALARIA DENGAN KOMBINASI ARTEMISININ

    Directory of Open Access Journals (Sweden)

    Emilianan Tjitra

    2012-09-01

    Full Text Available Previous approaches in malaria treatment fail to reduce the morbidity and mortality of malaria. Widespread overuse of antimalarial treatment of clinical malaria may have contributed to increase drug resistance. Moreover, poor compliance or inadequate dosage also selects for parasite resistance. The paradigm of radical treatment using drug combinations may improve the cure rate and compliance, thereby preventing or delaying the emergence of parasites resistant to antimalarial drugs. The ideal combined antimalarial regimen in Indonesia should be safe and tolerated by all age groups, effective and rapidly acting for both P.falciparum and P.vivax malaria, short course, good compliance and acceptable, without resistance and/or cross-resistance or , not widely spread use, cost-effective and affordable. Artemisinin derivatives are the best partner drug for combination, with advantages that include: well absorbed, safe and well tolerated, rapidly converted to active metabolite, having very short half-life, broad specificity of action, and extremely potent. Current artemisinin-based combinations which are suitable for Indonesia include: amodiaquine plus artesunate given as single daily dose for 3 days (AQ3+ATS3, mefloquine plus artesunate given as single daily dose for 3 days (MQ3+ATS3, lumefantrine/benflumetol plus artemether given as twice daily dose for 3 days (COARTEMETHER, piperaquine plus dihydroartemisinin given as single daily dose for 2-3 days (PPQ2-3+DHA2-3, and piperaquine plus artemisinin given as single daily dose for 2 days (PPQ2+ATM2. Given the imbalance between rapid development of parasite resistance and slow availability of new effective antimalarial drugs, research and development of antimalarial drugs must be encouraged.

  4. Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.

    Science.gov (United States)

    Piedade, Rita; Traub, Stefanie; Bitter, Andreas; Nüssler, Andreas K; Gil, José P; Schwab, Matthias; Burk, Oliver

    2015-01-01

    Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies.

  5. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

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    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  6. Post-marketing assessment of content and efficacy of preservatives in artemisinin-derived antimalarial dry suspensions for paediatric use

    Directory of Open Access Journals (Sweden)

    Plaizier-Vercammen Jacqueline

    2007-01-01

    Full Text Available Abstract Background Artemisinin-derivative formulations are now widely used to treat falciparum malaria. However, the dry powder suspensions developed for children are few and/or are of poor quality. In addition to the active compound, the presence of a suitable preservative in these medicines is essential. In this study, an evaluation of the preservative content and efficacy in some dry suspensions available on the Kenyan market was performed. Method UV spectrophotometry was used to identify the preservatives in each sample while HPLC-UV was used for quantification. After reconstitution of the powders in water, the dissolution of the preservatives was followed for 7 days. Antimicrobial efficacy of the preservatives was assessed by conducting a preservative efficacy test (PET following the European pharmacopoeia standards. Results Four different preservatives were identified namely methylparahydroxybenzoate (MP, propylparahydroxybenzoate (PP, benzoic acid and sorbic acid. MP and PP were identified in Artesiane® (artemether 300 mg/100 ml, Alaxin® (dihydroartemisinin 160 mg/80 ml andGvither ® (artemether 300 mg/100 ml respectively. Sorbic acid was presentin Artenam® (artemether 180 mg/60 ml while benzoic acid was identified in Santecxin® (dihydroartemisinin 160 mg/80 ml andArtexin® (dihydroartemisinin 160 mg/80 ml respectively. Cotecxin® (dihydroartemisinin 160 mg/80 ml did not contain any of the above preservatives. After reconstitution in water, preservativesin 50%(3/6 of the products did not completely dissolve and the PET results revealed that only Artenam® and Gvither® met the requirements for antimicrobial efficacy. The other products did not conform. Conclusion These results show that paediatric antimalarial dry powder formulations on the market may contain ineffective or incorrect amounts of preservatives. This is a potential risk to the patient. Studies conducted on the dry powder suspensions should include the analysis of both

  7. Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers

    NARCIS (Netherlands)

    Ginsburg, H.; Demel, R.A.

    1984-01-01

    Hemin, antimalarial drugs and complexes formed between them, have demonstrable effects on biological membranes. Using the phospholipid monolayer model, we show that hemin intercalates into the membrane and increases its surface pressure, depending on the lipid composition and the initial surface pre

  8. Artemisinin resistance or tolerance in human malaria patients

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai; Waranya Imprasittichai; Sumintra Otjungreed; Sawirasagee Pongsabut; Sudaratana R Krungkrai

    2010-01-01

    Malaria is a major cause of morbidity and mortality in the developing world. This situation is mainly due to emergence of resistance to most antimalarial drugs currently available. Artemisinin-based combination treatments are now first-line drugs forPlasmodium falciparum (P. falciparum) malaria. Artemisinin (qinghaosu) and its derivatives are the most rapid acting and efficacious antimalarial drugs. This review highlights most recent investigations into the emergence of artemisinin resistance in falciparum malaria patients on the Thai-Cambodian border, a historical epicenter for multidrug resistance spread spanning over50 years. The study presents the first evidence that highlights the parasites reduced susceptibility to artemisinin treatment by prolonged parasite-clearance times, raising considerable concern on resistance development. Although the exact mechanism of action remains unresolved, development of resistance was proposed based from bothin vitro experiments and human patients. Lines of evidence suggested that the parasites in the patients are in dormant forms, presumably tolerate to the drug pressure. The World Health Organization has launched for prevention and/or containment of the artemisinin-resistant malaria parasites. Taken together, the emergence of artemisinin resistance to the most potent antidote for falciparum malaria, poses a serious threat to global malaria control and prompts renewed efforts for urgent development of new antimalarial weapons.

  9. Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children

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    Zongo Issaka

    2008-08-01

    Full Text Available Abstract Background Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs will result in different estimates being reported, with implications for changes in treatment policy. Methods Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a reinfections excluded from the analysis (standard WHO per-protocol analysis or (1b reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a WHO (2001 definitions of failure, or (2b failure defined using parasitological criteria only. Results Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702, artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706 and artemether-lumefantrine (AL, N = 518. Using method (1a, the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference and the others were: (i method 1b = 1.3% [0 to24.8], (ii method 2a = 1.1% [0 to21.5], and (iii method 2b = 0% [-38 to19.3]. The standard per-protocol method (1a tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a. It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size

  10. The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya

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    Otieno Dorothy N

    2007-05-01

    Full Text Available Abstract Backgound Sulphadoxine/sulphalene-pyrimethamine (SP was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT in Africa are less well documented. Methods A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy. Results Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data

  11. Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.

    Science.gov (United States)

    Boss, Christoph; Aissaoui, Hamed; Amaral, Nathalie; Bauer, Aude; Bazire, Stephanie; Binkert, Christoph; Brun, Reto; Bürki, Cédric; Ciana, Claire-Lise; Corminboeuf, Olivier; Delahaye, Stephane; Dollinger, Claire; Fischli, Christoph; Fischli, Walter; Flock, Alexandre; Frantz, Marie-Céline; Girault, Malory; Grisostomi, Corinna; Friedli, Astrid; Heidmann, Bibia; Hinder, Claire; Jacob, Gael; Le Bihan, Amelie; Malrieu, Sophie; Mamzed, Saskia; Merot, Aurelien; Meyer, Solange; Peixoto, Sabrina; Petit, Nolwenn; Siegrist, Romain; Trollux, Julien; Weller, Thomas; Wittlin, Sergio

    2016-09-20

    More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.

  12. Pattern of drug utilization for treatment of uncomplicated malaria in urban Ghana following national treatment policy change to artemisinin-combination therapy

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    Tenkorang Ofori

    2009-01-01

    Full Text Available Abstract Background Change of first-line treatment of uncomplicated malaria to artemisinin-combination therapy (ACT is widespread in Africa. To expand knowledge of safety profiles of ACT, pharmacovigilance activities are included in the implementation process of therapy changes. Ghana implemented first-line therapy of artesunate-amodiaquine in 2005. Drug utilization data is an important component of determining drug safety, and this paper describes how anti-malarials were prescribed within a prospective pharmacovigilance study in Ghana following anti-malarial treatment policy change. Methods Patients with diagnosis of uncomplicated malaria were recruited from pharmacies of health facilities throughout Accra in a cohort-event monitoring study. The main drug utilization outcomes were the relation of patient age, gender, type of facility attended, mode of diagnosis and concomitant treatments to the anti-malarial regimen prescribed. Logistic regression was used to predict prescription of nationally recommended first-line therapy and concomitant prescription of antibiotics. Results The cohort comprised 2,831 patients. Curative regimens containing an artemisinin derivative were given to 90.8% (n = 2,574 of patients, although 33% (n = 936 of patients received an artemisinin-based monotherapy. Predictors of first-line therapy were laboratory-confirmed diagnosis, age >5 years, and attending a government facility. Analgesics and antibiotics were the most commonly prescribed concomitant medications, with a median of two co-prescriptions per patient (range 1–9. Patients above 12 years were significantly less likely to have antibiotics co-prescribed than patients under five years; those prescribed non-artemisinin monotherapies were more likely to receive antibiotics. A dihydroartemisinin-amodiaquine combination was the most used therapy for children under five years of age (29.0%, n = 177. Conclusion This study shows that though first-line therapy

  13. Pattern of drug utilization for treatment of uncomplicated malaria in urban Ghana following national treatment policy change to artemisinin-combination therapy.

    Science.gov (United States)

    Dodoo, Alexander N O; Fogg, Carole; Asiimwe, Alex; Nartey, Edmund T; Kodua, Augustina; Tenkorang, Ofori; Ofori-Adjei, David

    2009-01-05

    Change of first-line treatment of uncomplicated malaria to artemisinin-combination therapy (ACT) is widespread in Africa. To expand knowledge of safety profiles of ACT, pharmacovigilance activities are included in the implementation process of therapy changes. Ghana implemented first-line therapy of artesunate-amodiaquine in 2005. Drug utilization data is an important component of determining drug safety, and this paper describes how anti-malarials were prescribed within a prospective pharmacovigilance study in Ghana following anti-malarial treatment policy change. Patients with diagnosis of uncomplicated malaria were recruited from pharmacies of health facilities throughout Accra in a cohort-event monitoring study. The main drug utilization outcomes were the relation of patient age, gender, type of facility attended, mode of diagnosis and concomitant treatments to the anti-malarial regimen prescribed. Logistic regression was used to predict prescription of nationally recommended first-line therapy and concomitant prescription of antibiotics. The cohort comprised 2,831 patients. Curative regimens containing an artemisinin derivative were given to 90.8% (n = 2,574) of patients, although 33% (n = 936) of patients received an artemisinin-based monotherapy. Predictors of first-line therapy were laboratory-confirmed diagnosis, age >5 years, and attending a government facility. Analgesics and antibiotics were the most commonly prescribed concomitant medications, with a median of two co-prescriptions per patient (range 1-9). Patients above 12 years were significantly less likely to have antibiotics co-prescribed than patients under five years; those prescribed non-artemisinin monotherapies were more likely to receive antibiotics. A dihydroartemisinin-amodiaquine combination was the most used therapy for children under five years of age (29.0%, n = 177). This study shows that though first-line therapy recommendations may change, clinical practice may still be affected by

  14. High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery

    Directory of Open Access Journals (Sweden)

    Cervantes Serena

    2009-06-01

    Full Text Available Abstract Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency.

  15. Analytical sample preparation strategies for the determination of antimalarial drugs in human whole blood, plasma and urine

    DEFF Research Database (Denmark)

    Casas, Mònica Escolà; Hansen, Martin; Krogh, Kristine A

    2014-01-01

    Abstract Antimalarial drugs commonly referred to as antimalarials , include a variety of compounds with different physicochemical properties. There is a lack of information on antimalarial distribution in the body over time after administration, eg the drug ...

  16. Artemisinin-Resistant Plasmodium falciparum Malaria.

    Science.gov (United States)

    Fairhurst, Rick M; Dondorp, Arjen M

    2016-06-01

    For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.

  17. The antimalarial drug quinine interferes with serotonin biosynthesis and action

    DEFF Research Database (Denmark)

    Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmit...

  18. Medical need, scientific opportunity and the drive for antimalarial drugs.

    Science.gov (United States)

    Ridley, Robert G

    2002-02-07

    Continued and sustainable improvements in antimalarial medicines through focused research and development are essential for the world's future ability to treat and control malaria. Unfortunately, malaria is a disease of poverty, and despite a wealth of scientific knowledge there is insufficient market incentive to generate the competitive, business-driven industrial antimalarial drug research and development that is normally needed to deliver new products. Mechanisms of partnering with industry have been established to overcome this obstacle and to open up and build on scientific opportunities for improved chemotherapy in the future.

  19. Artemisinin, a miracle of traditional Chinese medicine.

    Science.gov (United States)

    Kong, Ling Yi; Tan, Ren Xiang

    2015-12-19

    The 2015 Nobel Prize in Physiology or Medicine, shared by Professor Youyou Tu, focused worldwide attention on artemisinin, a natural product antimalarial drug inspired by traditional Chinese medicine (TCM). This is the first Nobel Prize in natural sciences presented to a Chinese scientist for her impactful research work in China in collaboration with other Chinese scientists. We are delighted to provide the background and implications of the discovery of artemisinin, along with our personal viewpoints toward the affordability of modern medicines from natural products.

  20. High-level production of amorpha-4,11-diene, a precursor of the antimalarial agent artemisinin, in Escherichia coli.

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    Hiroko Tsuruta

    Full Text Available BACKGROUND: Artemisinin derivatives are the key active ingredients in Artemisinin combination therapies (ACTs, the most effective therapies available for treatment of malaria. Because the raw material is extracted from plants with long growing seasons, artemisinin is often in short supply, and fermentation would be an attractive alternative production method to supplement the plant source. Previous work showed that high levels of amorpha-4,11-diene, an artemisinin precursor, can be made in Escherichia coli using a heterologous mevalonate pathway derived from yeast (Saccharomyces cerevisiae, though the reconstructed mevalonate pathway was limited at a particular enzymatic step. METHODOLOGY/ PRINCIPAL FINDINGS: By combining improvements in the heterologous mevalonate pathway with a superior fermentation process, commercially relevant titers were achieved in fed-batch fermentations. Yeast genes for HMG-CoA synthase and HMG-CoA reductase (the second and third enzymes in the pathway were replaced with equivalent genes from Staphylococcus aureus, more than doubling production. Amorpha-4,11-diene titers were further increased by optimizing nitrogen delivery in the fermentation process. Successful cultivation of the improved strain under carbon and nitrogen restriction consistently yielded 90 g/L dry cell weight and an average titer of 27.4 g/L amorpha-4,11-diene. CONCLUSIONS/ SIGNIFICANCE: Production of >25 g/L amorpha-4,11-diene by fermentation followed by chemical conversion to artemisinin may allow for development of a process to provide an alternative source of artemisinin to be incorporated into ACTs.

  1. Chemical proteomics approach reveals the direct targets and the heme-dependent activation mechanism of artemisinin in Plasmodium falciparum using an activity-based artemisinin probe

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    Jigang Wang

    2016-04-01

    Full Text Available Artemisinin and its analogues are currently the most effective anti-malarial drugs. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources. Once activated, artemisinins attack macromolecules through alkylation and propagate a series of damages, leading to parasite death. Even though several parasite proteins have been reported as artemisinin targets, the exact mechanism of action (MOA of artemisinin is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted for. Recently, we have developed an unbiased chemical proteomics approach to directly probe the MOA of artemisinin in P. falciparum. We synthesized an activity-based artemisinin probe with an alkyne tag, which can be coupled with biotin through click chemistry. This enabled selective purification and identification of 124 protein targets of artemisinin. Many of these targets are critical for the parasite survival. In vitro assays confirmed the specific artemisinin binding and inhibition of selected targets. We thus postulated that artemisinin kills the parasite through disrupting its biochemical landscape. In addition, we showed that artemisinin activation requires heme, rather than free ferrous iron, by monitoring the extent of protein binding using a fluorescent dye coupled with the alkyne-tagged artemisinin. The extremely high level of heme released from the hemoglobin digestion by the parasite makes artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages compared to parasites at early ring stage, which have low level of heme, possibly derived from endogenous synthesis. Such a unique activation mechanism also confers artemisinin with extremely high specificity against the parasites, while the healthy red blood cells are unaffected. Our results provide a sound explanation of the MOA of artemisinin and its specificity against malaria

  2. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance.

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    Richard J Maude

    Full Text Available BACKGROUND: Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria. METHOD AND FINDINGS: A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity. CONCLUSIONS: The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite

  3. A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

    Science.gov (United States)

    Ismail, Hanafy M.; Barton, Victoria E.; Panchana, Matthew; Charoensutthivarakul, Sitthivut; Biagini, Giancarlo A.; Ward, Stephen A.

    2016-01-01

    Abstract In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross‐resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4‐trioxolane activity based protein‐profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi‐quantitatively, suggesting a common mechanism of action that raises concerns about potential cross‐resistance liabilities. PMID:27397940

  4. Effects of arbuscular mycorrhiza and phosphorus application on artemisinin concentration in Artemisia annua L.

    Science.gov (United States)

    Kapoor, Rupam; Chaudhary, Vidhi; Bhatnagar, A K

    2007-10-01

    Annual wormwood (Artemisia annua L.) produces an array of complex terpenoids including artemisinin, a compound of current interest in the treatment of drug-resistant malaria. However, this promising antimalarial compound remains expensive and is hardly available on the global scale. Synthesis of artemisinin has not been proved to be feasible commercially. Therefore, increase in yield of naturally occurring artemisinin is an important area of investigation. The effects of inoculation by two arbuscular mycorrhizal (AM) fungi, Glomus macrocarpum and Glomus fasciculatum, either alone or supplemented with P-fertilizer, on artemisinin concentration in A. annua were studied. The concentration of artemisinin was determined by reverse-phase high-performance liquid chromatography with UV detection. The two fungi significantly increased concentration of artemisinin in the herb. Although there was significant increase in concentration of artemisinin in nonmycorrhizal P-fertilized plants as compared to control, the extent of the increase was less compared to mycorrhizal plants grown with or without P-fertilization. This suggests that the increase in artemisinin concentration may not be entirely attributed to enhanced P-nutrition and improved growth. A strong positive linear correlation was observed between glandular trichome density on leaves and artemisinin concentration. Mycorrhizal plants possessed higher foliar glandular trichome (site for artemisinin biosynthesis and sequestration) density compared to nonmycorrhizal plants. Glandular trichome density was not influenced by P-fertilizer application. The study suggests a potential role of AM fungi in improving the concentration of artemisinin in A. annua.

  5. Antimicrobial peptides: a new class of antimalarial drugs?

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    Nuno eVale

    2014-12-01

    Full Text Available A range of antimicrobial peptides (AMP exhibit activity on malaria parasites, Plasmodium spp, in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.

  6. Antimalarial drugs for rheumatoid disease during pregnancy.

    OpenAIRE

    Koren, G.

    1999-01-01

    QUESTION: One of my patients, who has rheumatoid arthritis, has just found out she is pregnant. She is being treated with hydroxychloroquine. I could not find anything about the safety of this drug during pregnancy. ANSWER: Most of the literature on this drug relates to prophylaxis for malaria. Much lower doses than those used for rheumatic diseases are given with no adverse fetal effects. Several studies on use of the drug for rheumatic diseases during pregnancy also failed to show adverse f...

  7. Synthesis of triazol derivatives of lupeol with potential antimalarial activity

    OpenAIRE

    Tatiane Freitas Borgati; Guilherme Rocha Pereira; Geraldo Célio Brandão; Alaíde Braga Oliveira; José Dias Souza Filho

    2012-01-01

    The goal of this project is synthesize and characterization of derivatives of lupeol and evaluated antimalarial activity. Historically, plants are important source of antimalarial medicines, highlighting quinine (1) (Figure 1), an important      alkaloid from the Cinchona calisaya bark. This compound was an important model for cloroquine  synthesis, a drug that was widely used in malaria treatment. In addition, one of the principal medicines used today is artemisinine, isolated from the Chine...

  8. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.

    Science.gov (United States)

    Straimer, Judith; Gnädig, Nina F; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D; Urnov, Fyodor D; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M; Ménard, Didier; Fidock, David A

    2015-01-23

    The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.

  9. A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops

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    Ward Lorrayne

    2010-07-01

    Full Text Available Abstract Background Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs, the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility – malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. Methods Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. Results Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p Conclusions As this subsidy model is scaled up across multiple countries, these results confirm the potential for increased

  10. Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty

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    McKenzie F Ellis

    2010-07-01

    Full Text Available Abstract Background The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty. Methods Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models. Results Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT for malaria was estimated, and a policy of multiple first-line therapies (MFTs was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases. Conclusions At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.

  11. ISOLASI DAN IDENTIFIKASI ARTEMISININ DARI HERBA Artemisia annua L .

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    Sukmayati Alegantina

    2012-07-01

    Full Text Available Abstract. Malaria is still a major problem in Indonesia, because mortality in patients with severe malaria remains high. Many cases are occurs in endemic areas (e.g. Papua,Kalimantan, Bali and Sulawesi. Chloroquin is the most common antimalarial drug which is widely used since 1934. Plasmodium falciparum resistant to chloroquine was reported in some countries (e.g. Thailand, Vietnam, Indonesia, and Bangladesh. To delay the development of resistance, WHO recommended antimalarial combination therapy. Artemisinin and its derivatives (artesunate, artemether, dihydroartemisin produce rapid clearance of parasitemia and rapid resolution of symptoms compare with chloroquine. Artemisinin is obtained from Artemisia annua L. Even though there are some research produced a chemical synthetic of artemisinin, but it is not efficient and notstable. Our purposes are to conduct a preliminary research to obtain a method of isolation and identification of artemisinin which is the first step to develop a raw material of artemisinin as antimalarial drug in Indonesia.The first step of isolation is extraction from herb Artemisia annua L with n-hexane thatproduced n-hexane extract, this process is well-known as soxhletation. The second step isidentification of chemical substances from n-hexane extract. The third step is to obtain isolate from n-hexane extract by fractionation with acetonitril and separation with column chromatography. The last step is chemical and physical identification of isolateby TLC (Thin Layer (Chromatography and FT-IR.The result from n-hexane extract measurement is 4.33 % and from acetonitril fraction is2. 40 %. Chemical identification of n-hexan extract found there are terpenoid, phenol, flavonoid, fatty acid, atsiri oil and saponin. Organoleptic identification of isolate is white crystal, monosubstrate, odorless and bitter. Identification of isolate with TLC and FT-IR confirmed that the isolate is artemisinin.Keywords: artemisinin, Artemisia

  12. ISOLASI DAN IDENTIFIKASI ARTEMISININ DARI HERBA Artemisia annua L .

    Directory of Open Access Journals (Sweden)

    Sukmayati Alegantina

    2012-07-01

    Full Text Available Abstract. Malaria is still a major problem in Indonesia, because mortality in patients with severe malaria remains high. Many cases are occurs in endemic areas (e.g. Papua,Kalimantan, Bali and Sulawesi. Chloroquin is the most common antimalarial drug which is widely used since 1934. Plasmodium falciparum resistant to chloroquine was reported in some countries (e.g. Thailand, Vietnam, Indonesia, and Bangladesh. To delay the development of resistance, WHO recommended antimalarial combination therapy. Artemisinin and its derivatives (artesunate, artemether, dihydroartemisin produce rapid clearance of parasitemia and rapid resolution of symptoms compare with chloroquine. Artemisinin is obtained from Artemisia annua L. Even though there are some research produced a chemical synthetic of artemisinin, but it is not efficient and notstable. Our purposes are to conduct a preliminary research to obtain a method of isolation and identification of artemisinin which is the first step to develop a raw material of artemisinin as antimalarial drug in Indonesia.The first step of isolation is extraction from herb Artemisia annua L with n-hexane thatproduced n-hexane extract, this process is well-known as soxhletation. The second step isidentification of chemical substances from n-hexane extract. The third step is to obtain isolate from n-hexane extract by fractionation with acetonitril and separation with column chromatography. The last step is chemical and physical identification of isolateby TLC (Thin Layer (Chromatography and FT-IR.The result from n-hexane extract measurement is 4.33 % and from acetonitril fraction is2. 40 %. Chemical identification of n-hexan extract found there are terpenoid, phenol, flavonoid, fatty acid, atsiri oil and saponin. Organoleptic identification of isolate is white crystal, monosubstrate, odorless and bitter. Identification of isolate with TLC and FT-IR confirmed that the isolate is artemisinin.Keywords: artemisinin, Artemisia

  13. Study on the developmental toxicity of combined artesunate and mefloquine antimalarial drugs on rats.

    Science.gov (United States)

    Boareto, Ana Cláudia; Müller, Juliane Centeno; de Araujo, Samanta Luiza; Lourenço, Ana Carolina; Lourenço, Emerson Luiz Botelho; Gomes, Caroline; Minatovicz, Bruna; Lombardi, Natália; Paumgartten, Francisco Roma; Dalsenter, Paulo Roberto

    2012-12-01

    Antimalarial drug combinations containing artemisinins (ACTs) have become first choice therapies for Plasmodium falciparum malaria. Data on safety of ACTs in pregnancy are limited and no previous study has been conducted on the developmental toxicity of artesunate-mefloquine combinations on the first trimester of gestation. To evaluate the developmental toxicity of an artesunate/mefloquine combination, pregnant rats were treated orally with artesunate (15 and 40 mg/kg bwt/day), mefloquine (30 and 80 mg/kg bwt/day) and artesunate/mefloquine (15/30 and 40/80 mg/kg bwt/day) on gestation days 9-11. Dams were C-sectioned on day 20, and their uteri and fetuses removed and examined for soft tissue and skeleton abnormalities. Artesunate increased embryolethality and the incidence of limb long bone malformations on the absence of overt maternal toxicity. Mefloquine (80 mg/kg bwt/day) was maternally toxic and enhanced fetal variations. Combination of artesunate and mefloquine did not enhance their toxicity compared to the toxicity observed after its separate administration. Embryotoxicity of artesunate was apparently attenuated when it is co-administered with mefloquine.

  14. Induction of Haemolysis and DNA Fragmentation in a Normal and Malarial-Infected Blood by Commonly - used Antimalarial Drugs in the North-Western Region of Nigeria.

    Science.gov (United States)

    Muhammad, Aliyu; Ibrahim, Mohammed Auwal; Erukainure, Ochuko Lucky; Habila, Nathan; Idowu, Aimola Asegame; Ndidi, Uche Samuel; Malami, Ibrahim; Zailani, Halliru; Kudan, Zeenat Bello; Muhammad, Bilal Abdullahi

    2016-01-01

    Antimalarial drugs are medicines that are used to prevent or treat malaria effectively at different stages in the life cycle of the malarial parasites. In spite of this, a good number of these drugs have the potential to cause harm when they are misused or abused. This study was undertaken to evaluate the effects of commonly-used antimalarial drugs in the North Western region of Nigeria on haemolysis and DNA fragmentation in the blood of normal and malarial infected humans ex vivo. The drugs used were artemisinine, artesunate, chloroquine, coartem and quinine (0.5-8.0 mg/ml). Haemolysis, haemoglobin status and DNA fragmentations were assayed for using standard procedures. It was observed that all the drugs induced a remarkable dose-dependent haemolysis with more pronounced effects on apparently healthy humans. There was a significant (P DNA fragmentation when compared with control. Commonly-used antimalarial drugs induced haemolysis and altered haemoglobin status which may spontaneously increases the cellular iron levels; a substrate for Fenton and Haber Weiss reactions, and eventually induces DNA fragmentation. Hence, adequate care should be taken during prescription with total avoidance for self medications and/or drugs abuse as a result of their adverse effects within the red blood cells and its immediate microenvironment.

  15. Seasonal distribution of anti-malarial drug resistance alleles on the island of Sumba, Indonesia

    NARCIS (Netherlands)

    Asih, P.B.; Rogers, W.O.; Susanti, A.I.; Rahmat, A.; Rozi, I.E.; Kusumaningtyas, M.A.; Dewi, R.M.; Coutrier, F.N.; Sutamihardja, A.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    BACKGROUND: Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based com

  16. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

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    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  17. Recent progress in the development of anti-malarial quinolones.

    Science.gov (United States)

    Beteck, Richard M; Smit, Frans J; Haynes, Richard K; N'Da, David D

    2014-08-30

    Available anti-malarial tools have over the ten-year period prior to 2012 dramatically reduced the number of fatalities due to malaria from one million to less than six-hundred and thirty thousand. Although fewer people now die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones are a promising class of compounds, with some demonstrating potent in vitro activity against the malaria parasite. This review summarizes the progress made in the development of potential anti-malarial quinolones since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed.

  18. Insights following change in drug policy: A descriptive study for antimalarial prescription practices in children of public sector health facilities in Jharkhand state of India

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    Neelima Mishra

    2013-12-01

    Full Text Available Background & objectives: Widespread resistance to chloroquine was the mainstay to implement artemisininbased combination therapy (ACT in the year 2007 in few malaria endemic states in India including Jharkhand as the first line of treatment for uncomplicated Plasmodium falciparum malaria. This study was conducted in Jharkhand state of the country just after the implementation of ACT to assess the prevailing antimalarial drug prescribing practices, availability of antimalarial drugs and the acceptability of the new policy by the health professionals for the treatment of uncomplicated P. falciparum malaria patients particularly in children ≤15 yr of age. Methods: This is a cross-sectional study in children aged ≤15 yr with malaria or to whom antimalarial drug was prescribed. Main outcome measure was prescription of recommended ACT in children aged ≤15 yr with malaria in the selected areas of Jharkhand. Results: In the year 2008, artemisinin-based combination therapy (ACT was implemented in 12 districts of the studied state; however, the availability of ACT was confirmed only in five districts. Antimalarial prescription was prevalent amongst the undiagnosed (8.4%, malaria negative (64.3% and unknown blood test result (1.2% suggesting the prevalence of irrational treatment practices. ACT prescription was very low with only 3.2% of confirmed falciparum malaria patients receiving it while others received either non-artesunate (NA treatment (88.1% including chloroquine (CQ alone, CQ + Primaquine (PQ/other drugs, sulphadoxine-pyrimethamine (SP alone, SP + other drugs or artemisinin monotherapy (AM treatment (6.3%. Still others were given nonantimalarial treatment (NM in both malaria positive (0.3% and malaria negative (2.1% cases. Interpretation & conclusion: Despite the change in drug policy in the studied state the availability and implementation of ACT was a major concern. Nevertheless, the non-availability of blister packs for children aged

  19. Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery

    OpenAIRE

    Marques, Joana; Valle-Delgado, Juan J.; Urbán, Patricia; Baró, Elisabet; Prohens, Rafel; Mayor, Alfredo; Cisteró, Pau; Delves, Michael; Robert E Sinden; Grandfils, Christian; de Paz, José L.; García-Salcedo, José A.; Fernández-Busquets, Xavier

    2016-01-01

    The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial dru...

  20. The antimalarial drug quinine interferes with serotonin biosynthesis and action.

    Science.gov (United States)

    Islahudin, Farida; Tindall, Sarah M; Mellor, Ian R; Swift, Karen; Christensen, Hans E M; Fone, Kevin C F; Pleass, Richard J; Ting, Kang-Nee; Avery, Simon V

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.

  1. Artemisinins from folklore to modern medicine--transforming an herbal extract to life-saving drugs.

    Science.gov (United States)

    Weina, P J

    2008-06-01

    The history of the artemisinins from Ge Hong in China during the 4th century, to the re-discovery of the qing hao derivatives in the 1970s, to the explosion of artemisinin derivatives and combinations throughout the world today is a fascinating story. The central and underappreciated role of the United States Army's 'drug company' known as the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research is a story worth relating. From being the first group outside China to extract the active component of qing hao, to leading the work on neurotoxicity of the class in animals, to bringing a Good Manufacturing Practices intravenous formulation to the worldwide market is traced.

  2. Quality of antimalarial drugs and antibiotics in Papua New Guinea: a survey of the health facility supply chain.

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    Manuel W Hetzel

    Full Text Available BACKGROUND: Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT. In Papua New Guinea (PNG, Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. METHODS AND FINDINGS: Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC. Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3 contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4% primaquine, 3/70 (4.3% amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. CONCLUSIONS: This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and

  3. Analytical sample preparation strategies for the determination of antimalarial drugs in human whole blood, plasma and urine

    DEFF Research Database (Denmark)

    Casas, Monica Escolà; Hansen, Martin; Krogh, Kristine A;

    2014-01-01

    Antimalarial drugs commonly referred to as antimalarials, include a variety of compounds with different physicochemical properties. There is a lack of information on antimalarial distribution in the body over time after administration, e.g. the drug concentrations in whole blood, plasma, and urin...... summarized. Finally, the main problems that the researchers have dealt with are highlighted. This information will aid analytical chemists in the development of novel methods for determining existing antimalarials and upcoming new drugs.......Antimalarial drugs commonly referred to as antimalarials, include a variety of compounds with different physicochemical properties. There is a lack of information on antimalarial distribution in the body over time after administration, e.g. the drug concentrations in whole blood, plasma, and urine...

  4. Susceptibility of Thai isolates of Plasmodium falciparum to artemisinine (qinghaosu) and artemether

    Science.gov (United States)

    Thaithong, Sodsri; Beale, G. H.

    1985-01-01

    Eleven Thai isolates and one West African isolate of Plasmodium falciparum were tested for their susceptibility to the Chinese antimalarial drugs artemisinine (qinghaosu) and artemether. The isolates were cultivated by the Trager—Jensen candle-jar technique and exposed to the action of the drugs for 36-48 hours. Artemisinine inhibited growth of most isolates at 10-7-10-8 mol/litre and artemether at 10-8 mol/litre (with an initial parasitaemia of 0.5-1.0%). Slight variation in the sensitivity of different isolates was found, but there was no correlation between sensitivity to artemisinine or artemether and sensitivity to pyrimethamine, pyrimethamine/sulfadoxine, or chloroquine. The action of artemisinine and artemether was reduced when the initial parasitaemia of the treated cultures was raised. PMID:3899399

  5. Ex vivo susceptibility of Plasmodium falciparum isolates from Dakar, Senegal, to seven standard anti-malarial drugs

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    Pradines Bruno

    2011-10-01

    Full Text Available Abstract Background As a result of widespread chloroquine and sulphadoxine-pyrimethamine resistance, artemisinin-based combination therapy (ACT (which includes artemether-lumefantrine and artesunate-amodiaquine has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Since then, there have been very few reports on the ex vivo susceptibility of Plasmodium falciparum to anti-malarial drugs. To examine whether parasite susceptibility has been affected by the widespread use of ACT, the ex vivo susceptibility of local isolates was assessed at the military hospital of Dakar. Methods The ex vivo susceptibility of 93 P. falciparum isolates from Dakar was successfully determined using the Plasmodium lactate dehydrogenase (pLDH ELISA for the following drugs: chloroquine (CQ, quinine (QN, mefloquine (MQ, monodesethylamodiaquine (MDAQ, lumefantrine (LMF, dihydroartemisinin (DHA and doxycycline (DOX. Results After transformation of the isolate IC50 in ratio of IC50 according to the susceptibility of the 3D7 reference strain (isolate IC50/3D7 IC50, the prevalence of the in vitro resistant isolates with reduced susceptibility was 50% for MQ, 22% for CQ, 12% for DOX, 6% for both QN and MDAQ and 1% for the drugs LMF and DHA. The highest significant positive correlations were shown between responses to CQ and MDAQ (r = 0.569; P r = 0.511; P r = 0.428; P = 0.0001, LMF and MQ (r = 0.413; P = 0.0002, QN and DHA (r = 0.402; P = 0.0003 and QN and MQ (r = 0.421; P = 0.0001. Conclusions The introduction of ACT in 2002 has not induced a decrease in P. falciparum susceptibility to the drugs DHA, MDAQ and LMF, which are common ACT components. However, the prevalence of P. falciparum isolates with reduced susceptibility has increased for both MQ and DOX. Taken together, these data suggest that intensive surveillance of the P. falciparum in vitro susceptibility to anti-malarial drugs in Senegal is required.

  6. A partial convergence in action of methylene blue and artemisinins: antagonism with chloroquine, a reversal with verapamil, and an insight into the antimalarial activity of chloroquine.

    Science.gov (United States)

    Haynes, Richard K; Cheu, Kwan-Wing; Li, Ka-Yan; Tang, Maggie Mei-Ki; Wong, Ho-Ning; Chen, Min-Jiao; Guo, Zu-Feng; Guo, Zhi-Hong; Coghi, Paolo; Monti, Diego

    2011-09-05

    Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).

  7. Fixed dose combination of arterolane and piperaquine: a newer prospect in antimalarial therapy.

    Science.gov (United States)

    Patil, Cy; Katare, Ss; Baig, Ms; Doifode, Sm

    2014-07-01

    Malaria has been very prevalent vector-borne disease in India and until date bears enormous implications on health care services of the country. Over the period of time, the development of resistance to traditional antimalarials like chloroquine has been posed as major deterrent in efforts of malaria control. As the drug resistance is today universally prevalent, especially in Plasmodium falciparum species, major burden of malarial control resides with the new artemisinin drug class. However, arterolane is one of the first fully synthetic non-artemisinin antimalarial compound with rapid schizontocidal activity, hence offering an alternative to artemisinin drugs in malaria control. Piperaquine is a synthetic bisquinoline (4-amioquinoline Antimalarial) with slow and longer schizontocidal activity. Therefore their combination has been shown to provide rapid parasitemic clearance and quick relief of most malaria-related symptoms along with prevention of recrudescences. This combination was approved by Drugs Controller General of India in 2011 for treatment of uncomplicated P. falciparum malaria. The article is aimed at to review this newer prospect in antimalarial therapy for which comprehensive database search was done in Google, Google Scholar, PubMed using the terms "Malaria," "Arterolane," "OZ277," "Piperaquine," and "Artemisinin combination therapy." A total of 323 articles were screened and 28 articles were considered for this review along with the World Health Organization and National malarial program guidelines.

  8. Residual antimalarial concentrations before treatment in patients with malaria from Cambodia: indication of drug pressure.

    Science.gov (United States)

    Hodel, Eva Maria; Genton, Blaise; Zanolari, Boris; Mercier, Thomas; Duong, Socheat; Beck, Hans-Peter; Olliaro, Piero; Decosterd, Laurent Arthur; Ariey, Frédéric

    2010-10-01

    The Thai-Cambodian border has been known as the origin of antimalarial drug resistance for the past 30 years. There is a highly diverse market for antimalarials in this area, and improved knowledge of drug pressure would be useful to target interventions aimed at reducing inappropriate drug use. Baseline samples from 125 patients with falciparum malaria recruited for 2 in vivo studies (in Preah Vihear and Pursat provinces) were analyzed for the presence of 14 antimalarials in a single run, by means of a liquid chromatography-tandem mass spectrometry assay. Half of the patients had residual drug concentrations above the lower limit of calibration for at least 1 antimalarial at admission. Among the drugs detected were the currently used first-line drugs mefloquine (25% and 35% of patients) and piperaquine (15% of patients); the first-line drug against vivax malaria, chloroquine (25% and 41% of patients); and the former first-line drug, quinine (5% and 34% patients). The findings demonstrate that there is high drug pressure and that many people still seek treatment in the private and informal sector, where appropriate treatment is not guaranteed. Promotion of comprehensive behavioral change, communication, community-based mobilization, and advocacy are vital to contain the emergence and spread of parasite resistance against new antimalarials.

  9. Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

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    Rosi Bissinger

    2015-07-01

    Full Text Available Background: The antimalarial drug mefloquine has previously been shown to stimulate apoptosis of nucleated cells. Similar to apoptosis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca2+-activity ([Ca2+]i, and ceramide. Methods: Phosphatidylserine abundance at the cell surface was estimated from annexin V binding, cell volume from forward scatter, reactive oxidant species (ROS from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA fluorescence, [Ca2+]i from Fluo3-fluorescence, and ceramide abundance from specific antibody binding. Results: A 48 h treatment of human erythrocytes with mefloquine significantly increased the percentage of annexin-V-binding cells (≥5 µg/ml, significantly decreased forward scatter (≥5 µg/ml, significantly increased ROS abundance (5 µg/ml, significantly increased [Ca2+]i (7.5 µg/ml and significantly increased ceramide abundance (10 µg/ml. The up-regulation of annexin-V-binding following mefloquine treatment was significantly blunted but not abolished by removal of extracellular Ca2+. Even in the absence of extracellular Ca2+, mefloquine significantly increased annexin-V-binding. Conclusions: Mefloquine treatment leads to erythrocyte shrinkage and erythrocyte membrane scrambling, effects at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance.

  10. Emerging drug resistance in Plasmodium falciparum: A review of well-characterized drug targets for novel antimalarial chemotherapy

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    Arnish Chakraborty

    2016-07-01

    Full Text Available Malaria is a life-threatening, highly infectious parasitic disease caused by the intracellular, protozoan parasites of Plasmodium species. The most severe form of the disease is caused by Plasmodium falciparum, an Apicomplexa parasite with a remarkable ability to acquire resistance to antimalarial medications. Drug resistant malaria is a serious public health concern in the tropical and sub-tropical nations of the world, rendering conventional antimalarial medication ineffective in several regions. Since an effective malaria vaccine is not yet available to the masses, novel antimalarial drugs need to be developed to control the disease on the face of ever increasing reports of drug resistance. The review acquaints the readers to the current situation of chemotherapy and drug resistance in malaria across the globe, the existing antimalarial medications in use, their mechanism of action and how the malaria parasite evolves resistance to them. The review also focuses on the identification, characterization and validation of a plethora of novel drug targets in Plasmodium falciparum from the oxidoreductase, hydrolase and protein kinase groups of enzymes. The work highlights the importance of these drug targets in Plasmodium biology and shines a spotlight on novel inhibitors which have the potential to be developed as future antimalarial drugs. The review ends with a detailed discussion on the prospects and challenges in antimalarial drug discovery.

  11. In vitro sensitivity of chloroquine sensitive and resistant Plasmodium falciparum to artemisinin antimalarials%恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物体外敏感性的研究

    Institute of Scientific and Technical Information of China (English)

    黄芳; 冯晓平; 周水森; 汤林华

    2008-01-01

    目的 测定恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物的体外敏感性. 方法 运用体外微量法与酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)测定青蒿琥酯、蒿甲醚及双氢青蒿素等3种青蒿素类抗疟药物对体外培养的恶性疟原虫氯喹敏感株与氯喹抗性株的体外敏感性,并比较两种方法测定的IC50值. 结果 体外微量法测定的3种药物对恶性疟原虫氯喹敏感株的IC50值依次为3.12 nmol/L、4.30 nmol/L、2.18 nmol/L,对恶性疟原虫氯喹抗性株的IC50值依次为4.31nmol/L、3.90 nmol/L、3.17 nmol/L;同时,将体外微量法与ELISA法所获的结果进行相关性分析,两种方法结果基本一致(r2=0.93,P<0.001). 结论 恶性疟原虫氯喹抗性株对青蒿素类药物无明显的交叉抗性;ELISA法可用于恶性疟原虫对抗疟药物的体外敏感性检测.%Objective To test the sensitivity of chloroquine sensitive and resistant Plasmodium falciparum to artemisinin anfimalarials. Method The responses of chloroquine sensitive and resistant P.falciparum to artemisinin antimalarials including artesunate,artemether and dihydroartemisinin were determined with Rieckmann s in vitro micro-technique and enzyme-linked immunosorbent assay(ELISA).The values of 50%inhibition of parasitemia(IC50)were compared with above two methods. Results The IC50 of artemisinin antimalarials in chloroquine sensitive P.falciparum were 3.12 nmoL/L,4.30 nmol/L,2.18 nmol/L respectively,while that in chloroquine resistant P. falciparum were 4.31nmol/L,3.90 nmol/L,3.17 nmol/L.The results obtained with both techniques were similar or identical by correlation analysis(r2=0.93,P<0.001).Conclusions There were no apparent cross-resistance of chloroquine resistant P.falciparum to artemisinin antimalarials.The ELISA test would be suitable for testing antimalarial drugs sensitivitv in vitro.

  12. Case management of malaria fever in Cambodia: results from national anti-malarial outlet and household surveys

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    Littrell Megan

    2011-10-01

    Full Text Available Abstract Background Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT. The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Methods Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Results Most public outlets (85% and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%, drug stores (14%, mobile providers (4% and grocery stores (2%. Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61% and private (42% sectors. Conclusions While data on the anti-malarial

  13. Characterization of xanthophyll pigments, photosynthetic performance, photon energy dissipation, reactive oxygen species generation and carbon isotope discrimination during artemisinin-induced stress in Arabidopsis thaliana.

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    M Iftikhar Hussain

    Full Text Available Artemisinin, a potent antimalarial drug, is phytotoxic to many crops and weeds. The effects of artemisinin on stress markers, including fluorescence parameters, photosystem II photochemistry, photon energy dissipation, lipid peroxidation, reactive oxygen species generation and carbon isotope discrimination in Arabidopsis thaliana were studied. Arabidopsis ecotype Columbia (Col-0 seedlings were grown in perlite and watered with 50% Hoagland nutrient solution. Adult plants of Arabidopsis were treated with artemisinin at 0, 40, 80, 160 μM for one week. Artemisinin, in the range 40-160 μM, decreased the fresh biomass, chl a, b and leaf mineral contents. Photosynthetic efficiency, yield and electron transport rate in Arabidopsis were also reduced following exposure to 80 and 160 μM artemisinin. The ΦNPQ and NPQ were less than control. Artemisinin treatment caused an increase in root oxidizability and lipid peroxidation (MDA contents of Arabidopsis. Calcium and nitrogen contents decreased after 80 and 160 μM artemisinin treatment compared to control. δ13C values were less negative following treatment with artemisinin as compared to the control. Artemisinin also decreased leaf protein contents in Arabidopsis. Taken together, these data suggest that artemisinin inhibits many physiological and biochemical processes in Arabidopsis.

  14. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria.

    Science.gov (United States)

    Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V; Rizk, Shahir S; Njimoh, Dieudonne L; Ryan, Yana; Chotivanich, Kesinee; Nguon, Chea; Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan; Pfrender, Michael; Emrich, Scott; Mohandas, Narla; Dondorp, Arjen M; Wiest, Olaf; Haldar, Kasturi

    2015-04-30

    Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.

  15. Important drug interactions in patients with rheumatic disorders: interactions of glucocorticoids, immunosuppressants and antimalarial drugs.

    Science.gov (United States)

    Hromadkova, L; Soukup, T; Vlcek, J

    2012-08-01

    Despite the fact that biological treatments are very promising, classical immunosuppressants, antimalarial drugs and glucocorticosteroids are still very important and widely used in practice. Although drug interactions can have fatal consequences, few studies have reviewed drug interactions of these classical drugs used in rheumatology, and very few guidelines are available on this subject. Therefore, this report summarizes important interactions of immunosuppressants, antimalarial drugs and glucocorticosteroids with drugs commonly used in internal medicine. In the present study, more than 300 interactions were retrieved from the Micromedex ® database. The selection was reduced to the interactions rated as moderate, major or contraindicated. The selected interactions were further checked against PubMed ®, MEDLINE ®, InfoPharm Compendium of Drug Interactions and Summaries of Product Characteristics. For each interaction, its nature, mechanism, onset and clinical severity were indicated, documentation quality was rated and recommendations for clinical practice were formulated. Twenty significant interactions that we rated as moderate, severe and very severe were identified. Interacting drugs were warfarin, fluoroquinolones, azole antifungals, co-trimoxazole, proton pump inhibitors, amiodarone, cholestyramine, activated carbon, allopurinol, angiotensin-converting enzyme inhibitors, statins, digoxin, iron, aluminium and magnesium salts, and hepatotoxic and nephrotoxic agents.

  16. Does anti-malarial drug knowledge predict anti-malarial dispensing practice in drug outlets? A survey of medicine retailers in western Kenya

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    Rusk Andria

    2012-08-01

    Full Text Available Abstract Background Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial. Methods To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of the Webuye Health and Demographic Surveillance Site in the Bungoma East District of western Kenya. Results Most of the medicine retailers surveyed (65% were able to identify artemether-lumefantrine (AL as the Kenyan Ministry of Health recommended first-line anti-malarial therapy for uncomplicated malaria. Retailers who correctly identified this treatment were also more likely to recommend AL to adult and paediatric customers. However, the proportion of medicine retailers who recommend the correct treatment is disappointingly low. Only 48% would recommend AL to adults, and 37% would recommend it to children. It was discovered that customer demand has an influence on retailer behaviour. Retailer training and education were found to be correlated with anti-malarial drug knowledge, which in turn is correlated with dispensing practices. Medicine retailer behaviour, including patient referral practice and dispensing practices, are also correlated with knowledge of the first-line anti-malarial medication. The Kenya Ministry of Health guidelines were found to influence retailer drug stocking and dispensing behaviours. Conclusion Most medicine retailers could identify the recommended first-line treatment for uncomplicated malaria, but the percentage that could

  17. Brands, costs and registration status of antimalarial drugs in the Kenyan retail sector

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    Snow Robert W

    2005-07-01

    Full Text Available Abstract Background Although an important source of treatment for fevers, little is known about the structure of the retail sector in Africa with regard to antimalarial drugs. This study aimed to assess the range, costs, sources and registration of antimalarial drugs in the Kenyan retail sector. Methods In 2002, antimalarial drug registration and trade prices were established by triangulating national registration lists, government gazettes and trade price indices. Data on registration status and trade prices were compared with similar data generated through a retail audit undertaken among 880 randomly sampled retailers in four districts of Kenya. Results Two hundred and eighteen antimalarial drugs were in circulation in Kenya in 2002. These included 65 "sulfur"-pyrimethamine (sulfadoxine-pyrimethamine and sulfalene-pyrimethamine (SP, the first-line recommended drug in 2002 and 33 amodiaquine (AQ, the second-line recommended drug preparations. Only half of SP and AQ products were registered with the Pharmacy and Poisons Board. Of SP and AQ brands at district level, 40% and 44% were officially within legal registration requirements. 29% of retailers at district level stocked SP and 95% stocked AQ. The retail price of adult doses of SP and AQ were on average 0.38 and 0.76 US dollars, 100% and 347% higher than trade prices from manufacturers and importers. Artemether-lumefantrine, the newly announced first-line recommended antimalarial drug in 2004, was found in less than 1% of all retail outlets at a median cost of 7.6 US dollars. Conclusion There is a need to ensure that all antimalarial drugs are registered with the Pharmacy and Poisons Board to facilitate a more stringent post-marketing surveillance system to ensure drugs are safe and of good quality post-registration.

  18. Extraction of Artemisinin, an Active Antimalarial Phytopharmaceutical from Dried Leaves of Artemisia annua L., Using Microwaves and a Validated HPTLC-Visible Method for Its Quantitative Determination

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    Himanshu Misra

    2014-01-01

    Full Text Available A simple, rapid, precise, and accurate high-performance thin-layer chromatographic method coupled with visible densitometric detection of artemisinin is developed and validated. Samples of the dried Artemisia annua leaves were extracted via microwaves using different solvents. This method shows the advantage of shorter extraction time of artemisinin from leaves under the influence of electromagnetic radiations. Results obtained from microwave-assisted extraction (MAE were compared with hot soxhlet extraction. Chromatographic separation of artemisinin from plant extract was performed over silica gel 60 F254 HPTLC plate using n-hexane : ethyl acetate as mobile phase in the ratio of 75 : 25, v/v. The plate was developed at room temperature 25 ± 2.0°C. Artemisinin separation over thin-layer plate was visualized after postchromatographic derivatization with anisaldehyde-sulphuric acid reagent. HPTLC plate was scanned in a CAMAG’s TLC scanner 3 at 540 nm. Artemisinin responses were found to be linear over a range of 400–2800 ng spot−1 with a correlation coefficient 0.99754. Limits of detection and quantification were 40 and 80 ng spot−1, respectively. The HPTLC method was validated in terms of system suitability, precision, accuracy, sensitivity (LOD and LOQ, and robustness. Additionally, calculation of plate efficiency and flow constant were included as components of validation. Extracts prepared from different parts of the plant (leaves, branches, main stem, and roots were analyzed for artemisinin content, in which, artemisinin content was found higher in the leaf extract with respect to branches and main stem extracts; however, no artemisinin was detected in root extract. The developed HPTLC-visible method of artemisinin determination will be very useful for pharmaceutical industries, which are involved in monitoring of artemisinin content during different growth stages (in vitro and in vivo of A. annua for qualitative

  19. Putting the genie back in the bottle? Availability and presentation of oral artemisinin compounds at retail pharmacies in urban Dar-es-Salaam

    Directory of Open Access Journals (Sweden)

    Black Carolyn

    2006-03-01

    Full Text Available Abstract Background Recently global health advocates have called for the introduction of artemisinin-containing antimalarial combination therapies to help curb the impact of drug-resistant malaria in Africa. Retail trade in artemisinin monotherapies could undermine efforts to restrict this class of medicines to more theoretically sound combination treatments. Methods This paper describes a systematic search for artemisinin-containing products at a random sample of licensed pharmacies in Dar-es-Salaam, Tanzania in July 2005. Results Nineteen different artemisinin-containing oral pharmaceutical products, including one co-formulated product, one co-packaged product, and 17 monotherapies were identified. All but one of the products were legally registered and samples of each product were obtained without a prescription. Packaging and labeling of the products seldom included local language or illustrated instructions for low-literate clients. Packaging and inserts compared reasonably well with standards recommended by the national regulatory authority with some important exceptions. Dosing instructions were inconsistent, and most recommended inadequate doses based on international standards. None of the monotherapy products mentioned potential benefits of combining the treatment with another antimalarial drug. Conclusion The findings confirm the widespread availability of artemisinin monotherapies that led the World Health Organization to call for the voluntary withdrawal of these drugs in malaria-endemic countries. As the global public health community gathers resources to deploy artemisinin-containing combination therapies in Africa, planners should be mindful that these drugs will coexist with artemisinin monotherapies in an already well-established market place. In particular, regulatory authorities should be incorporated urgently into the process of planning for rational deployment of artemisinin-containing antimalarial combination therapies.

  20. Efficacy of antimalarial treatment in Guinea: in vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zérékoré

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    Coulibaly Léonie

    2007-05-01

    Full Text Available Abstract Background In the last five years, countries have been faced with changing their malaria treatment policy to an artemisinin-based combination therapy (ACT, many with no national data on which to base their decision. This is particularly true for a number of West African countries, including Guinea, where these studies were performed. Two studies were conducted in 2004/2005 in programmes supported by Medecins Sans Frontieres, when chloroquine was still national policy, but artesunate (AS/sulphadoxine-pyrimethamine (SP had been used in refugee camps for two years. Methods In Dabola (central Guinea, 220 children aged 6–59 months with falciparum malaria were randomized to receive either AS/amodiaquine (AQ or AS/SP. In vivo efficacy was assessed following the 2003 World Health Organization guidelines. In a refugee camp in Laine (south of Guinea, where an in vivo study was not feasible due to the unstable context, a molecular genotyping study in 160 patients assessed the prevalence of mutations in the dihydrofolate reductase (dhfr (codons 108, 51, 59 and dihydropteroate synthase (dhps (codons 436, 437, 540 genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulphadoxine, respectively. Results In Dabola, after 28 days of follow-up, Polymerase Chain Reaction (PCR-adjusted failure rates were 1.0% (95%CI 0–5.3 for AS/AQ and 1.0% (95%CI 0–5.5 for AS/SP. In the refugee camp in Laine, the molecular genotyping study found three dhfr mutations in 85.6% (95%CI 79.2–90.7 patients and quintuple dhfr/dhps mutations in 9.6% (95%CI 5.2–15.9. Conclusion Both AS/AQ and AS/SP are highly efficacious in Dabola, whereas there is molecular evidence of established SP resistance in Laine. This supports the choice of the national programme of Guinea to adopt AS/AQ as first line antimalarial treatment. The results highlight the difficulties faced by control programmes, which have gone through the upheaval of

  1. Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable antimalarial drugs

    National Research Council Canada - National Science Library

    Hale, Victoria; Keasling, Jay D; Renninger, Neil; Diagana, Thierry T

    2007-01-01

    .... With a grant from the Bill and Melinda Gates Foundation, a partnership between Amyris Biotechnologies, the Institute for OneWorld Health, and the University of California, Berkeley is using synthetic...

  2. Two years post affordable medicines facility for malaria program: availability and prices of anti-malarial drugs in central Ghana.

    Science.gov (United States)

    Freeman, Alexander; Kwarteng, Anthony; Febir, Lawrence Gyabaa; Amenga-Etego, Seeba; Owusu-Agyei, Seth; Asante, Kwaku Poku

    2017-01-01

    The Affordable Medicines Facility for malaria (AMFm) Program was a subsidy aimed at artemisinin-based combination therapies (ACTs) in order to increase availability, affordability, and market share of ACTs in 8 malaria endemic countries in Africa. The WHO supervised the manufacture of the subsidized products, named them Quality Assured ACTs (QAACT) and printed a Green Leaf Logo on all QAACT packages. Ghana began to receive the subsidized QAACTs in 2010. A cross-sectional stock survey was conducted at 63 licensed chemical shops (LCS) and private pharmacies in two districts of the Brong-Ahafo region of Ghana to determine the availability and price of all anti-malarial treatments. Drug outlets were visited over a 3-weeks period in October and November of 2014, about 2 years after the end of AMFm program. At least one QAACT was available in 88.9% (95% CI 80.9% - 96.8%) of all drug outlets with no difference between urban and rural locations. Non-Assured ACTs (NAACT) were significantly more available in urban drug outlets [75.0% availability (95% CI 59.1% - 90.9%)] than in rural drug outlets [16.1% availability (95% CI 2.4% - 29.9%)]. The top selling product was Artemether Lumefantrine with the Green Leaf Logo, a QAACT. There was a significant difference in the mean price of a QAACT [$1.04 USD (95% CI $0.98 - $1.11)], and the mean price of a NAACT in both the urban and rural areas [$2.46 USD (95% CI $2.11 - $2.81)]. There was no significant difference in the price of any product that was available in urban and rural settings. About 2 years after the AMFm program, subsidized QAACTs in Ghana were widely available and more affordable than NAACTs in the Kintampo North District and Kintampo South Municipality of Ghana. The AMFm program appeared to have mostly succeeded in making QAACTs available and affordable.

  3. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono District, Uganda.

    Science.gov (United States)

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony; Clarke, Sian; Cundill, Bonnie; Magnussen, Pascal; Yeung, Shunmay

    2013-03-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how much customers would be willing to pay for an RDT if offered in these settings. We conducted a contingent valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP) for an RDT and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly associated with a higher WTP for these commodities included having a higher socio-economic status, no fever/malaria in the household in the past 2 weeks and if a malaria diagnosis had been obtained from a qualified health worker prior to visiting the drug shop. The findings further suggest that the WTP for an RDT and a course of ACT among drug shop customers is considerably lower than prevailing and estimated end-user prices for these commodities. Increasing the uptake of ACTs in drug shops and restricting the sale of ACTs to parasitologically confirmed malaria will therefore require additional measures.

  4. Retinal toxicity induced by antimalarial drugs: literature review and case report.

    Science.gov (United States)

    Garza-Leon, Manuel; Flores-Alvarado, Diana Elsa; Muñoz-Bravo, Juan Manuel

    2016-06-17

    Antimalarial drugs are widely used in several countries for control of rheumatologic diseases such as systemic lupus erythematosus and rheumatoid arthritis. They are still used in Mexico because of their low cost and few secondary effects, most of which are mild and reversible. Even so, at an ophthalmological level, they could produce irreversible visual damage, which is why it is important to have ophthalmological evaluation and proper follow up. We present a clinical case as an example of characteristic ophthalmological findings as well as risk factors for retinal toxicity. We then discuss guidelines for diagnosis and follow up of patients who use antimalarial drugs for the treatment of rheumatologic illnesses.

  5. A reaction-diffusion system modeling the spread of resistance to an antimalarial drug.

    Science.gov (United States)

    Bacaer, Nicolas; Sokhna, Cheikh

    2005-04-01

    A mathematical model representing the difusion of resistance to an antimalarial drug is developed. Resistance can spread only when the basic reproduction number of the resistant parasites is bigger than the basic reproduction number of the sensitive parasites (which depends on the fraction of infected people treated with the antimalarial drug). Based on a linearization study and on numerical simulations, an expression for the speed at which resistance spreads is conjectured. It depends on the ratio of the two basic reproduction numbers, on a coefficient representing the difusion of mosquitoes, on the death rate of mosquitoes infected by resistant parasites, and on the recovery rate of nonimmune humans infected by resistant parasites.

  6. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    OpenAIRE

    Asrar Alam

    2014-01-01

    Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes...

  7. High School Students Are a Target Group for Fight against Self-Medication with Antimalarial Drugs: A Pilot Study in University of Kinshasa, Democratic Republic of Congo

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    Ramsès Kabongo Kamitalu

    2016-01-01

    Full Text Available Aim. To assess the self-medication against malaria infection in population of Congolese students in Kinshasa, Democratic Republic of Congo (DRC. Methods. A cross-sectional study was carried out in University of Kinshasa, Kinshasa, Democratic Republic of Congo. Medical records of all students with malaria admitted to Centre de Santé Universitaire of University of Kinshasa from January 1, 2008, to April 30, 2008, were reviewed retrospectively. Results. The median age of the patients was 25.4 years (range: from 18 to 36 years. The majority of them were male (67.9%. Artemisinin-based combination treatments (ACTs was the most used self-prescribed antimalarial drugs. However, self-medication was associated with the ingestion of quinine in 19.9% of cases. No case of ingestion of artesunate/artemether in monotherapy was found. All the medicines taken were registered in DRC. In this series, self-prescribed antimalarial was very irrational in terms of dose and duration of treatment. Conclusion. This paper highlights self-medication by a group who should be aware of malaria treatment protocols. The level of self-prescribing quinine is relatively high among students and is disturbing for a molecule reserved for severe disease in Congolese health care policy in management of malaria.

  8. Effects of Overexpression of the Endogenous Farnesyl Diphosphate Synthase on the Artemisinin Content in Artemisia annua L.

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Artemisinin Is a novel effective antimalarial drug extracted from the medicinal plant Artemisia annua L. Owing to the tight market and low yield of artemislnin, there is great interest in enhancing the production of artemisinin.In the present study, farnesyl dlphosphate synthase (FPS) was overexpressed in high-yield A. annua to increase the artemislnin content. The FPS activity in transgenic A. annua was two- to threefold greater than that in non-transgenic A. annua. The highest artemisinin content in transgenic A. annua was approximately 0.9% (dry weight), which was 34.4% higher than that in non-transgenic A. annua. The results demonstrate the regulatory role of FPS in artemisinin biosynthesis.

  9. Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus Are Absent in Plasmodium falciparum Isolates from Haiti

    Science.gov (United States)

    Carter, Tamar E.; Boulter, Alexis; Existe, Alexandre; Romain, Jean R.; St. Victor, Jean Yves; Mulligan, Connie J.; Okech, Bernard A.

    2015-01-01

    Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations. PMID:25646258

  10. Safety, pharmacokinetics and efficacy of artemisinins in pregnancy

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    Veronica Ades

    2011-05-01

    Full Text Available Malaria in pregnancy can lead to serious maternal and fetal morbidity and mortality. Access to the most effective antimalarials in pregnancy is essential. Resistance to current therapies is high for all antimalarial therapies except artemisinins. Artemisinin-based combination therapy is current the first line of malaria treatment recommended by the WHO for children, adults and pregnant women in second or third trimester. Due to potential embryotoxicity of artemisinins identified in animal studies, artemisinins are not considered safe for use in first trimester of pregnancy. Artemisinins are more rapidly metabolized in pregnant women, but this does not seem to reduce efficacy. Most studies show very high cure rates for pregnant women. Areas for further research include the safety profile in first trimester of pregnancy, the effect of HIV infection on artemisinin use in pregnancy, the relationship between the pharmacokinetic profile and efficacy, and the use of artemisinin-based combination therapy for intermittent preventive treatment in pregnancy.  

  11. Syntheses and antimalarial activities of N-substituted 11-azaartemisinins.

    Science.gov (United States)

    Torok, D S; Ziffer, H; Meshnick, S R; Pan, X Q; Ager, A

    1995-12-22

    A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.

  12. ANTIMALARIAL DRUGS IN THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS: PAST, PRESENT, FUTURE

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    Tatyana Andreyevna Lisitsyna

    2010-01-01

    Full Text Available The data available in the literature on experience in using antimalarial drugs in the treatment of systemic lupus erythematosus are summarized. A major emphasis is placed on therapy with hydroxychlorochine (plaquenil versus chlorine. Possible mechanisms of action of the drug and its effect on the course of the disease itself and concomitant abnormalities are described. Data on the toxicity of the drug and its safe use in pregnancy and lactation are also discussed

  13. UV-B and UV-C pre-treatments induce physiological changes and artemisinin biosynthesis in Artemisia annua L. - an antimalarial plant.

    Science.gov (United States)

    Rai, Rashmi; Meena, Ram Prasad; Smita, Shachi Shuchi; Shukla, Aparna; Rai, Sanjay Kumar; Pandey-Rai, Shashi

    2011-12-02

    Present study was undertaken to investigate if short-term UV-B (4.2 kJ m(-2) day(-1)) and UV-C (5.7 kJ m(-2) day(-1)), pre-treatments can induce artemisinin biosynthesis in Artemisia annua. Twenty-one day old Artemisia seedlings were subjected to short-term (14 days) UV pre-treatment in an environmentally controlled growth chamber and then transplanted to the field under natural conditions. Treatment of A. annua with artificial UV-B and UV-C radiation not only altered the growth responses, biomass, pigment content and antioxidant enzyme activity but enhanced the secondary metabolites (artemisinin and flavonoid) content at all developmental stages as compared to non-irradiated plants. The extent of oxidative damage was measured in terms of the activities of enzymes such as catalase, superoxide dismutase and ascorbate peroxidase. Reinforcement in the antioxidative defense system seems to be a positive response of plants in ameliorating the negative effects of UV-B and UV-C radiations. While the carotenoid content was elevated, the chlorophyll content decreased under UV-B and UV-C pre-treatments. The reverse transcription PCR analysis of the genes associated in artemisinin/isoprenoid biosynthesis like 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), cytochrome P450 oxidoreductase (CPR) and amorpha-4,11-diene synthase (ADS) genes at different growth stages revealed UV induced significant over-expression of the above protein genes. UV-B and UV-C pre-treatments, led to an increase in the concentrations of artemisinin at full bloom stage by 10.5% and 15.7% than that of the control respectively. Thus, the result of our study suggests that short term UV-B pre-treatment of seedlings in greenhouse prior to transplantation into the field enhances artemisinin production with lesser yield related damages as compared to UV-C radiation in A. annua.

  14. Formation of the diuretic chlorazanil from the antimalarial drug proguanil--implications for sports drug testing.

    Science.gov (United States)

    Thevis, Mario; Geyer, Hans; Thomas, Andreas; Tretzel, Laura; Bailloux, Isabelle; Buisson, Corinne; Lasne, Francoise; Schaefer, Maximilian S; Kienbaum, Peter; Mueller-Stoever, Irmela; Schänzer, Wilhelm

    2015-11-10

    Chlorazanil (Ordipan, N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analytical findings were registered only in 2014, being motive for an in-depth investigation of these cases. Both individuals denied the intake of the drug; however, the athletes did declare the use of the antimalarial prophylactic agent proguanil due to temporary residences in African countries. A structural similarity between chlorazanil and proguanil is given but no direct metabolic relation has been reported in the scientific literature. Moreover, chlorazanil has not been confirmed as a drug impurity of proguanil. Proguanil however is metabolized in humans to N-(4-chlorophenyl)-biguanide, which represents a chemical precursor in the synthesis of chlorazanil. In the presence of formic acid, formaldehyde, or formic acid esters, N-(4-chlorophenyl)-biguanide converts to chlorazanil. In order to probe for potential sources of the chlorazanil detected in the doping control samples, drug formulations containing proguanil and urine samples of individuals using proguanil as antimalarial drug were subjected to liquid chromatography-high resolution/high accuracy mass spectrometry. In addition, in vitro simulations with 4-chlorophenyl-biguanide and respective reactants were conducted in urine and resulting specimens analyzed for the presence of chlorazanil. While no chlorazanil was found in drug formulations, the urine samples of 2 out of 4 proguanil users returned findings for chlorazanil at low ng/mL levels, similar to the adverse analytical findings in the doping control samples. Further, in the presence of formaldehyde, formic acid and related esters, 4-chlorophenyl-biguanide was found to produce chlorazanil in human urine, suggesting that the detection of the obsolete diuretic

  15. Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

    Science.gov (United States)

    Kaur, Harparkash; Allan, Elizabeth Louise; Mamadu, Ibrahim; Hall, Zoe; Ibe, Ogochukwu; El Sherbiny, Mohamed; van Wyk, Albert; Yeung, Shunmay; Swamidoss, Isabel; Green, Michael D.; Dwivedi, Prabha; Culzoni, Maria Julia; Clarke, Siân; Schellenberg, David; Fernández, Facundo M.; Onwujekwe, Obinna

    2015-01-01

    Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained

  16. Quality of artemisinin-based combination formulations for malaria treatment: prevalence and risk factors for poor quality medicines in public facilities and private sector drug outlets in Enugu, Nigeria.

    Directory of Open Access Journals (Sweden)

    Harparkash Kaur

    Full Text Available Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296 of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs in Enugu metropolis, Nigeria, and compared the resulting quality estimates.ACAs were purchased using three sampling approaches--convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified.Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200, mystery (n=1,919 and overt (n=905 approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified and dihydroartemisinin (n=14 monotherapy tablets, not recommended by WHO, were also identified.Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained.

  17. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    Directory of Open Access Journals (Sweden)

    Asrar Alam

    2014-01-01

    Full Text Available Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found in P. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. In P. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential of P. falciparum serine proteases as antimalarial drug targets.

  18. Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    Katherine Kay

    Full Text Available Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii multiple drugs within a treatment combination; (iii differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very

  19. Reactions of antimalarial peroxides with each of leucomethylene blue and dihydroflavins: flavin reductase and the cofactor model exemplified.

    Science.gov (United States)

    Haynes, Richard K; Cheu, Kwan-Wing; Tang, Maggie Mei-Ki; Chen, Min-Jiao; Guo, Zu-Feng; Guo, Zhi-Hong; Coghi, Paolo; Monti, Diego

    2011-02-07

    Flavin adenine dinucleotide (FAD) is reduced by NADPH-E. coli flavin reductase (Fre) to FADH(2) in aqueous buffer at pH 7.4 under argon. Under the same conditions, FADH(2) in turn cleanly reduces the antimalarial drug methylene blue (MB) to leucomethylene blue. The latter is rapidly re-oxidized by artemisinins, thus supporting the proposal that MB exerts its antimalarial activity, and synergizes the antimalarial action of artemisinins, by interfering with redox cycling involving NADPH reduction of flavin cofactors in parasite flavin disulfide reductases. Direct treatment of the FADH(2) generated from NADPH-Fre-FAD by artemisinins and antimalaria-active tetraoxane and trioxolane structural analogues under physiological conditions at pH 7.4 results in rapid reduction of the artemisinins, and efficient conversion of the peroxide structural analogues into ketone products. Comparison of the relative rates of FADH(2) oxidation indicate optimal activity for the trioxolane. Therefore, the rate of intraparastic redox perturbation will be greatest for the trioxolane, and this may be significant in relation to its enhanced in vitro antimalarial activities. (1)H NMR spectroscopic studies using the BNAH-riboflavin (RF) model system indicate that the tetraoxane is capable of using both peroxide units in oxidizing the RFH(2) generated in situ. Use of the NADPH-Fre-FAD catalytic system in the presence of artemisinin or tetraoxane confirms that the latter, in contrast to artemisinin, consumes two reducing equivalents of NADPH. None of the processes described herein requires the presence of ferrous iron. Ferric iron, given its propensity to oxidize reduced flavin cofactors, may play a role in enhancing oxidative stress within the malaria parasite, without requiring interaction with artemisinins or peroxide analogues. The NADPH-Fre-FAD system serves as a convenient mimic of flavin disulfide reductases that maintain redox homeostasis in the malaria parasite.

  20. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

    Directory of Open Access Journals (Sweden)

    Newton Paul N

    2011-12-01

    Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

  1. General Pharmacology of Artesunate, a Commonly used Antimalarial Drug:Effects on Central Nervous, Cardiovascular, and Respiratory System.

    Science.gov (United States)

    Lee, Hyang-Ae; Kim, Ki-Suk; Kim, Eun-Joo

    2010-09-01

    Artesunate, a semi-synthetic derivative of artemisinin, is used primarily as a treatment for malaria. Its effects on the central nervous system, general behavior, and cardiovascular, respiratory, and other organ systems were studied using mice, rats, guinea pigs, and dogs. Artesunate was administered orally to mice at doses of 125, 250, and 500 mg/kg and to rats and guinea pigs at 100, 200, and 400 mg/kg. In dogs, test drugs were administered orally in gelatin capsules at doses of 50, 100, and 150 mg/kg. Artesunate induced insignificant changes in general pharmacological studies, including general behavior, motor coordination, body temperature, analgesia, convulsion modulation, blood pressure, heart rate (HR) , and electrocardiogram (ECG) in dogs in vivo; respiration in guinea pigs; and gut motility or direct effects on isolated guinea pig ileum, contractile responses, and renal function. On the other hand, artesunate decreased the HR and coronary flow rate (CFR) in the rat in vitro; however, the extent of the changes was small and they were not confirmed in in vivo studies in the dog. Artesunate increased hexobarbital-induced sleeping time in a dose-related manner. Artesunate induced dose-related decreases in the volume of gastric secretions and the total acidity of gastric contents, and induced increases in pH at a dose of 400 mg/kg. However, all of these changes were observed at doses much greater than clinical therapeutic doses (2.4 mg/kg in humans, when used as an anti-malarial) . Thus, it can be concluded that artesunate is safe at clinical therapeutic doses.

  2. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway.

    Directory of Open Access Journals (Sweden)

    Chang Cheng

    Full Text Available BACKGROUND: Phosphoinositide 3-kinase (PI3K/Akt pathway is linked to the development of asthma. Anti-malarial drug artesunate is a semi-synthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua, and has been shown to inhibit PI3K/Akt activity. We hypothesized that artesunate may attenuate allergic asthma via inhibition of the PI3K/Akt signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Female BALB/c mice sensitized and challenged with ovalbumin (OVA developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E-binding protein 1, and transactivation of NF-κB. Similarly, artesunate blocked the phosphorylation of Akt and its downstream substrates in lung tissues from OVA-challenged mice. Anti-inflammatory effect of artesunate was further confirmed in a house dust mite mouse asthma model. CONCLUSION/SIGNIFICANCE: Artesunate ameliorates experimental allergic airway inflammation probably via negative regulation of PI3K/Akt pathway and the downstream NF-κB activity. These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma.

  3. Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

    Energy Technology Data Exchange (ETDEWEB)

    Pashynska, Vlada, E-mail: vlada@vl.kharkov.ua [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Stepanian, Stepan [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Gömöry, Agnes; Vekey, Karoly [Institute of Organic Chemistry of Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar tudosok korutja, 2, Budapest H-1117 (Hungary); Adamowicz, Ludwik [University of Arizona, Department of Chemistry and Biochemistry, Tucson, AZ 85721 (United States)

    2015-07-09

    Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms.

  4. A new in vivo screening paradigm to accelerate antimalarial drug discovery.

    Directory of Open Access Journals (Sweden)

    María Belén Jiménez-Díaz

    Full Text Available The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR, which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0 of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1 or induce parasite clearance (PRR >1 with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a

  5. Drug resistance in malaria

    Directory of Open Access Journals (Sweden)

    S C Parija

    2011-01-01

    Full Text Available Antimalarial chemotherapy is an important component of all malaria control programmes throughout the world. This is especially so in light of the fact that there are no antimalarial vaccines which are available for clinical use at present. Emergence and spread of malaria parasites which are resistant to many of the available antimalarials today is, therefore, a major cause for concern. Till date, resistance to all groups of antimalarials excluding artemisinin has been reported. In recent years, in vitro resistance to even artemisinin has been described. While resistance to antibacterial agents has come to prominence as a clinical problem in recent years, antiparasitic resistance in general and antimalarial resistance in particular has not received much attention, especially in the Indian scenario. The present review deals with commonly used antimalarial drugs and the mechanisms of resistance to them. Various methods of detecting antimalarial resistance and avoiding the same have also been dealt with. Newer parasite targets which can be used in developing newer antimalarial agents and antimalarials obtained from plants have also been mentioned.

  6. Artemisinin and its derivatives in treating protozoan infections beyond malaria.

    Science.gov (United States)

    Loo, Cecilia Shi Ni; Lam, Nelson Siu Kei; Yu, Deying; Su, Xin-Zhuan; Lu, Fangli

    2017-03-01

    Parasitic protozoan diseases continue to rank among the world's greatest global health problems, which are also common among poor populations. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. Artemisinin (ART) and its derivatives are some of the most important classes of antimalarial agents originally derived from Artemisia annua L. However, besides the outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess activities against other parasitic protozoa. In this paper we review the activities of ART and its derivatives against protozoan parasites in vitro and in vivo, including Leishmania spp., Trypanosoma spp., Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fowleri, Cryptosporidium parvum, Giardia lamblia, and Babesia spp. We conclude that ART and its derivatives may be good alternatives for treating other non-malarial protozoan infections in developing countries, although more studies are necessary before they can be applied clinically.

  7. Availability and quality of anti-malarials among private sector outlets in Myanmar in 2012: results from a large, community-based, cross-sectional survey before a large-scale intervention.

    Science.gov (United States)

    Khin, Hnin Su Su; Chen, Ingrid; White, Chris; Sudhinaraset, May; McFarland, Willi; Littrell, Megan; Montagu, Dominic; Aung, Tin

    2015-07-14

    Global malaria control efforts are threatened by the spread and emergence of artemisinin-resistant Plasmodium falciparum parasites. In 2012, the widespread sale of partial courses of artemisinin-based monotherapy was suspected to take place in the highly accessed, weakly regulated private sector in Myanmar, posing potentially major threats to drug resistance. This study investigated the presence of artemisinin-based monotherapies in the Myanmar private sector, particularly as partial courses of therapy, to inform the targeting of future interventions to stop artemisinin resistance. A large cross-sectional survey comprised of a screening questionnaire was conducted across 26 townships in Myanmar between March and May, 2012. For outlets that stocked anti-malarials at the time of survey, a stock audit was conducted, and for outlets that stocked anti-malarials within 3 months of the survey, a provider survey was conducted. A total of 3,658 outlets were screened, 83% were retailers (pharmacies, itinerant drug vendors and general retailers) and 17% were healthcare providers (private facilities and health workers). Of the 3,658 outlets screened, 1,359 outlets (32%) stocked at least one anti-malarial at the time of study. Oral artemisinin-based monotherapy comprised of 33% of self-reported anti-malarials dispensing volumes found. The vast majority of artemisinin-based monotherapy was sold by retailers, where 63% confirmed that they sold partial courses of therapy by cutting blister packets. Very few retailers (5%) had malaria rapid diagnostic tests available, and quality-assured artemisinin-based combination therapy was virtually nonexistent among retailers. Informal private pharmacies, itinerant drug vendors and general retailers should be targeted for interventions to improve malaria treatment practices in Myanmar, particularly those that threaten the emergence and spread of artemisinin resistance.

  8. Applying green chemistry to the photochemical route to artemisinin.

    Science.gov (United States)

    Amara, Zacharias; Bellamy, Jessica F B; Horvath, Raphael; Miller, Samuel J; Beeby, Andrew; Burgard, Andreas; Rossen, Kai; Poliakoff, Martyn; George, Michael W

    2015-06-01

    Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else-solvents, photocatalyst and aqueous acid-can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.

  9. Applying green chemistry to the photochemical route to artemisinin

    Science.gov (United States)

    Amara, Zacharias; Bellamy, Jessica F. B.; Horvath, Raphael; Miller, Samuel J.; Beeby, Andrew; Burgard, Andreas; Rossen, Kai; Poliakoff, Martyn; George, Michael W.

    2015-06-01

    Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else—solvents, photocatalyst and aqueous acid—can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.

  10. Saleability of anti-malarials in private drug shops in Muheza, Tanzania

    DEFF Research Database (Denmark)

    Ringsted, Frank M; Massawe, Isolide S; Lemnge, Martha M;

    2011-01-01

    prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results......: All surveyed drug shops illicitly sold SP and quinine (QN), and legally amodiaquine (AQ). Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%), QN (11%) and ACT (2%). Conclusions: In community...... resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug...

  11. Prescription practices and availability of artemisinin monotherapy in India: where do we stand?

    Directory of Open Access Journals (Sweden)

    Mishra Neelima

    2011-12-01

    Full Text Available Abstract Background The World Health Organization has urged all member states to deploy artemisinin-based combination therapy and progressively withdraw oral artemisinin monotherapies from the market due to their high recrudescence rates and to reduce the risk of drug resistance. Prescription practices by physicians and the availability of oral artemisinin monotherapies with pharmacists directly affect the pattern of their use. Thus, treatment practices for malaria, with special reference to artemisinin monotherapy prescription, in selected states of India were evaluated. Methods Structured, tested questionnaires were used to conduct convenience surveys of physicians and pharmacists in eleven purposively selected districts across six states in 2008. In addition, exit interviews of patients with a diagnosis of uncomplicated malaria or a prescription for an anti-malarial drug were also performed. Logistic regression was used to determine patient clinical care, and institutional factors associated with artemisinin monotherapy prescription. Results Five hundred and eleven physicians from 196 health facilities, 530 pharmacists, and 1, 832 patients were interviewed. Artemisinin monotherapy was available in 72.6% of pharmacies and was prescribed by physicians for uncomplicated malaria in all study states. Exit interviews among patients confirmed the high rate of use of artemisinin monotherapy with 14.8% receiving such a prescription. Case management, i.e. method of diagnosis and overall treatment, varied by state and public or private sector. Treatment in the private sector (OR 8.0, 95%CI: 3.8, 17 was the strongest predictor of artemisinin monotherapy prescription when accounting for other factors. Use of the combination therapy recommended by the national drug policy, artesunate + sulphadoxine-pyrimethamine, was minimal (4.9%, with the exception of one state. Conclusions Artemisinin monotherapy use was widespread across India in 2008. The accessible

  12. Efficacy of artemisinin-based combination therapy for treatment of persons with uncomplicated Plasmodium falciparum malaria in West Sumba District, East Nusa Tenggara Province, Indonesia, and genotypic profiles of the parasite.

    NARCIS (Netherlands)

    Asih, P.B.; Dewi, R.M.; Tuti, S.; Sadikin, M.; Sumarto, W.; Sinaga, B.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    Reports on treatment failures associated with the use of first-and second-line antimalarial drugs chloroquine and sulfadoxine-pyrimethamine have recently increased in many parts of Indonesia. The present study evaluated artemisinin-based combination therapy for treatment of persons with

  13. Efficacy of artemisinin-based combination therapy for treatment of persons with uncomplicated Plasmodium falciparum malaria in West Sumba District, East Nusa Tenggara Province, Indonesia, and genotypic profiles of the parasite.

    NARCIS (Netherlands)

    Asih, P.B.; Dewi, R.M.; Tuti, S.; Sadikin, M.; Sumarto, W.; Sinaga, B.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    Reports on treatment failures associated with the use of first-and second-line antimalarial drugs chloroquine and sulfadoxine-pyrimethamine have recently increased in many parts of Indonesia. The present study evaluated artemisinin-based combination therapy for treatment of persons with uncomplicate

  14. Assessing the quality of anti-malarial drugs from Gabonese pharmacies using the MiniLab®: a field study.

    Science.gov (United States)

    Visser, Benjamin J; Meerveld-Gerrits, Janneke; Kroon, Daniëlle; Mougoula, Judith; Vingerling, Rieke; Bache, Emmanuel; Boersma, Jimmy; van Vugt, Michèle; Agnandji, Selidji T; Kaur, Harparkash; Grobusch, Martin P

    2015-07-15

    Recent studies alluded to the alarming scale of poor anti-malarial drug quality in malaria-endemic countries, but also illustrated the major geographical gaps in data on anti-malarial drug quality from endemic countries. Data are particularly scarce from Central Africa, although it carries the highest burden of malaria. The aim of this medicine quality field survey was to determine the prevalence of poor-quality anti-malarial drugs in Gabon. A field survey of the quality of anti-malarial drugs in Gabonese pharmacies was conducted using the Global Pharma Health Fund Minilab(®) tests, following the Medicine Quality Assessment Reporting Guidelines. Anti-malarial drugs were purchased randomly from selected pharmacies in Gabon. Semi-quantitative thin-layer chromatography (TLC) and disintegration testing were carried out to measure the concentration of active pharmaceutical ingredients (APIs). The samples failing the TLC test were analysed by high-performance liquid chromatography. Following the collection of anti-malarial drugs, a street survey was conducted to understand where people purchase their anti-malarial drugs. A total of 432 samples were purchased from 41 pharmacies in 11 cities/towns in Gabon. The prevalence of poor-quality anti-malarial drugs was 0.5% (95% CI 0.08-1.84%). Two out of 432 samples failed the MiniLab(®) semi-quantitative TLC test, of which a suspected artemether-lumefantrine (AL) sample was classified as falsified and one sulfadoxine-pyrimethamine (SP) sample as substandard. High performance liquid chromatography with ultraviolet photo diode array detection analysis confirmed the absence of APIs in the AL sample, and showed that the SP sample did contain the stated APIs but the amount was half the stated dose. Of the people interviewed, 92% (187/203) purchased their anti-malarial drugs at a pharmacy. Using the GPHF Minilab(®), the prevalence of poor-quality anti-malarial drugs is far lower than anticipated. The findings emphasize the need for

  15. In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

    Directory of Open Access Journals (Sweden)

    Birgit Viira

    2016-06-01

    Full Text Available Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

  16. In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.

    Science.gov (United States)

    Viira, Birgit; Gendron, Thibault; Lanfranchi, Don Antoine; Cojean, Sandrine; Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre; Maes, Louis; Maran, Uko; Loiseau, Philippe M; Davioud-Charvet, Elisabeth

    2016-06-29

    Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

  17. Operational strategies of anti-malarial drug campaigns for malaria elimination in Zambia's southern province: a simulation study.

    Science.gov (United States)

    Stuckey, Erin M; Miller, John M; Littrell, Megan; Chitnis, Nakul; Steketee, Rick

    2016-03-09

    Malaria elimination requires reducing both the potential of mosquitoes to transmit parasites to humans and humans to transmit parasites to mosquitoes. To achieve this goal in Southern province, Zambia a mass test and treat (MTAT) campaign was conducted from 2011-2013 to complement high coverage of long-lasting insecticide-treated nets (LLIN). To identify factors likely to increase campaign effectiveness, a modelling approach was applied to investigate the simulated effect of alternative operational strategies for parasite clearance in southern province. OpenMalaria, a discrete-time, individual-based stochastic model of malaria, was parameterized for the study area to simulate anti-malarial drug administration for interruption of transmission. Simulations were run for scenarios with a range of artemisinin-combination therapies, proportion of the population reached by the campaign, targeted age groups, time between campaign rounds, Plasmodium falciparum test protocols, and the addition of drugs aimed at preventing onward transmission. A sensitivity analysis was conducted to assess uncertainty of simulation results. Scenarios were evaluated based on the reduction in all-age parasite prevalence during the peak transmission month one year following the campaign, compared to the currently-implemented strategy of MTAT 19 % population coverage at pilot and 40 % coverage during the first year of implementation in the presence of 56 % LLIN use and 18 % indoor residual spray coverage. Simulation results suggest the most important determinant of success in reducing prevalence is the population coverage achieved in the campaign, which would require more than 1 year of campaign implementation for elimination. The inclusion of single low-dose primaquine, which acts as a gametocytocide, or ivermectin, which acts as an endectocide, to the drug regimen did not further reduce parasite prevalence one year following the campaign compared to the currently-implemented strategy

  18. Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs

    OpenAIRE

    Movellan, Julie; Urbán, Patricia; Moles, Ernest; de la Fuente, Jesús M.; Sierra, Teresa; Serrano, José Luis; Fernàndez-Busquets, Xavier

    2014-01-01

    It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest. With this objective, dendritic derivatives based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Pl...

  19. Ex vivo susceptibility of Plasmodium falciparum to antimalarial drugs in western, northern, and eastern Cambodia, 2011-2012: association with molecular markers.

    Science.gov (United States)

    Lim, Pharath; Dek, Dalin; Try, Vorleak; Eastman, Richard T; Chy, Sophy; Sreng, Sokunthea; Suon, Seila; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Ashley, Elizabeth A; Miotto, Olivo; Dondorp, Arjen M; White, Nicholas J; Su, Xin-zhuan; Char, Meng Chuor; Anderson, Jennifer M; Amaratunga, Chanaki; Menard, Didier; Fairhurst, Rick M

    2013-11-01

    In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated Plasmodium falciparum malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the ex vivo 50% inhibitory concentrations (IC50s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC50s (GMIC50s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P ≤ 0.001). An increased copy number of P. falciparum mdr1 (pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC50s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The ex vivo IC50 and pfmdr1 copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR P. falciparum is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance.

  20. Artemisinin-based combination therapies for uncomplicated malaria.

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    Davis, Timothy M E; Karunajeewa, Harin A; Ilett, Kenneth F

    2005-02-21

    There has been a relentless increase in resistance of malaria parasites to conventional antimalarial drugs, including chloroquine, sulfadoxine-pyrimethamine and mefloquine. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The World Health Organization has endorsed ACT as first-line treatment where the potentially life-threatening parasite Plasmodium falciparum is the predominant infecting species. ACTs combine the rapid schizontocidal activity of an artemisinin derivative (artesunate, artemether or dihydroartemisinin) with a longer-half-life partner drug. Although the use of chloroquine and sulfadoxine-pyrimethamine as partners in ACT improves their efficacy, this may only have value as a short-term measure in patients with a degree of immunity to malaria. Alternative currently available partner drugs include mefloquine, lumefantrine and piperaquine. Artesunate-mefloquine is highly effective but is expensive and side effects (mainly neurotoxicity) can be problematic. Artemether-lumefantrine, the only ACT available in Australia, appears less effective than artesunate-mefloquine and needs to be administered with food to ensure adequate bioavailability. Dihydroartemisinin-piperaquine is highly effective, well tolerated and relatively inexpensive. The goal of potent, safe, easy-to-administer and inexpensive ACTs may see trioxolanes in place of artemisinin derivatives, as well as novel partner drugs such as pyronaridine or naphthoquine, in the future.

  1. The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

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    van Eijk, Anna Maria; Sevene, Esperanca; Dellicour, Stephanie; Weiss, Noel S.; Emerson, Scott; Steketee, Richard; ter Kuile, Feiko O.; Stergachis, Andy

    2016-01-01

    Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24–0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31–1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27–3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77–1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79–1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37–1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews

  2. [Plasmodium falciparum susceptibility to antimalarial drugs: global data issued from the Pasteur Institutes international network].

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    Ménard, Didier; Ariey, Frédéric; Mercereau-Puijalon, Odile

    2013-01-01

    Malaria research units within the Institut Pasteur international network (RIIP-Palu) located in Africa, in South-East Asia and in South America, work for many years in close collaboration with the National malaria control programmes. Relying on technical platforms with well-equipped laboratories and scientific expertise, they are at the forefront of research on the antimalarial drug resistance by working together for training young scientists and developping similar protocols allowing comprehensive comparisons. Including fundamental and operational researches, they conduct regional and international projects which aim (1) to detect the emergence of antimalarial drugs resistant parasites and to evaluate their spatio-temporal distribution, (2) to develop in vitro and molecular tools, (3) to identify epidemiological factors involved in the emergence and the spread of antimalarial drugs resistant parasites and (4) to understand the molecular and cellular mechanisms implicated in resistance. In this review, will be presented methodological approaches and data obtained since 2000.

  3. Glycosides as possible lead antimalarial in new drug discovery: future perspectives.

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    Marya; Khan, Haroon; Ahmad, Izhar

    2017-01-15

    Malaria remains one of the major public health problems worldwide and is responsible for a large number of morbidity and mortality. Especially, in the third world countries, it is still alarming. The development of drug-resistant to Plasmodium falciparum strains has further degraded the overall situation. However, a limited number of effective drugs available emphasizes how essential it is to establish new anti-malarial compounds. New antimalarial agents with distinctive structures and mechanism of action from the natural origin are thus immediately required to treat sensitive and drug-resistant strains of malaria. over the years, phytopharmaceuticals have provided numerous lead compounds. Similarly, the success rate of botanicals in terms of clinical significance is also very high. Of them, glycosides is one of the most widely distributed and emerging class of plant secondary metabolites. This review provides an outlook to recently isolated glycosides from plants with marked antimalarial effects in an in-vitro and in-vivo protocols and thus ideal candidates for clinical trials to ascertain their clinical utility and or led compounds.

  4. Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

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    Menard Sandie

    2012-04-01

    Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a

  5. Fake anti-malarials: start with the facts.

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    Kaur, Harparkash; Clarke, Siȃn; Lalani, Mirza; Phanouvong, Souly; Guérin, Philippe; McLoughlin, Andrew; Wilson, Benjamin K; Deats, Michael; Plançon, Aline; Hopkins, Heidi; Miranda, Debora; Schellenberg, David

    2016-02-13

    This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting.

  6. Co-treatment with the anti-malarial drugs mefloquine and primaquine highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition.

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    Kim, Ju-Hwa; Choi, Ae-Ran; Kim, Yong Kee; Yoon, Sungpil

    2013-11-22

    The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs.

  7. In vitro antimalarial drug susceptibility in Thai border areas from 1998–2003

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    Mungthin Mathirut

    2005-08-01

    Full Text Available Abstract Background The Thai-Myanmar and Thai-Cambodia borders have been historically linked with the emergence and spread of Plasmodium falciparum parasites resistant to antimalarial drugs. Indeed, the areas are often described as harbouring multi-drug resistant parasites. These areas of Thailand have experienced significant changes in antimalarial drug exposure patterns over the past decade. This study describes the in vitro antimalarial susceptibility patterns of 95 laboratory-adapted P. falciparum isolates, collected between 1998 and 2003,. Methods Ninety five P. falciparum isolates were collected from five sites in Thailand between 1998 and 2003. After laboratory adaptation to in vitro culture, the susceptibility of these parasites to a range of established antimalarial drugs (chloroquine [CQ], mefloquine [MQ], quinine [QN] and dihydroartemisinin [DHA] was determined by the isotopic microtest. Results Mefloquine (MQ sensitivity remained poorest in areas previously described as MQ-resistant areas. Sensitivity to MQ of parasites from this area was significantly lower than those from areas reported to harbour moderate (p = 0.002 of low level MQ resistance (p = 000001. Importantly for all drugs tested, there was a considerable range in absolute parasite sensitivities. There was a weak, but statistically positive correlation between parasite sensitivity to CQ and sensitivity to both QN and MQ and a positive correlation between MQ and QN. In terms of geographical distribution, parasites from the Thai-Cambodia were tended to be less sensitive to all drugs tested compared to the Thai-Myanmar border. Parasite sensitivity to all drugs was stable over the 6-year collection period with the exception of QN. Conclusion This study highlights the high degree of variability in parasite drug sensitivity in Thailand. There were geographical differences in the pattern of resistance which might reflect differences in drug usage in each area. In contrast to many

  8. Factors determining anti-malarial drug use in a peri-urban population from malaria holoendemic region of western Kenya.

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    Watsierah, Carren A; Jura, Walter G Z O; Oyugi, Henry; Abong'o, Benard; Ouma, Collins

    2010-10-26

    Interventions to reverse trends in malaria-related morbidity and mortality in Kenya focus on preventive strategies and drug efficacy. However, the pattern of use of anti-malarials in malaria-endemic populations, such as in western Kenya, is still poorly understood. It is critical to understand the patterns of anti-malarial drug use to ascertain that the currently applied new combination therapy to malaria treatment, will achieve sustained cure rates and protection against parasite resistance. Therefore, this cross-sectional study was designed to determine the patterns of use of anti-malarial drugs in households (n = 397) in peri-urban location of Manyatta-B sub-location in Kisumu in western Kenya. Household factors, associated with the pattern of anti-malarials use, were evaluated. Using clusters, questionnaire was administered to a particular household member who had the most recent malaria episode (within malaria care and decrease malaria-related morbidity and mortality by increasing drug affordability, ensuring that the recommended anti-malarial drugs are easily available in all government approved drug outlets and educates the local shopkeepers on the symptoms and appropriate treatment of malaria. Following a switch to ACT in national drug policy, education on awareness and behaviour change is recommended, since the efficacy of ACT alone is not sufficient to reduce morbidity and mortality due to malaria.

  9. Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials.

    Science.gov (United States)

    Oliveira, Rudi; Guedes, Rita C; Meireles, Patrícia; Albuquerque, Inês S; Gonçalves, Lídia M; Pires, Elisabete; Bronze, Maria Rosário; Gut, Jiri; Rosenthal, Philip J; Prudêncio, Miguel; Moreira, Rui; O'Neill, Paul M; Lopes, Francisca

    2014-06-12

    The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.

  10. Synthesis of triazol derivatives of lupeol with potential antimalarial activity

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    Tatiane Freitas Borgati

    2012-06-01

    Full Text Available The goal of this project is synthesize and characterization of derivatives of lupeol and evaluated antimalarial activity. Historically, plants are important source of antimalarial medicines, highlighting quinine (1 (Figure 1, an important      alkaloid from the Cinchona calisaya bark. This compound was an important model for cloroquine  synthesis, a drug that was widely used in malaria treatment. In addition, one of the principal medicines used today is artemisinine, isolated from the Chinese plant Artemisia annua L (2 (Figure 1, and their semi synthetic derivatives (artesunate, artemeter, arteter. However, the malaria parasite has already shown resistance    to most of these current drugs and  the search for new candidates is essential. Lupeol (3 (Figura 1 is a compound that occurs in many plant species and discloses antimalarial, antiinflamatoryl and antitumoral activities. Considering its potential as a lead antimalarial molecule, we focused our work in the synthesis of new lupeol derivatives with increased antimalarial activity(scheme 1.

  11. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

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    S M D K Ganga Senarathna

    Full Text Available The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10(-6 cm/sec, followed by amodiaquine around 20 x 10(-6 cm/sec; both mefloquine and artesunate were around 10 x 10(-6 cm/sec. Methylene blue was between 2 and 6 x 10(-6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine.

  12. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation

    Science.gov (United States)

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  13. Why hospital pharmacists have failed to manage antimalarial drugs stock-outs in pakistan? A qualitative insight.

    Science.gov (United States)

    Malik, Madeeha; Hassali, Mohamed Azmi Ahmad; Shafie, Asrul Akmal; Hussain, Azhar

    2013-01-01

    Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital) and Rawalpindi (twin city). Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors' analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs.

  14. Why Hospital Pharmacists Have Failed to Manage Antimalarial Drugs Stock-Outs in Pakistan? A Qualitative Insight

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    Madeeha Malik

    2013-01-01

    Full Text Available Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital and Rawalpindi (twin city. Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors’ analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs.

  15. Maximizing antimalarial efficacy and the importance of dosing strategies.

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    Beeson, James G; Boeuf, Philippe; Fowkes, Freya J I

    2015-05-09

    Artemisinin-based combination therapies (ACTs) are the cornerstone for the treatment of malaria. However, confirmed resistance to artemisinins in South-East Asia, and reports of reduced efficacy of ACTs raise major concerns for malaria treatment and control. Without new drugs to replace artemisinins, it is essential to define dosing strategies that maximize therapeutic efficacy, limit the spread of resistance, and preserve the clinical value of ACTs. It is important to determine the extent to which reduced efficacy of ACTs reflects true resistance versus sub-optimal dosing, and quantify other factors that determine treatment failure. Pooled analyses of individual patient data from multiple clinical trials, by investigators in the Worldwide Antimalarial Resistance Network, have shown high overall efficacy for three widely used ACTs, artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine. Analyses also highlight that suboptimal dosing leads to increased risk of treatment failure, especially among children. In the most recent study, an analysis of clinical trials of artesunate-amodiaquine, widely used among children in Africa, revealed a superior efficacy for fixed-dose combination tablets compared to loose non-fixed dose combinations. This highlights the benefits of fixed-dose combinations as a practical strategy for ensuring optimal antimalarial dosing and maximizing efficacy. Please see related article: http://www.biomedcentral.com/1741-7015/13/66.

  16. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1 for antimalarial drug development

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    Roman Deniskin

    2016-04-01

    Full Text Available Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs. Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1. Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1 homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([3H]adenosine and pyrimidines ([3H]uridine, whereas wild type (fui1Δ yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM, compared to guanosine (14.9 μM and adenosine (142 μM. For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range. IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1. The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel

  17. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1) for antimalarial drug development.

    Science.gov (United States)

    Deniskin, Roman; Frame, I J; Sosa, Yvett; Akabas, Myles H

    2016-04-01

    Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs). Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1). Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1) homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([(3)H]adenosine) and pyrimidines ([(3)H]uridine), whereas wild type (fui1Δ) yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM), compared to guanosine (14.9 μM) and adenosine (142 μM). For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range). IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR) had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1). The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs) with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel antimalarial drugs

  18. Access to artemisinin combination therapy for malaria in remote areas of Cambodia

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    Socheat Doung

    2008-05-01

    Full Text Available Abstract Background Malaria-endemic countries are switching antimalarial drug policy to artemisinin combination therapies (ACTs and the global community are considering the setting up of a global subsidy mechanism in order to make them accessible and affordable. However, specific interventions may be needed to reach remote at-risk communities and to ensure that they are used appropriately. This analysis documents the coverage with ACTs versus artemisinin monotherapies, and the effectiveness of malaria outreach teams (MOTs and Village Malaria Workers (VMWs in increasing access to appropriate diagnosis and treatment with ACTs in Cambodia, the first country to switch national antimalarial drug policy to an ACT of artesunate and mefloquine (A+M in 2000. Methods A cross-sectional survey was carried out in three different types of intervention area: with VMWs, MOTs and no specific interventions. Individuals with a history of fever in the last three weeks were included in the study and completed a questionnaire on their treatment seeking and drug usage behaviour. Blood was taken for a rapid diagnostic test (RDT and data on the household socio-economic status were also obtained. Results In areas without specific interventions, only 17% (42/251 of respondents received a biological diagnosis, 8% (17/206 of respondents who received modern drug did so from a public health facility, and only 8% of them (17/210 received A+M. Worryingly, 78% (102/131 of all artemisinin use in these areas was as a monotherapy. However, both the VMW scheme and MOT scheme significantly increased the likelihood of being seen by a trained provider (Adjusted Odds Ratios (AOR of 148 and 4 respectively and of receiving A+M (AORs of 2.7 and 7.7 respectively. Conclusion The coverage rates of appropriate diagnosis and treatment of malaria were disappointingly low and the use of artemisinin monotherapy alarmingly high. This reflects the fragmented nature of Cambodia's health system in

  19. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    Directory of Open Access Journals (Sweden)

    Huthmacher Carola

    2010-08-01

    Full Text Available Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte. Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. Conclusions The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.

  20. Investigations of the effects of the antimalarial drug dihydroartemisinin (DHA) using the Frog Embryo Teratogenesis Assay-Xenopus (FETAX).

    Science.gov (United States)

    Longo, Monica; Zanoncelli, Sara; Della Torre, Paola; Rosa, Francesco; Giusti, AnnaMaria; Colombo, Paolo; Brughera, Marco; Mazué, Guy; Olliaro, Piero

    2008-08-01

    Artemisinin derivatives are effective and safe drugs for treating malaria, but they are not recommended during the first trimester of pregnancy because of resorptions and abnormalities observed in animal reproduction studies. Previous studies in rats showed that artemisinin embryotoxicity derives from the depletion of primitive red blood cells (RBCs) over a narrow critical time window (gestation Days 9-14). In order to further investigate the susceptibility of primitive RBCs to artemisinins and to establish whether this susceptibility is species-specific or inherent to the compound, we studied dihydroartemisinin (DHA), both a drug in its own right and the main metabolite of current artemisinin derivatives in use, in the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). This model readily allows investigation and monitoring of primitive and definitive RBCs. Effects on frog larvae exposed to DHA for 48 h during early embryonic development, starting from 24 h post fertilization, were similar to those on rat embryos in terms of reduction in the number of primitive RBCs (clonally produced within the ventral blood island). In contrast, RBCs of older larvae (stage 47, produced at the definitive sites of hematopoiesis) were affected minimally and subsequently recovered. Compared to rat embryos, the frog larvae had no areas of necrosis but they shared similar heart defects. The mitochondrion appeared to be the main subcellular target, similar to observations in Plasmodium. These results implicate artemisinin-induced embryotoxicity through perturbation of metabolically active RBCs; whereas this mode of action does not appear to be species-specific, the stages of susceptibility varied between different species. The window of susceptibility and duration of exposure must be considered to evaluate the clinical relevance of these findings.

  1. Increasing use of artemisinin-based combination therapy for treatment of malaria infection in Nigerian hospitals.

    Science.gov (United States)

    Igboeli, Nneka U; Ukwe, Chinwe V; Ekwunife, Obinna I

    2010-10-01

    This study aimed at describing the pattern of outpatient antimalarial drug prescribing in a secondary and a tertiary hospital, and to assess adherence to the National Antimalarial Treatment Guideline (ATG). An audit of antimalarial prescription files from the two health facilities for a period of six months in 2008 was conducted. Semi structured questionnaires were used to collect information from the doctors and pharmacists on their awareness and knowledge of the National Antimalarial Treatment Guideline. Artemisinin-based combination therapies (ACTs) were the most prescribed antimalarials. Overall, 81.4% of the total prescriptions contained ACTs, out of which 56.8% were artemetherlumefantrine. However, adherence to the drugs indicated by national guideline within the DU90% was 38.5% for the tertiary and 66.7 % for the secondary hospital. The standard practice of prescribing with generic name was still not adhered to as evidenced in the understudied hospitals. The percentage of health care providers that were aware of the ATG was 88.2% for doctors and 85.1% for pharmacists. However, 13.3% and 52.2% of doctors and pharmacists respectively could not properly list the drugs specified in the guideline. Amodiaquine was the most commonly preferred option for managing children aged 0 - 3 months with malaria infection against the indicated oral quinine. This study showed an increased use of artemisinin-based combination therapy for the treatment of uncomplicated malaria compared previous reports in Nigeria. This study also highlights the need for periodic in-service quality assurance among health professionals with monitoring of adherence to and assessment of knowledge of clinical guidelines to ensure the practice of evidence based medicine.

  2. Increasing use of artemisinin-based combination therapy for treatment of malaria infection in Nigerian hospitals

    Directory of Open Access Journals (Sweden)

    Igboeli NU

    2010-12-01

    Full Text Available Objectives: This study aimed at describing the pattern of outpatient antimalarial drug prescribing in a secondary and a tertiary hospital, and to assess adherence to the National Antimalarial Treatment Guideline (ATG. Methods: An audit of antimalarial prescription files from the two health facilities for a period of six months in 2008 was conducted. Semi structured questionnaires were used to collect information from the doctors and pharmacists on their awareness and knowledge of the National Antimalarial Treatment Guideline. Results: Artemisinin-based combination therapies (ACTs were the most prescribed antimalarials. Overall, 81.4% of the total prescriptions contained ACTs, out of which 56.8% were artemether-lumefantrine. However, adherence to the drugs indicated by national guideline within the DU90% was 38.5% for the tertiary and 66.7 % for the secondary hospital. The standard practice of prescribing with generic name was still not adhered to as evidenced in the understudied hospitals. The percentage of health care providers that were aware of the ATG was 88.2% for doctors and 85.1% for pharmacists. However, 13.3% and 52.2% of doctors and pharmacists respectively could not properly list the drugs specified in the guideline. Amodiaquine was the most commonly preferred option for managing children aged 0 – 3 months with malaria infection against the indicated oral quinine.Conclusion: This study showed an increased use of artemisinin-based combination therapy for the treatment of uncomplicated malaria compared previous reports in Nigeria. This study also highlights the need for periodic in-service quality assurance among health professionals with monitoring of adherence to and assessment of knowledge of clinical guidelines to ensure the practice of evidence based medicine.

  3. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

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    Gonzalez-Block Miguel A

    2005-10-01

    Full Text Available Abstract Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ with sulfadoxine-pyrimethamine (SP as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ. Research also indicated that since SP was also facing

  4. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug.

    Science.gov (United States)

    Mubyazi, Godfrey M; Gonzalez-Block, Miguel A

    2005-10-20

    Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. To describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania. In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ--the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend, the need for a more effective drug was

  5. Understanding the biology of the Plasmodium falciparum apicoplast; an excellent target for antimalarial drug development.

    Science.gov (United States)

    Chakraborty, Arnish

    2016-08-01

    Malaria is a life-threatening tropical disease, caused by the intracellular parasite Plasmodium falciparum. The World Health Organization counts malaria as one of the top ten causes of worldwide death. The unavailability of a successful malaria vaccine and the ever-increasing instances of drug resistance in the malaria parasite demand the discovery of new targets within P. falciparum for the development of next generation antimalarials. Fortunately, all apicomplexan parasites, including P. falciparum harbor a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is a semi-autonomous organelle within P. falciparum containing a 35kb circular genome. Despite a genome of its own, majority of the apicoplast proteins are encoded by the parasite nucleus and imported into the apicoplast. The organelle has been shown to be essential to P. falciparum survival and the loss the apicoplast manifests as a 'delayed death' response in the parasite. The apicoplast has evolved out of cyanobacteria in a complex, two step endosymbiotic event. As a result the architecture and the gene expression machinery of the apicoplast is quite bacteria-like and is susceptible to a wide range of antibiotics such as fosmidomycin, tetracycline, azithromycin, clindamycin and triclosan. The biosynthetic pathways for isoprenoids, fatty acids and heme operate within the malaria apicoplast, making the organelle an excellent target for drug development. The review focuses on the evolution, biology and the essentiality of the apicoplast within the malaria parasite and discusses some of the recent achievements towards the design and discovery of apicoplast targeted antimalarial compounds.

  6. Change in molecular weight due to important pfatp6 and pfmdr1 polymorphisms and susceptibility to antimalarial drug: Possible role of epigenetic phenomenon

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    Somsri Wiwanitkit

    2017-03-01

    Full Text Available Malaria is an important tropical mosquito borne infection. It is still the present global public health issue. The management of malaria requires antimalarial drugs. The resistance to antimalarial drugs is a very big problem. The genetic variant is proposed to be an important factor affecting susceptibility to antimalarial drug. Here, the authors studied the change in molecular weight due to important pfatp6 and pfmdr1 polymorphisms and further implied the interrelationship with susceptibility to antimalarial drug. The greatest change can be seen in case of G639D (of pfatp6 polymorphism while the least change can be seen in the case of N1042D (of pfmdr1 polymorphism. The results from some studies imply that there must be other factors that affect the susceptibility to antimalarial drugs. Those factors might be protein conformation factors, epigenetic factors or environmental factors. Further studies on these aspects should be carried out. It is concluded for possible role of epigenetic phenomenon.

  7. A cross-sectional study of the availability and price of anti-malarial medicines and malaria rapid diagnostic tests in private sector retail drug outlets in rural Western Kenya, 2013.

    Science.gov (United States)

    Kioko, Urbanus; Riley, Christina; Dellicour, Stephanie; Were, Vincent; Ouma, Peter; Gutman, Julie; Kariuki, Simon; Omar, Ahmeddin; Desai, Meghna; Buff, Ann M

    2016-07-12

    Although anti-malarial medicines are free in Kenyan public health facilities, patients often seek treatment from private sector retail drug outlets. In mid-2010, the Affordable Medicines Facility-malaria (AMFm) was introduced to make quality-assured artemisinin-based combination therapy (ACT) accessible and affordable in private and public sectors. Private sector retail drug outlets stocking anti-malarial medications within a surveillance area of approximately 220,000 people in a malaria perennial high-transmission area in rural western Kenya were identified via a census in September 2013. A cross-sectional study was conducted in September-October 2013 to determine availability and price of anti-malarial medicines and malaria rapid diagnostic tests (RDTs) in drug outlets. A standardized questionnaire was administered to collect drug outlet and personnel characteristics and availability and price of anti-malarials and RDTs. Of 181 drug outlets identified, 179 (99 %) participated in the survey. Thirteen percent were registered pharmacies, 25 % informal drug shops, 46 % general shops, 13 % homesteads and 2 % other. One hundred sixty-five (92 %) had at least one ACT type: 162 (91 %) had recommended first-line artemether-lumefantrine (AL), 22 (12 %) had recommended second-line dihydroartemisinin-piperaquine (DHA-PPQ), 85 (48 %) had sulfadoxine-pyrimethamine (SP), 60 (34 %) had any quinine (QN) formulation, and 14 (8 %) had amodiaquine (AQ) monotherapy. The mean price (range) of an adult treatment course for AL was $1.01 ($0.35-4.71); DHA-PPQ was $4.39 ($0.71-7.06); QN tablets were $2.24 ($0.12-4.71); SP was $0.62 ($0.24-2.35); AQ monotherapy was $0.42 ($0.24-1.06). The mean AL price with or without the AMFm logo did not differ significantly ($1.01 and 1.07, respectively; p = 0.45). Only 17 (10 %) drug outlets had RDTs; 149 (84 %) never stocked RDTs. The mean RDT price was $0.92 ($0.24-2.35). Most outlets never stocked RDTs; therefore, testing prior to

  8. Effect of antimalarial drugs on stimulation and interleukin 2 production of human lymphocytes

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Svenson, M; Theander, T G

    1987-01-01

    Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic...

  9. A review of age-old antimalarial drug to combat malaria:efficacy up-gradation by nanotechnology based drug delivery

    Institute of Scientific and Technical Information of China (English)

    Satyajit Tripathy; Somenath Roy

    2014-01-01

    Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades, any anti-malarial drug can able to eradicate completely till now. Many anti-malarial substances are practically ineffectual because of their physicochemical limitations, cytotoxicity, chemical instability and degradation, and limited activities against intracellular parasites.Taking into consideration, the amount of research is going to conduct in the field of nanoparticle based drug delivery systems, lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug applicationfor the opening out of novel chemotherapeutics in laboratory research, which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.

  10. Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar.

    Science.gov (United States)

    Thein, Si Thu; Sudhinaraset, May; Khin, Hnin Su Su; McFarland, Willi; Aung, Tin

    2016-06-22

    Artemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts. A cross-sectional survey of all types of private sector outlets that were stocking anti-malarial drugs in 13 townships of Eastern Myanmar was implemented from July to August 2014. A total of 573 outlets were included. Bivariate and multivariable logistic regressions were conducted to assess outlet and provider-level characteristics associated with stocking oral AMT. In total, 2939 outlets in Eastern Myanmar were screened for presence of any anti-malarial drugs in August 2014. The study found that 573 (19.5 %) had some kind of oral anti-malarial drug in stock at the time of survey and among them, 96 (16.8 %) stocked oral AMT. In bivariate analyses, compared to health care facilities, itinerant drug vendors, retailers and health workers were less likely to stock oral AMT (33.3 vs 12.9, 10.0, 8.1 %, OR = 0.30, 0.22, 0.18, respectively). Providers who cut blister pack or sell partial courses (40.6 vs 11.7 %, OR 5.18, CI 3.18-8.44) and those who based their stock decision on consumer demand (32.8 vs 12.1 %, OR 3.54, CI 2.21-5.63) were more likely to stock oAMT. Multivariate logistic regressions produced similar significant associations. Private healthcare facilities and drug

  11. Artemisinin concentration and antioxidant capacity of Artemisia annua distillation byproduct

    Science.gov (United States)

    Artemisia annua is mostly known as the source of artemisinin, the raw material for the production of artemisinin-based combination therapy, used against drug-resistant Plasmodium falciparum where malaria is endemic. Artemisinin drugs are also effective against helminthic and protozoan parasites tha...

  12. Antimalarial Drug Resistance: Surveillance and Molecular Methods for National Malaria Control Programmes

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    Umberto D'Alessandro

    1998-09-01

    Full Text Available National malaria control programmes have the responsibility to develop a policy for malaria disease management based on a set of defined criteria as efficacy, side effects, costs and compliance. These will fluctuate over time and national guidelines will require periodic re-assessment and revision. Changing a drug policy is a major undertaking that can take several years before being fully operational. The standard methods on which a decision can be taken are the in vivo and the in vitro tests. The latter allow a quantitative measurement of the drug response and the assessment of several drugs at once. However, in terms of drug policy change its results might be difficult to interpret although they may be used as an early warning system for 2nd or 3rd line drugs. The new WHO 14-days in vivo test addresses mainly the problem of treatment failure and of haematological parameters changes in sick children. It gives valuable information on whether a drug still `works'. None of these methods are well suited for large-scale studies. Molecular methods based on detection of mutations in parasite molecules targeted by antimalarial drugs could be attractive tools for surveillance. However, their relationship with in vivo test results needs to be established

  13. Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

    Science.gov (United States)

    Wright, Megan H.; Clough, Barbara; Rackham, Mark D.; Rangachari, Kaveri; Brannigan, James A.; Grainger, Munira; Moss, David K.; Bottrill, Andrew R.; Heal, William P.; Broncel, Malgorzata; Serwa, Remigiusz A.; Brady, Declan; Mann, David J.; Leatherbarrow, Robin J.; Tewari, Rita; Wilkinson, Anthony J.; Holder, Anthony A.; Tate, Edward W.

    2014-02-01

    Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

  14. Finding parasites and finding challenges: improved diagnostic access and trends in reported malaria and anti-malarial drug use in Livingstone district, Zambia

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    Masaninga Freddie

    2012-10-01

    Full Text Available Abstract Background Understanding the impact of malaria rapid diagnostic test (RDT use on management of acute febrile disease at a community level, and on the consumption of anti-malarial medicines, is critical to the planning and success of scale-up to universal parasite-based diagnosis by health systems in malaria-endemic countries. Methods A retrospective study of district-wide community-level RDT introduction was conducted in Livingstone District, Zambia, to assess the impact of this programmed on malaria reporting, incidence of mortality and on district anti-malarial consumption. Results Reported malaria declined from 12,186 cases in the quarter prior to RDT introduction in 2007 to an average of 12.25 confirmed and 294 unconfirmed malaria cases per quarter over the year to September 2009. Reported malaria-like fever also declined, with only 4,381 RDTs being consumed per quarter over the same year. Reported malaria mortality declined to zero in the year to September 2009, and all-cause mortality declined. Consumption of artemisinin-based combination therapy (ACT dropped dramatically, but remained above reported malaria, declining from 12,550 courses dispensed by the district office in the quarter prior to RDT implementation to an average of 822 per quarter over the last year. Quinine consumption in health centres also declined, with the district office ceasing to supply due to low usage, but requests for sulphadoxine-pyrimethamine (SP rose to well above previous levels, suggesting substitution of ACT with this drug in RDT-negative cases. Conclusions RDT introduction led to a large decline in reported malaria cases and in ACT consumption in Livingstone district. Reported malaria mortality declined to zero, indicating safety of the new diagnostic regime, although adherence and/or use of RDTs was still incomplete. However, a deficiency is apparent in management of non-malarial fever, with inappropriate use of a low-cost single dose drug, SP

  15. Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.

    Science.gov (United States)

    Green, Michael D; Nettey, Henry; Villalva Rojas, Ofelia; Pamanivong, Chansapha; Khounsaknalath, Lamphet; Grande Ortiz, Miguel; Newton, Paul N; Fernández, Facundo M; Vongsack, Latsamy; Manolin, Ot

    2007-01-04

    The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.

  16. [Research Progress on Artemisinin Resistance in Plasmodium falciparum].

    Science.gov (United States)

    Zhang, Yi-long; Pan, Wei-qing

    2015-12-01

    Artemisinin (ART) is a novel and effective antimalarial drug discovered in China. As recommended by the World Health Organization, the ART-based combination therapies (ACTs) have become the first-line drugs for the treatment of falciparum malaria. ART and its derivatives have contributed greatly to the effective control of malaria globally, leading to yearly decrease of malaria morbidity and mortality. However, there have recently been several reports on the resistance of Plasmodium falciparum to ART in Southeast Asia. This is deemed a serious threat to the global malaria control programs. In this paper, we reviewed recent research progress on ART resistance to P. falciparum, including new tools for resistance measurement, resistance-associated molecular markers, and the origin and spread of the ART-resistant parasite strains.

  17. Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

    Science.gov (United States)

    Howard, Brittany L.; Thompson, Philip E.; Manallack, David T.

    2011-08-01

    The similarity between Plasmodium falciparum phosphodiesterase enzymes ( PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

  18. Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence "transmission blocking" assay.

    Directory of Open Access Journals (Sweden)

    Joël Lelièvre

    Full Text Available BACKGROUND: Current anti-malarial drugs have been selected on the basis of their activity against the symptom-causing asexual blood stage of the parasite. Which of these drugs also target gametocytes, in the sexual stage responsible for disease transmission, remains unknown. Blocking transmission is one of the main strategies in the eradication agenda and requires the identification of new molecules that are active against gametocytes. However, to date, the main limitation for measuring the effect of molecules against mature gametocytes on a large scale is the lack of a standardized and reliable method. Here we provide an efficient method to produce and purify mature gametocytes in vitro. Based on this new procedure, we developed a robust, affordable, and sensitive ATP bioluminescence-based assay. We then assessed the activity of 17 gold-standard anti-malarial drugs on Plasmodium late stage gametocytes. METHODS AND FINDINGS: Difficulties in producing large amounts of gametocytes have limited progress in the development of malaria transmission blocking assays. We improved the method established by Ifediba and Vanderberg to obtain viable, mature gametocytes en masse, whatever the strain used. We designed an assay to determine the activity of antimalarial drugs based on the intracellular ATP content of purified stage IV-V gametocytes after 48 h of drug exposure in 96/384-well microplates. Measurements of drug activity on asexual stages and cytotoxicity on HepG2 cells were also obtained to estimate the specificity of the active drugs. CONCLUSIONS: The work described here represents another significant step towards determination of the activity of new molecules on mature gametocytes of any strain with an automated assay suitable for medium/high-throughput screening. Considering that the biology of the forms involved in the sexual and asexual stages is very different, a screen of our 2 million-compound library may allow us to discover novel anti-malarial

  19. The biological and clinical activity of anti-malarial drugs in autoimmune disorders.

    Science.gov (United States)

    Taherian, Elham; Rao, Anshul; Malemud, Charles J; Askari, Ali D

    2013-01-01

    Chloroquine and hydroxychloroquine are 4-aminoquinoline compounds commonly employed as anti-malarial drugs. Chloroquine and its synthetic analogue, hydroxychloroquine also belong to the disease-modifying anti-rheumatic drug class because these drugs are immunosuppressive. The immunosuppressive activity of chloroquine and hydroxychloroquine is likely to account for their capacity to reduce T-cell and B-cell hyperactivity as well as pro-inflammatory cytokine gene expression. This review evaluated experimental and clinical trials results as well as clinical response data relative to the use of chloroquine and/or hydroxychloroquine as first-line medical therapies in systemic lupus erythematosus, rheumatoid arthritis, primary Sjogren's syndrome, the anti-phospholipid syndrome and in the treatment of sarcoidosis. A primary outcomes measure in these clinical trials was the extent to which chloroquine and/or hydroxychloroquine reduced disease progression or exacerbations and/or the use and dosage of corticosteroids. The relative efficacy of chloroquine and hydroxychloroquine in modifying the clinical course of these autoimmune disorders is balanced against evidence that these drugs induce adverse effects which may reduce their use and effectiveness in the therapy of autoimmune disorders.

  20. Mass administration of the antimalarial drug mefloquine to Guantánamo detainees: a critical analysis.

    Science.gov (United States)

    Nevin, Remington L

    2012-10-01

    Recently, evidence has emerged from an unusual form of mass drug administration practised among detainees held at US Naval Station Guantánamo Bay, Cuba ('Guantánamo'), ostensibly as a public health measure. Mefloquine, an antimalarial drug originally developed by the US military, whose use is associated with a range of severe neuropsychiatric adverse effects, was administered at treatment doses to detainees immediately upon their arrival at Guantánamo, prior to laboratory testing for malaria and irrespective of symptoms of disease. In this analysis, the history of mefloquine's development is reviewed and the indications for its administration at treatment doses are discussed. The stated rationale for the use of mefloquine among Guantánamo detainees is then evaluated in the context of accepted forms of population-based malaria control. It is concluded that there was no plausible public health indication for the use of mefloquine at Guantánamo and that based on prevailing standards of care, the clinical indications for its use are decidedly unclear. This analysis suggests the troubling possibility that the use of mefloquine at Guantánamo may have been motivated in part by knowledge of the drug's adverse effects, and points to a critical need for further investigation to resolve unanswered questions regarding the drug's potentially inappropriate use.

  1. A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire

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    Toure Walamtchin

    2009-07-01

    Full Text Available Abstract Background Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL is highly effective and well-tolerated. Artemisinin/naphtoquine (AN is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast. Methods We enrolled 122 participants aged 6 months or more with uncomplicated falciparum malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. Results Among 125 participants enrolled, 123 (98.4% completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance. Interpretation These data suggest that Arco® could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.

  2. Synthesis of N11-anchoring biotinylated artemisinin derivatives and their preliminary biological assessment

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Unique endoperoxide moiety of artemisinin and its derivatives has been considered the functionality exhibiting highly potent antimalarial and anticancer activities.To investigate the mechanisms of their biological actions,development of suitable molecular probes including biotinylated derivatives is of extreme significance.The synthesis and preliminary biological assessment of four new biotinylated artemisinin derivatives have been reported in this work.

  3. Assessment of the efficacy of first-line antimalarial drugs after 5 years of deployment by the National Malaria Control Programme in Côte d'Ivoire

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    Offianan AT

    2011-11-01

    Full Text Available Andre T Offianan1, Serge B Assi2, Aristide MA Coulibaly1, Landry T N'guessan1, Aristide A Ako1, Florence K Kadjo2, Moïse K San2, Louis K Penali2 1Malariology Department, Institut Pasteur de Côte d'Ivoire, Abidjan, Côte d'Ivoire; 2National Malaria Control Programme, Abidjan, Côte d'Ivoire Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. Artesunate + amodiaquine (ASAQ and artemether-lumefantrine (AL are respectively the first- and second-line treatments for uncomplicated falciparum malaria in Côte d'Ivoire. A comparison of the efficacy and safety of these two drug combinations was necessary to make evidence-based drug treatment policies. Methods: In an open-label, non inferiority, randomized, controlled clinical trial, children aged 6–59 months were randomized to receive ASAQ or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rates and was defined as proportion of patients with polymerase chain reaction (PCR-corrected cure rate after 28 days of follow-up. Findings: A total of 251 patients who were attending the Ayame and Dabakala hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive ASAQ (128 and AL (123. The intention-to-treat analysis showed effectiveness rates of 94.5% and 93.5% for ASAQ and AL, respectively on day 28. After adjustment for PCR results, these rates were 96.1% and 96.8%, respectively. On day 28, the per-protocol analysis showed effectiveness rates of 98.4% and 96.6% for ASAQ and AL, respectively. After adjustment by PCR for reinfection, these rates were 100% for each drug, and both regimens were well tolerated. Conclusion: ASAQ and AL remain efficacious treatments of uncomplicated falciparum malaria in Ivorian children 5 years after adoption. The efficacy of ASAQ and AL in Côte d'Ivoire requires, therefore, continuous

  4. Detection, characterization, and screening of heme-binding molecules by mass spectrometry for malaria drug discovery

    NARCIS (Netherlands)

    Munoz-Durango, K.; Maciuk, A.; Harfouche, A.; Torijano-Gutierrez, S.; Jullian, J.C.; Quintin, J.; Spelman, K.; Mouray, E.; Grellier, P.; Figadere, B.

    2012-01-01

    Drug screening for antimalarials uses heme biocrystallization inhibition methods as an alternative to parasite cultures, but they involve complex processes and cannot detect artemisinin-like molecules. The described method detects heme-binding compounds by mass spectrometry, using dissociation of th

  5. Cost-effectiveness study of three antimalarial drug combinations in Tanzania.

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    Virginia Wiseman

    2006-10-01

    Full Text Available BACKGROUND: As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs. Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations. METHODS AND FINDINGS: An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ, AQ with sulfadoxine-pyrimethamine (AQ+SP, AQ with artesunate (AQ+AS, and artemether-lumefantrine (AL in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28. All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US1.70 dollars or a net saving of US22.40 dollars per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy. CONCLUSIONS: In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is

  6. Modeling the decomposition mechanism of artemisinin.

    Science.gov (United States)

    Moles, Pamela; Oliva, Mónica; Safont, Vicent S

    2006-06-08

    A theoretical study on artemisinin decomposition mechanisms is reported. The calculations have been done at the HF/3-21G and B3LYP/6-31G(d,p) theoretical levels, by using 6,7,8-trioxybicyclo[3.2.2]nonane as the molecular model for artemisinin, and a hydrogen atom, modeling the single electron transfer from heme or Fe(II) in the highly acidic parasite's food vacuole, as inductor of the initial peroxide bond cleavage. All relevant stationary points have been characterized, and the appearance of the final products can be explained in a satisfactory way. Several intermediates and radicals have been found as relatively stable species, thus giving support to the current hypothesis that some of these species can be responsible for the antimalarial action of artemisinin and its derivatives.

  7. Development of a TaqMan Allelic Discrimination Assay for detection of Single Nucleotides Polymorphisms associated with anti-malarial drug resistance

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    Kamau Edwin

    2012-01-01

    Full Text Available Abstract Background Anti-malarial drug resistance poses a threat to current global efforts towards control and elimination of malaria. Several methods are used in monitoring anti-malarial drug resistance. Molecular markers such as single nucleotide polymorphism (SNP for example are increasingly being used to identify genetic mutations related to anti-malarial drug resistance. Several methods are currently being used in analysis of SNP associated with anti-malarial drug resistance and although each one of these methods has unique strengths and shortcoming, there is still need to improve and/or develop new methods that will close the gap found in the current methods. Methods TaqMan Allelic Discrimination assays for detection of SNPs associated with anti-malarial drug resistance were designed for analysis on Applied Biosystems PCR platform. These assays were designed by submitting SNP sequences associated with anti-malarial drug resistance to Applied Biosystems website. Eleven SNPs associated with resistance to anti-malarial drugs were selected and tested. The performance of each SNP assay was tested by creating plasmid DNAs carrying codons of interests and analysing them for analysis. To test the sensitivity and specificity of each SNP assay, 12 clinical samples were sequenced at codons of interest and used in the analysis. Plasmid DNAs were used to establish the Limit of Detection (LoD for each assay. Results Data from genetic profiles of the Plasmodium falciparum laboratory strains and sequence data from 12 clinical samples was used as the reference method with which the performance of the SNP assays were compared to. The sensitivity and specificity of each SNP assay was establish at 100%. LoD for each assay was established at 2 GE, equivalent to less than 1 parasite/μL. SNP assays performed well in detecting mixed infection and analysis of clinical samples. Conclusion TaqMan Allelic Discrimination assay provides a good alternative tool in

  8. Drug: D02482 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02482 Drug Artesunate (USAN); Artesunic acid; Arsumax (TN) C19H28O8 384.1784 384.4...ODUCTS, INSECTICIDES AND REPELLENTS P01 ANTIPROTOZOALS P01B ANTIMALARIALS P01BE Artemisinin and derivatives, plain P01BE03 Artes...unate D02482 Artesunate (USAN) Antiinfectives [BR:br08307] Antiparasitics Antmalarials s...arcoplasmic/endoplasmic-reticulum Ca2+-ATPase (SERCA) inhibitor Artemisinin and derivatives Artes...unate [ATC:P01BE03] D02482 Artesunate (USAN) CAS: 88495-63-0 PubChem: 17396661 LigandBox: D0

  9. Vector incrimination and effects of antimalarial drugs on malaria transmission and control in the Amazon Basin of Brazil

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    T. A. Klein

    1992-01-01

    Full Text Available World ecosystems differ significantly and a multidisciplinary malaria control approach must be adjusted to meet these requirements. These include a comprehensive understanding of the malaria vectors, their behavior, seasonal distribution and abundance, susceptibility to insecticides (physiological and behavioral, methods to reduce the numbers of human gametocyte carriers through effective health care systems and antimalarial drug treatment, urban malaria transmission versus rural or forest malaria transmission, and the impact of vaccine development. Many malaria vectors are members of species complexes and individual relationship to malaria transmission, seasonal distribution, bitting behavior, etc. is poorly understood. Additionaly, malaria patients are not examined for circulating gametocytes and both falciparum and vivax malaria patients may be highly infective to mosquitoes after treatment with currently used antimalarial drugs. Studies on the physiological and behavioral effects of DDT and other insecticides are inconclusive and need to be evalusted.

  10. Genotyping of Plasmodium falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh

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    Akter Jasmin

    2012-11-01

    Full Text Available Abstract Background In the past many regions of Bangladesh were hyperendemic for malaria. Malaria control in the 1960s to 1970s eliminated malaria from the plains but in the Chittagong Hill Tracts remained a difficult to control reservoir. The Chittagong Hill Tracts have areas with between 1 and 10% annual malaria rates, predominately 90-95% Plasmodium falciparum. In Southeast Asia, multiplicity of infection for hypo-endemic regions has been approximately 1.5. Few studies on the genetic diversity of P. falciparum have been performed in Bangladesh. Anderson et al. performed a study in Khagrachari, northern Chittagong Hill Tracts in 2002 on 203 patients and found that parasites had a multiplicity of infection of 1.3 by MSP-1, MSP-2 and GLURP genotyping. A total of 94% of the isolates had the K76T Pfcrt chloroquine resistant genotype, and 70% showed the N86Y Pfmdr1 genotype. Antifolate drug resistant genotypes were high with 99% and 73% of parasites having two or more mutations at the dhfr or dhps loci. Methods Nested and real-time polymerase chain reaction (PCR methods were used to genotype P. falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh. Results The analysis of polymorphic and drug resistant genotype on 33 paired recrudescent infections after drug treatment in the period 2004 to 2008 in the Chittagong Hill Tracts, which is just prior to countrywide provision of artemisinin combination therapy. Overall the multiplicity of infection for MSP-1 was 2.7 with a slightly smaller parasite diversity post-treatment. The 13 monoclonal infections by both GLURP and MSP-1 were evenly divided between pre- and post-treatment. The MSP-1 MAD block was most frequent in 66 of the samples. The prevalence of the K76T PfCRT chloroquine resistant allele was approximately 82% of the samples, while the resistant Pfmdr1 N86Y was present in 33% of the samples. Interestingly, the post

  11. Ferroquine, an Ingenious Antimalarial Drug –Thoughts on the Mechanism of Action

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    Faustine Dubar

    2008-11-01

    Full Text Available Ferroquine (FQ or SR97193 is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. After fifteen years of effort, it is now possible to propose a multifactorial mechanism of action of FQ by its capacity to target lipids, to inhibit the formation of hemozoin and to generate reactive oxygen species.

  12. Genetic Transformation of Artemisia carvifolia Buch with rol Genes Enhances Artemisinin Accumulation.

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    Erum Dilshad

    Full Text Available The potent antimalarial drug artemisinin has a high cost, since its only viable source to date is Artemisia annua (0.01-0.8% DW. There is therefore an urgent need to design new strategies to increase its production or to find alternative sources. In the current study, Artemisia carvifolia Buch was selected with the aim of detecting artemisinin and then enhancing the production of the target compound and its derivatives. These metabolites were determined by LC-MS in the shoots of A. carvifolia wild type plants at the following concentrations: artemisinin (8μg/g, artesunate (2.24μg/g, dihydroartemisinin (13.6μg/g and artemether (12.8μg/g. Genetic transformation of A. carvifolia was carried out with Agrobacterium tumefaciens GV3101 harboring the rol B and rol C genes. Artemisinin content increased 3-7-fold in transgenics bearing the rol B gene, and 2.3-6-fold in those with the rol C gene. A similar pattern was observed for artemisinin analogues. The dynamics of artemisinin content in transgenics and wild type A.carvifolia was also correlated with the expression of genes involved in its biosynthesis. Real time qPCR analysis revealed the differential expression of genes involved in artemisinin biosynthesis, i.e. those encoding amorpha-4, 11 diene synthase (ADS, cytochrome P450 (CYP71AV1, and aldehyde dehydrogenase 1 (ALDH1, with a relatively higher transcript level found in transgenics than in the wild type plant. Also, the gene related to trichome development and sesquiterpenoid biosynthesis (TFAR1 showed an altered expression in the transgenics compared to wild type A.carvifolia, which was in accordance with the trichome density of the respective plants. The trichome index was significantly higher in the rol B and rol C gene-expressing transgenics with an increased production of artemisinin, thereby demonstrating that the rol genes are effective inducers of plant secondary metabolism.

  13. Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

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    Leslie Toby

    2008-12-01

    Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

  14. The role of antimalarial treatment in the elimination of malaria.

    Science.gov (United States)

    Gosling, R D; Okell, L; Mosha, J; Chandramohan, D

    2011-11-01

    With declining transmission of malaria in several regions of the world and renewed interest in the elimination of malaria, strategies for malaria control using antimalarial drugs are being revisited. Drug-based strategies to reduce transmission of malaria need to target the asymptomatic carriers of infection. Drugs that are effective against gametocytes are few in number, but it may be possible to reduce gametocyte production by killing the asexual stages, for which more drugs are available. Drugs for use in large-scale programmes must be safe and tolerable. Strategies include improving access to treatment for malaria with an efficacious drug, intermittent-treatment programmes, and mass drug administration, with and without screening for malaria. Recent proposals have targeted high-risk groups for interventions. None of the strategies has been rigorously tested with appropriate control groups for comparison. Because of the lack of field evidence, modelling has been used. Models have shown, first, that for long-lasting effects, drug administration programmes should be linked with vector control, and second, that if elimination is the aim, programmes are likely to be more successful when applied to smaller populations of a few thousand or less. In order to sustain the gains following the scaling up of vector control and use of artemisinin combination therapies (ACTs), strategies that use antimalarials effectively need to be devised and evidence generated for the most cost-efficient way forward.

  15. Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications

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    Chance Michael L

    2011-08-01

    Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum

  16. Plasmodium falciparum Polymorphisms associated with ex vivo drug susceptibility and clinical effectiveness of artemisinin-based combination therapies in Benin.

    Science.gov (United States)

    Dahlström, Sabina; Aubouy, Agnès; Maïga-Ascofaré, Oumou; Faucher, Jean-François; Wakpo, Abel; Ezinmègnon, Sèm; Massougbodji, Achille; Houzé, Pascal; Kendjo, Eric; Deloron, Philippe; Le Bras, Jacques; Houzé, Sandrine

    2014-01-01

    Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n = 96), fixed-dose artesunate-amodiaquine (n = 96), and sulfadoxine-pyrimethamine (n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex

  17. Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

    Science.gov (United States)

    Veiga, Maria Isabel; Osório, Nuno S; Ferreira, Pedro Eduardo; Franzén, Oscar; Dahlstrom, Sabina; Lum, J Koji; Nosten, Francois; Gil, José Pedro

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.

  18. Cyclosporin A in Membrane Lipids Environment: Implications for Antimalarial Activity of the Drug--The Langmuir Monolayer Studies.

    Science.gov (United States)

    Dynarowicz-Łątka, Patrycja; Wnętrzak, Anita; Makyła-Juzak, Katarzyna

    2015-12-01

    Cyclosporin A (CsA), a hydrophobic cyclic peptide produced by the fungus Tolypocladium inflatum, is well known for its high efficiency as an immunosuppressor for transplanted organs and anti-inflammatory properties; however, it is also active as antiparasitic (antimalarial) drug. Antimalarial mechanism of CsA action lacks a detailed understanding at molecular level. Due to a high lipophilicity of CsA, it is able to interact with lipids of cellular membrane; however, molecular targets of this drug are still unknown. To get a deeper insight into the mode of antimalarial activity of CsA, it is of utmost importance to examine its interactions with membrane components. To reach this goal, the Langmuir monolayer technique, which serves as a very useful, easy to handle and controllable model of biomembranes, has been employed. In this work, the interactions between CsA and main membrane lipids, i.e., cholesterol (Chol), 2-oleoyl-1-palmitoyl-3-phosphocholine (POPC), and sphingomyelin (SM), have been investigated. Attractive interactions are observed only for CsA mixtures with SM, while repulsive forces occur in systems containing remaining membrane lipids. Taking into consideration mutual interactions between membrane lipids (Chol-SM; Chol-POPC and SM-POPC), the behavior of CsA in model erythrocyte membrane of normal and infected cells has been analyzed. Our results prove strong affinity of CsA to SM in membrane environment. Since normal and parasitized erythrocytes differ significantly in the level of SM, this phospholipid may be considered as a molecular target for antimalarial activity of CsA.

  19. The challenge of artemisinin resistance can only be met by eliminating Plasmodium falciparum malaria across the Greater Mekong subregion.

    Science.gov (United States)

    Smith Gueye, Cara; Newby, Gretchen; Hwang, Jimee; Phillips, Allison A; Whittaker, Maxine; MacArthur, John R; Gosling, Roly D; Feachem, Richard G A

    2014-01-01

    Artemisinin-based combinations are currently the most effective anti-malarials and, in addition to vector control, have led to significant declines in malaria morbidity and mortality. However, foci of artemisinin drug resistance have been identified in the Greater Mekong subregion (GMS) of the Asia Pacific, threatening the major gains made in malaria control and potentially creating a parasite pool that is more difficult to treat and eliminate. Efforts are underway to halt the spread of artemisinin resistance, including coordination of activities and funding, and identification of areas of suspected artemisinin resistance, now using a newly identified molecular marker. However, targeting resources to the containment of resistant parasites is likely inefficient and monitoring impact is challenging. A more sustainable solution is the rapid elimination of all Plasmodium falciparum parasites from the GMS. This strategy is more efficient for several reasons. First, a subregional strategy is in line with current commitment to elimination and will build upon the existing national political support for elimination as well as enhancing collaboration among countries. Second, the challenge of human mobility in the GMS is subregional in scope and requires a harmonized elimination strategy. Third, countries will need to improve and intensify malaria operations to reach elimination, and this will be a singular goal across the subregion. Rallying around the goal of P. falciparum elimination will not only utilize existing regional bodies to catalyze political and funding support, but will also leverage the funding already in place to achieve this subregional goal.

  20. Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria

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    Jamsen Kris M

    2012-07-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is currently recommended as first-line treatment for uncomplicated malaria, but of concern, it has been observed that the effectiveness of the main artemisinin derivative, artesunate, has been diminished due to parasite resistance. This reduction in effect highlights the importance of the partner drugs in ACT and provides motivation to gain more knowledge of their pharmacokinetic (PK properties via population PK studies. Optimal design methodology has been developed for population PK studies, which analytically determines a sampling schedule that is clinically feasible and yields precise estimation of model parameters. In this work, optimal design methodology was used to determine sampling designs for typical future population PK studies of the partner drugs (mefloquine, lumefantrine, piperaquine and amodiaquine co-administered with artemisinin derivatives. Methods The optimal designs were determined using freely available software and were based on structural PK models from the literature and the key specifications of 100 patients with five samples per patient, with one sample taken on the seventh day of treatment. The derived optimal designs were then evaluated via a simulation-estimation procedure. Results For all partner drugs, designs consisting of two sampling schedules (50 patients per schedule with five samples per patient resulted in acceptable precision of the model parameter estimates. Conclusions The sampling schedules proposed in this paper should be considered in future population pharmacokinetic studies where intensive sampling over many days or weeks of follow-up is not possible due to either ethical, logistic or economical reasons.

  1. Low-cost, high-speed identification of counterfeit antimalarial drugs on paper.

    Science.gov (United States)

    Koesdjojo, Myra T; Wu, Yuanyuan; Boonloed, Anukul; Dunfield, Elizabeth M; Remcho, Vincent T

    2014-12-01

    With the emergence of artesunate antimalarial counterfeiting in Southeast Asia and sub-Saharan Africa, we present the production of a rapid, inexpensive and simple colorimetric-based testing kit for the detection of counterfeit artesunate in order to preserve life and prevent the development of multi-drug resistant malaria. The kit works based on paper microfluidics which offer several advantages over conventional microfluidics, and has great potential to generate inexpensive, easy-to-use, rapid and disposable diagnostic devices. Here, we have developed a colorimetric assay that is specific to artesunate and turns yellow upon addition of the sample. The test can be done within minutes, and allows for a semi-quantitative analysis of the artesunate tablets by comparing the developed yellow color on the paper test to a color-coded key chart that comes with the kit. A more accurate and precise analysis is done by utilizing a color analyzer on an iPhone camera that measures the color intensity of the developed color on the paper chip. A digital image of the chip was taken and analyzed by measuring the average gray intensity of the color developed on the paper circle. A plot of the artesunate concentration versus the average gray scale intensity was generated. Results show that the intensity of the yellow color developed on the paper test was consistent and proportional to the amount of artesunate present in the sample. With artesunate concentrations ranging from 0.0 to 20mg/mL, a linear calibration plot was obtained with a detection limit of 0.98 mg/mL.

  2. Anti-malarial drug quality in Lagos and Accra - a comparison of various quality assessments

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    Bate Roger

    2010-06-01

    Full Text Available Abstract Background Two major cities in West Africa, Accra, the capital of Ghana, and Lagos, the largest city of Nigeria, have significant problems with substandard pharmaceuticals. Both have actively combated the problem in recent years, particularly by screening products on the market using the Global Pharma Health Fund e.V. Minilab® protocol. Random sampling of medicines from the two cities at least twice over the past 30 months allows a tentative assessment of whether improvements in drug quality have occurred. Since intelligence provided by investigators indicates that some counterfeit producers may be adapting products to pass Minilab tests, the results are compared with those from a Raman spectrometer and discrepancies are discussed. Methods Between mid-2007 and early-2010, samples of anti-malarial drugs were bought covertly from pharmacies in Lagos on three different occasions (October 2007, December 2008, February 2010, and from pharmacies in Accra on two different occasions (October 2007, February 2010. All samples were tested using the Minilab® protocol, which includes disintegration and active ingredient assays as well as visual inspection, and most samples were also tested by Raman spectrometry. Results In Lagos, the failure rate in the 2010 sampling fell to 29% of the 2007 finding using the Minilab® protocol, 53% using Raman spectrometry, and 46% using visual inspection. In Accra, the failure rate in the 2010 sampling fell to 54% of the 2007 finding using the Minilab® protocol, 72% using Raman spectrometry, and 90% using visual inspection. Conclusions The evidence presented shows that drug quality is probably improving in both cities, especially Lagos, since major reductions of failure rates over time occur with all means of assessment. Many more samples failed when examined by Raman spectrometry than by Minilab® protocol. The discrepancy is most likely caused by the two techniques measuring different aspects of the medication

  3. Potentiation of antimalarial activity of arteether in combination with Vetiver root extract.

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    Dhawan, Sangeeta; Gunjan, Sarika; Pal, Anirban; Tripathi, Renu

    2016-05-01

    In malaria, development of resistance towards artemisinin derivatives has urged the need for new drugs or new drug combinations to tackle the drug resistant malaria. We studied the fresh root extract of Vetiver zizanioides (Linn.) Nash (VET) with a CDRI-CIMAP antimalarial α/β arteether (ART) together for their antimalarial potential. Our results showed additive to synergistic antimalarial activity of VET and ART with sum fractional inhibitory concentrations Σ FICs 1.02 ± 0.24 and 1.12 ± 0.32 for chloroquine sensitive (CQS) and chloroquine resistant (CQR) strain of Plasmodium falciparum (William H. Welch), respectively. Further, these combinations were explored against multidrug resistant rodent malaria parasite i.e. P. yoelii nigeriensis. Analysis of in vivo interaction of ART and VET showed that 10 mg/kg x 5 days of ART with 1000 mg/kg of VET x 5 days cured 100% mice infected with MDR parasite, while the same dose of ART could produce only up to 30% cure and VET fraction was not curative at all. Synergism/additiveness, found between VET and ART is reported for the first time. The curative dose of ART in the combination was reduced to its one fourth, and thus limits the side effects, if any. Although antimalarial potential of ART was enhanced by VET, action mechanism of later needs to be elucidated in detail.

  4. Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective

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    Dillip Angel

    2010-06-01

    Full Text Available Abstract Background To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP to artemether-lumefantrine (ALu in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania. Methods The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS and in Ifakara town. Data collection consisted of: 1 yearly censuses of shops selling drugs; 2 collection of monthly data on availability of anti-malarials in public health facilities; and 3 retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data. Results Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008 and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008 of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock, but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock, but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti-malarial

  5. Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective.

    Science.gov (United States)

    Alba, Sandra; Hetzel, Manuel W; Goodman, Catherine; Dillip, Angel; Liana, Jafari; Mshinda, Hassan; Lengeler, Christian

    2010-06-15

    To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO) was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu) in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania. The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS) and in Ifakara town. Data collection consisted of: 1) yearly censuses of shops selling drugs; 2) collection of monthly data on availability of anti-malarials in public health facilities; and 3) retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data. Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008) and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008) of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock), but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock), but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti-malarial sales) The public health and private retail

  6. The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review

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    Krettli Antoniana U

    2001-01-01

    Full Text Available In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae. Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

  7. Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria

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    Uzochukwu Benjamin

    2009-02-01

    Full Text Available Abstract Background There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. Methods The study was undertaken in six towns (three urban and three rural in Anambra state, south-east Nigeria. Anti-malarials (225 samples, which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP, quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC. Findings It was found that 60 (37% of the anti-malarials tested did not meet the United States Pharmacopoeia (USP specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46% and SP formulations (39% were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors. Conclusion This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs.

  8. Pattern of the Antimalarials Prescription during Pregnancy in Bangui, Central African Republic

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    Alexandre Manirakiza

    2011-01-01

    Full Text Available Introduction. The aim of this study was to identify the antimalarials prescribed during the pregnancy and to document their timing. Method. From June to September 2009, a survey was conducted on 565 women who gave birth in the Castors maternity in Bangui. The antenatal clinics cards were checked in order to record the types of antimalarials prescribed during pregnancy according to gestational age. Results. A proportion of 28.8% ANC cards contained at least one antimalarial prescription. The commonest categories of antimalarials prescribed were: quinine (56.7%, artemisinin-based combinations (26.8% and artemisinin monotherapy (14.4%. Among the prescriptions that occurred in the first trimester of pregnancy, artemisinin-based combinations and artemisinin monotherapies represented the proportions of (10.9% and (13.3%. respectively. Conclusion. This study showed a relatively high rate (>80% of the recommended antimalarials prescription regarding categories of indicated antimalarials from national guidelines. But, there is a concern about the prescription of the artemisinin derivatives in the first trimester of pregnancy, and the prescription of artemisinin monotherapy. Thus, the reinforcement of awareness activities of health care providers on the national malaria treatment during pregnancy is suggested.

  9. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    Energy Technology Data Exchange (ETDEWEB)

    Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N. E-mail: crist.filer@perkinelmer.com

    2002-09-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3-{sup 3}H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl-{sup 3}H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [{sup 3}H] ethyl iodide.

  10. Analysis of the electrochemical reactivity of natural hemozoin and {beta}-hemozoin in the presence of antimalarial drugs

    Energy Technology Data Exchange (ETDEWEB)

    Esteban Reyes-Cruz, Victor, E-mail: reyescruz16@yahoo.com [Area Academica de Ciencias de la Tierra y Materiales, Instituto de Ciencias Basicas e Ingenieria, Universidad Autonoma del Estado de Hidalgo (Mexico); Urbano Reyes, Gustavo, E-mail: gurbano2003@yahoo.com.mx [Area Academica de Ciencias de la Tierra y Materiales, Instituto de Ciencias Basicas e Ingenieria, Universidad Autonoma del Estado de Hidalgo (Mexico); Veloz Rodriguez, Maria Aurora, E-mail: maveloz70@yahoo.com.mx [Area Academica de Ciencias de la Tierra y Materiales, Instituto de Ciencias Basicas e Ingenieria, Universidad Autonoma del Estado de Hidalgo (Mexico); Imbert Palafox, Jose Luis, E-mail: imbertox@hotmail.com [Area Academica de Medicina, Instituto de Ciencias de la Salud, Universidad Autonoma del Estado de Hidalgo (Mexico)

    2011-11-30

    We report an evaluation of the reactivity of hemozoin (HZ) and {beta}-hemozoin ({beta}-HZ) obtained from the Triatoma Meccus longipennis, alone and in combination with quinine and amodiaquine. Using cyclic voltammetry and carbon paste electrodes, the redox processes that these compounds undergo were analysed. The results indicated that the atom Fe presence, the substance concentration, the drugs existence and the nature of the electrolytic medium are important in the redox processes. The strongest reactivity was for {beta}-HZ from Triatoma, which suggests that cellular molecules are embedded in an oxidising environment due to the presence of {beta}-HZ and indicates that like HZ, {beta}-HZ could be associate with phospholipid bilayers and interfere with their physical and chemical integrity, contributing to membrane breakdown and hyper-oxidation of molecules. It was further observed that when measuring the reactivity of HZ and {beta}-HZ with quinine and amodiaquine, a more oxidative stress was generated between the second one and the {beta}-HZ, which could explain the effectiveness of amodiaquine as a better antimalarial drug. Finally, it was concluded that electrochemical evaluation may be a convenient tool in determining the efficiency of antimalarial drugs and the identification of their redox processes.

  11. Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

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    Mpimbaza Arthur

    2008-06-01

    Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of

  12. Molecular evidence of increased resistance to anti-folate drugs in Plasmodium falciparum in North-East India: a signal for potential failure of artemisinin plus sulphadoxine-pyrimethamine combination therapy.

    Science.gov (United States)

    Mohapatra, Pradyumna Kishore; Sarma, Devojit Kumar; Prakash, Anil; Bora, Khukumoni; Ahmed, Md Atique; Sarma, Bibhas; Goswami, Basanta Kumar; Bhattacharyya, Dibya Ranjan; Mahanta, Jagadish

    2014-01-01

    North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant pfcrt genotype (76 T), while 68% had mutant pfmdr-1 genotype (86 Y). Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T) at dhps locus. Detection of quadruple mutants (51 I/59 R/108 N/164 L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine

  13. An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

    Science.gov (United States)

    Najer, Adrian; Wu, Dalin; Nussbaumer, Martin G.; Schwertz, Geoffrey; Schwab, Anatol; Witschel, Matthias C.; Schäfer, Anja; Diederich, François; Rottmann, Matthias; Palivan, Cornelia G.; Beck, Hans-Peter; Meier, Wolfgang

    2016-08-01

    Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL-1. Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (+/-)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.Medical applications of anticancer and antimalarial drugs often suffer from low aqueous

  14. Effect of transmission reduction by insecticide-treated bednets (ITNs on antimalarial drug resistance in western Kenya.

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    Monica Shah

    Full Text Available Despite the clear public health benefit of insecticide-treated bednets (ITNs, the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP and chloroquine (CQ in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250 and five years post-ITN intervention (year 5 survey, n = 242 were genotyped for single nucleotide polymorphisms (SNPs at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance, and pfcrt-76 and pfmdr1-86 (CQ resistance. The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria

  15. Drug resistant falciparum malaria and the use of artesunate-based combinations : focus on clinical trials sponsored by TDR

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    Walter R.J. Taylor, Jean Rigal & Piero L. Olliaro

    2003-09-01

    Full Text Available Antimalarial drug resistance has now become a serious global challenge and is the principal reasonfor the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficaciousdrugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rollingback malaria. Artemisinin-based combinations offer a new and potentially highly effective way tocounter drug resistance. Clinical trials conducted in African children have attested to the good tolerabilityof oral artesunate when combined with standard antimalarial drugs. The cure rates of thedifferent combinations were generally dependent on the degree of resistance to the companiondrug. They were high for amodiaquine-artesunate, variable for sulfadoxine/pyrimethamine-artesunate,and poor for chloroquine-artesunate.

  16. Longitudinal in vitro surveillance of Plasmodium falciparum sensitivity to common anti-malarials in Thailand between 1994 and 2010

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    Parker Daniel

    2012-08-01

    Full Text Available Abstract Background Drug and multidrug-resistant Plasmodium falciparum malaria has existed in Thailand for several decades. Furthermore, Thailand serves as a sentinel for drug-resistant malaria within the Greater Mekong sub-region. However, the drug resistance situation is highly dynamic, changing quickly over time. Here parasite in vitro drug sensitivity is reported for artemisinin derivatives, mefloquine, chloroquine and quinine, across Thailand. Methods Blood was drawn from patients infected with P. falciparum in seven sentinel provinces along Thai international borders with Cambodia, Myanmar, Laos, and Malaysia. In vitro parasite sensitivity was tested using the World Health Organization’s microtest (mark III (between 1994 and 2002 and the histidine-rich protein-2 (HRP2-based enzyme-linked immunosorbent assay (in 2010. Following World Health Organization protocol, at least 30 isolates were collected for each province and year represented in this study. Where possible, t-tests were used to test for significant differences. Results There appears to be little variation across study sites with regard to parasite sensitivity to chloroquine. Quinine resistance appears to have been rising prior to 1997, but has subsequently decreased. Mefloquine sensitivity appears high across the provinces, especially along the north-western border with Myanmar and the eastern border with Cambodia. Finally, the data suggest that parasite sensitivity to artemisinin and its derivatives is significantly higher in provinces along the north-western border with Myanmar. Conclusions Parasite sensitivity to anti-malarials in Thailand is highly variable over time and largely mirrors official drug use policy. The findings with regard to reduced sensitivity to artemisinin derivatives are supported by recent reports of reduced parasite clearance associated with artemisinin. This trend is alarming since artemisinin is considered the last defence against malaria. Continued

  17. A small-fish model for behavioral-toxicological screening of new antimalarial drugs: a comparison between erythro- and threo-mefloquine

    OpenAIRE

    Maaswinkel, Hans; Zhu, Liqun; Weng, Wei

    2015-01-01

    Background New antimalarial drugs need to be developed because over time resistance against the existing drugs develops. Furthermore, some of the drugs have severe side effects. Here we describe a behavioral small-fish model for early detection of neurotoxic effects of new drugs. As case example we compare the effects of two mefloquine diastereomers on the behavior of goldfish using an automated 3D tracking system. Findings In a preliminary experiment, the overall toxic effects in terms of mo...

  18. Subsidizing artemisinin-based combination therapies: a preliminary investigation of the Affordable Medicines Facility – malaria

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    Bate R

    2012-07-01

    Full Text Available Roger Bate,1,2 Kimberly Hess,2 Richard Tren,2 Lorraine Mooney,3 Franklin Cudjoe,4 Thompson Ayodele,5 Amir Attaran61American Enterprise Institute, Washington, DC, USA; 2Africa Fighting Malaria, Washington, DC, USA; 3Africa Fighting Malaria, Cambridge, United Kingdom; 4IMANI Center for Policy and Education, Accra, Ghana; 5Initiative for Public Policy Analysis, Lagos, Nigeria; 6University of Ottawa, Ottawa, ON, CanadaBackground: The Affordable Medicines Facility – malaria (AMFm is a subsidy mechanism to lower the price of, and hence increase access to, the best antimalarial medicines, artemisinin-based combination therapies (ACTs. While the AMFm stipulates that only quality-approved products are eligible for subsidy, it is not known whether those products, when actually supplied, are of good quality and comport with established pharmacopeial guidance on formulation and content of active ingredients. This study aimed to assess price and quality of AMFm ACTs, to compare AMFm ACTs with non-AMFm ACTs and artemisinin monotherapies, and to assess whether AMFm ACTs have been pilfered and diverted to a nearby country.Methods: In all, 140 artemisinin-based antimalarial drugs were acquired from 37 pharmacies in Lagos, Nigeria, and Accra, Ghana. An additional ten samples of AMFm ACTs were collected from Lomé, Togo (not participating in the AMFm. Samples were analyzed using high-performance liquid chromatography.Results: The AMFm ACTs were lower in price than many of the other drugs collected, but by less than anticipated or stipulated by the participating governments of Nigeria and Ghana. The quality of the AMFm ACTs was not universally good: overall, 7.7% had too little active pharmaceutical ingredient (API and none had too much – these results are not likely to be as a result of random chance. AMFm ACTs were also found to have been diverted, both to pharmacies in Lagos not participating in the AMFm and to a foreign city (Lomé where the AMFm is not

  19. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono district, Uganda

    DEFF Research Database (Denmark)

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony

    2013-01-01

    as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how much customers would be willing to pay for an RDT if offered in these settings. We conducted a contingent...... valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP) for an RDT...... for an RDT and a course of ACT among drug shop customers is considerably lower than prevailing and estimated end-user prices for these commodities. Increasing the uptake of ACTs in drug shops and restricting the sale of ACTs to parasitologically confirmed malaria will therefore require additional measures....

  20. Degradation of Artemisinin-Based Combination Therapies under Tropical Conditions

    Science.gov (United States)

    Hall, Zoe; Allan, Elizabeth Louise; van Schalkwyk, Donelly Andrew; van Wyk, Albert; Kaur, Harparkash

    2016-01-01

    Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. “Forced degradation” in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. “Natural aging” of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0–7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. PMID:26951346

  1. Food-borne trematodiasis: current chemotherapy and advances with artemisinins and synthetic trioxolanes.

    Science.gov (United States)

    Keiser, Jennifer; Utzinger, Jürg

    2007-11-01

    Over 40 million people are infected with food-borne trematodes and 750 million are at risk of food-borne trematodiasis, and yet this tropical disease is neglected. The current arsenal for the treatment and control of food-borne trematodiasis comprises praziquantel and triclabendazole, which were developed 20-30 years ago. The safety, therapeutic profiles and concern about resistance of these two drugs are summarized here. Recent advances with the artemisinins, which are best known for their antimalarial and antischistosomal properties, and the synthetic trioxolanes in different trematode-rodent models are reviewed. Lastly, prospects for the development of a safe, efficacious, inexpensive and broad-spectrum trematocidal drug are considered.

  2. Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.

    Science.gov (United States)

    Pieroni, Marco; Azzali, Elisa; Basilico, Nicoletta; Parapini, Silvia; Zolkiewski, Michal; Beato, Claudia; Annunziato, Giannamaria; Bruno, Agostino; Vacondio, Federica; Costantino, Gabriele

    2017-03-09

    Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.

  3. Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparum isolates after the change of anti-malarial drug treatment policy.

    Science.gov (United States)

    Duah, Nancy O; Matrevi, Sena A; de Souza, Dziedzom K; Binnah, Daniel D; Tamakloe, Mary M; Opoku, Vera S; Onwona, Christiana O; Narh, Charles A; Quashie, Neils B; Abuaku, Benjamin; Duplessis, Christopher; Kronmann, Karl C; Koram, Kwadwo A

    2013-10-30

    With the introduction of artemisinin-based combination therapy (ACT) in 2005, monitoring of anti-malarial drug efficacy, which includes the use of molecular tools to detect known genetic markers of parasite resistance, is important for first-hand information on the changes in parasite susceptibility to drugs in Ghana. This study investigated the Plasmodium falciparum multidrug resistance gene (pfmdr1) copy number, mutations and the chloroquine resistance transporter gene (pfcrt) mutations in Ghanaian isolates collected in seven years to detect the trends in prevalence of mutations. Archived filter paper blood blots collected from children aged below five years with uncomplicated malaria in 2003-2010 at sentinel sites were used. Using quantitative real-time polymerase chain reaction (qRT-PCR), 756 samples were assessed for pfmdr1 gene copy number. PCR and restriction fragment length polymorphism (RFLP) were used to detect alleles of pfmdr1 86 in 1,102 samples, pfmdr1 184, 1034, 1042 and 1246 in 832 samples and pfcrt 76 in 1,063 samples. Merozoite surface protein 2 (msp2) genotyping was done to select monoclonal infections for copy number analysis. The percentage of isolates with increased pfmdr1 copy number were 4, 27, 9, and 18% for 2003-04, 2005-06, 2007-08 and 2010, respectively. Significant increasing trends for prevalence of pfmdr1 N86 (×(2) = 96.31, p resistance has been reported. The decreasing trend in the prevalence of chloroquine resistance markers after change of treatment policy presents the possibility for future introduction of chloroquine as prophylaxis for malaria risk groups such as children and pregnant women in Ghana.

  4. Investigating South African plants as a source of new antimalarial drugs

    CSIR Research Space (South Africa)

    Pillay, P

    2008-10-01

    Full Text Available ; Izbosarov et al., 2000) but this (Pillay et al., 2007b) was the first report of any of them having antiplasmodial properties. Salvia species (sage) is well known as a folk-medicine and is used to treat fevers and digestive disorders in South Africa... antimalarial (Lopes et al., 1999) and cytotoxic properties (van Zyl and Viljoen, 2003). In a recent follow-up study (Kamatou et al., 2008) solvent extracts of seventeen Salvia species (Lamiaceae) used in traditional medicine in South Africa were...

  5. Antimalarial drug resistance of Plasmodium falciparum in India: changes over time and space

    OpenAIRE

    Shah, Naman K.; Dhillon, Gajender P S; Dash, Adtiya P; Arora, Usha; Meshnick, Steven R.; Valecha, Neena

    2011-01-01

    After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965. However, the initial success could not be maintained and a resurgence of malaria began in the late 1960s. Resistance of Plasmodium falciparum to chloroquine was first reported in 1973 and increases in antimalarial resistance, along with rapid urbanisation and labour migration, complicated the challenge that India’s large geographical...

  6. Is primaquine useful and safe as true exo-erythrocytic merontocidal, hypnozoitocidal and gametocidal antimalarial drug?

    Directory of Open Access Journals (Sweden)

    Francisco Javier López-Antuñano

    1999-10-01

    Full Text Available The main objective of this paper is to make available in a single document, a sequence of events that have been published on the biology of malaria parasites and their interaction with the human host, looking for arguments for effective and save treatment: what we know and what we would like to know about the effects of primaquine in order to justify its use in clinical and public health practice. The practicioner should be aware that the antimalarial activity, hemolytic and methemoglobinemic side effects, and detoxification of primaquine are all thought to depend on various biotransformation products of the drug. In spite of the universal use during over six decades, their site and mechanism of formation and degradation and their specific biologic effects remain very poorly understood in human beings. The mature gametocytes of P. falciparum are naturally resistant to chloroquine and other blood merontocides, but they are usually eliminated with a single dose of 1.315 mg/kg per os (p.o. of primaquine phosphate (equivalent to 0.75 mg-base. Rather than empirically, related with relapses frequency, dosage schedules should only be determined through consideration of the kinetics and dynamics of the drug and its effect on sporozoites, pre and exo-erythrocytic merontes, hypnozoites and gametocytes of P. vivax. Where medical care services are not available or not capable to detect glucose -6- phosphate dehydrogenese- (G-6-PD deficiencies and deleterious effects of the drug, we recommend not to use primaquine. Both, P. vivax primary clinical attack and P. vivax relapses, as and when they occur should be treated with a course of 10 mg/kg chloroquine-base p.o. Prevention of relapses is probably related to strain characteristics of P. vivax hypnozoites populations envolved. If well informed and qualified medical care workers decide to use primaquine in the absence of enzime defficiencies and are able to follow-up the clinical, toxicological and parasitic

  7. Temperature-dependent toxicity of artemisinin toward the macrophyte Lemna minor and the algae Pseudokirchneriella subcapitata

    DEFF Research Database (Denmark)

    Jessing, Karina Knudsmark; Andresen, Marianne; Cedergreen, Nina

    2014-01-01

    Artemisinin, an antimalarial compound derivated from the cultivated plant Artemisia annua L., is produced in situ through cultivation of A. annua under different climatic conditions. The bioactive compound artemisinin has been observed to spread to the surroundings as well as to leach to surface-...

  8. Prevalence of malaria parasitemia and purchase of artemisinin-based combination therapies (ACTs among drug shop clients in two regions in Tanzania with ACT subsidies.

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    Melissa A Briggs

    Full Text Available BACKGROUND: Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs, a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. METHOD AND FINDINGS: A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6-18%. Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was 5 years, experience (aOR: 2.8; 95% CI: 1.2-6.3. Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5-7.4. CONCLUSION: Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops.

  9. Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development.

    Science.gov (United States)

    Paddon, Chris J; Keasling, Jay D

    2014-05-01

    Recent developments in synthetic biology, combined with continued progress in systems biology and metabolic engineering, have enabled the engineering of microorganisms to produce heterologous molecules in a manner that was previously unfeasible. The successful synthesis and recent entry of semi-synthetic artemisinin into commercial production is the first demonstration of the potential of synthetic biology for the development and production of pharmaceutical agents. In this Review, we describe the metabolic engineering and synthetic biology approaches that were used to develop this important antimalarial drug precursor. This not only demonstrates the incredible potential of the available technologies but also illuminates how lessons learned from this work could be applied to the production of other pharmaceutical agents.

  10. The ACTwatch project: methods to describe anti-malarial markets in seven countries

    Directory of Open Access Journals (Sweden)

    Chapman Steven

    2011-10-01

    Full Text Available Abstract Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT and malaria diagnostics including rapid diagnostic tests (RDTs. To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the

  11. Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

    Science.gov (United States)

    2016-01-01

    The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work. PMID:27800551

  12. LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma.

    Science.gov (United States)

    Aziz, Mohd Yusmaidie; Hoffmann, Kurt-Jürgen; Ashton, Michael

    2017-09-15

    This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma. Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9-2508nM with a runtime of 7.0min per sample. The method was applied to clinical samples from healthy volunteers. This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo. Copyright © 2017. Published by Elsevier B.V.

  13. Effects of the combined artesunate and mefloquine antimalarial drugs on rat embryos.

    Science.gov (United States)

    Boareto, A C; Müller, J C; Lourenço, E L B; Lombardi, N; Lourenço, A C; Rabitto, I; de Morais, R N; Rios, F S; Dalsenter, P R

    2013-09-01

    Artemisinins combination therapy (ACT) is the first choice therapy for falciparum malaria. Data on the safety of ACTs in pregnancy are limited and controversial and the use is not recommended on the first trimester. To evaluate the effects of isolated and combined artesunate (AS)/mefloquine (MQ) on embryo rats, pregnant rats were treated orally with AS (15 and 40 mg/kg body weight (bwt)/day), MQ (30 and 80 mg/kg bwt/day) and AS/MQ (15/30 and 40/80 mg/kg bwt/day) on days 9-11 post coitum (pc). The dams were euthanized on day 12 pc and gestational and embryos histological parameters were evaluated. Embryolethality and histopathological anomalies were significant when AS was given alone or combined with MQ. Combination of AS and MQ did not enhance their toxicity compared to their separate administrations; on the other side, there was a reduction in the toxic effects of the AS when combined with MQ. Isolated MQ did not induce developmental toxicity.

  14. Analysis on the Application and Development of Antimalarials Drugs%抗疟药物的应用与发展

    Institute of Scientific and Technical Information of China (English)

    张楠

    2016-01-01

    人类在抗疟药物的应用过程中,先后经历了蚊帐、纱窗、巫术、中草药等传统办法,由金鸡纳树皮的疗效促使了奎宁、氯喹的产生,以及DDT杀虫剂和青蒿素类药物的使用,上述治疗手段和方法都对控制疟疾的传播扩散发挥了重要作用。本文通过回顾这些抗疟药物应用历程的同时,以期展望该领域的发展前景和未来趋势。%In the history, human used several ways, such as mosquito nets, screens, witchcraft, Chinese herbal medicine and other traditional ways, and due to the curative effect of cinchona bark, human find quinine and chloroquine, later, the pesticide DDT and arte-misinin drugs also can be found.All of them played an important role to control the spread of malaria.This paper is overviewed how many treatments and methods which by human used and found, and its development is also prospected.

  15. Clinical development of new prophylactic antimalarial drugs after the 5th Amendment to the Declaration of Helsinki.

    Science.gov (United States)

    Dow, Geoffrey S; Magill, Alan J; Ohrt, Colin

    2008-08-01

    Malaria is of continuing concern in nonimmune traveling populations. Traditionally, antimalarial drugs have been developed as agents for dual indications (treatment and prophylaxis). However, since 2000, when the 5th Amendment to the Declaration of Helsinki (DH2000) was adopted, development of new malaria prophylaxis drugs in this manner has ceased. As a consequence, there may not be any new drugs licensed for this indication in the foreseeable future. Major pharmaceutical companies have interpreted DH2000 to mean that the traditional development paradigm may be considered unethical because of doubt over the likelihood of benefit to endemic populations participating in clinical studies, the use of placebo, and the sustainability of post-trial access to study medications. In this article, we explore the basis of these concerns and suggest that the traditional development paradigm remains ethical under certain circumstances. We also consider alternative approaches that may be more attractive to sponsors as they either do not use placebo, or utilize populations in endemic countries who may unambiguously benefit. These approaches represent the way forward in the future, but are at present unproven in clinical practice, and face numerous regulatory, logistical and technical challenges. Consequently, in the short term, we argue that the traditional clinical development paradigm remains the most feasible approach and is ethical and consistent with the spirit of DH2000 under the appropriate circumstances.

  16. Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos, Nigeria.

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    Chimere Obiora Agomo

    Full Text Available The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1 and type 1 antifolate antimalarial medicines (Pfdhfr.Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72-76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt gene by real time polymerase chain reaction (PCR using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1 gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.Two haplotypes of Pfcrt (n = 54 were observed: CVMNK 13(24.2% and CVIET 41 (75.9% of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28 haplotypes were NYSND 15(53.6%, YYSND 5(17.9%, NFSND 6(21.4% and YFSND 2(7.1%. The Pfdhfr (n = 15 were ACNCSVI 4(26.7%, and ACICNSVI 1(6.7% and ACIRNVI 10 (66.7%. The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Y and 184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024 while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006. The median parasitaemia were similar (P>0.05 in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt

  17. Anti-malarial drug safety information obtained through routine monitoring in a rural district of South-Western Senegal

    Directory of Open Access Journals (Sweden)

    Brasseur Philippe

    2012-12-01

    Full Text Available Abstract Background Knowing the safety profile of anti-malarial treatments in routine use is essential; millions of patients receive now artemisinin combination therapy (ACT annually, but the return on information through current systems is as yet inadequate. Cohort event monitoring (CEM is a WHO (World Health Organization-recommended practice; testing its performance and feasibility in routine practice in malaria-endemic is important. Methods A nine-year CEM-based study of the safety of artesunate-amodiaquine (ASAQ at five peripheral health facilities in a rural district of South-western Senegal. Staff (nurses, health workers were trained to collect actively and systematically information on the patient, treatment and events on a purposely designed questionnaire. The occurrence and severity of events was collected before, during and after treatment up to 28 days in order to generate information on all adverse events (AEs as well as treatment-emerging signs/symptoms (TESS. Laboratory tests (haematology, liver and renal was planned for at least 10% of cases. Results During 2001–2009, 3,708 parasitologically-confirmed malaria cases (mean age = 16.0 ± 12.7 years were enrolled (26% and 52% of all and parasitologically-confirmed ASAQ treatments, respectively. Treatment was supervised in 96% of cases. Products changed over time: 49% were a loose combination of individually-packaged products (available 2001–03, 42% co-blistered products (2004–09 and 9% a fixed-dose co-formulation (2006–09; dosing was age-based for 42%, weight-based for 58%. AS and AQ were correctly dosed in 97% and 82% of cases with the loose and 93% and 86% with the fixed combination, but only 50% and 42% with the co-blistered product. Thirty-three per cent (33% of patients had at least one sign/symptom pre-treatment, 12% had at least one AE and 9% a TESS (total events 3,914, 1,144 and 693, respectively. AEs overestimated TESS by 1.2-2 fold (average 1.7. Changes in

  18. Effect of antimalarial drugs on the bioavailability of the methylenediphosphonic acid labeled with technetium99m (99mTc-MDP in Wistar rats

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    Cecília Maria de Carvalho Xavier Holanda

    2006-03-01

    Full Text Available The aim of this work was to study the effect of antimalarial drugs on the bioavailability of 99mTc-MDP in rats. Mefloquine (MQ and artemisinin (AM were administered in two treated groups (T and sorbitol in control group (C for 7 days. Then, 99mTc-MDP was injected in all groups and %ATI was calculated. A significant increase of %ATI in MQ group, from C to T, occurred in spleen (0.35±0.10to0.58±0.13, liver (1.69±0.28to3.31±0.07 and blood (0.79±0.17to2.09±0.53. The %ATI increased significantly in AM group:femur (2.76±0.59to5.98±0.70, liver (1.69±0.28to4.59±0.68, lungs (0.29±0.05to6.22±0.86, spleen (0.35±0.10 to0.86±0.15 and blood (0.79±0.17 to4.65 ±0.74. A significant decrease of %ATI occurred in MQ group:bladder (0.75±0.07to0.26±0.05, stout bowel (2.13±0.34to0.66±0.19, pancreas (0.87±0.24to0.28±0.18, kidneys (7.00±1.52to3.46±0.62, brain (0.27±0.08to 0.05±0.01 and also in AM group:bladder (0.75±0.07to0.30±0.05, stout bowel (2.13±0.34to0.36±0.08, muscle (2.04±0.39to0.26±0.06, pancreas (0.87±0.24to0.46±0.12 and kidneys (7.00±1.52to4.35±0.28. These results could be associated to biological effects of antimalarial drugs.Há evidências que algumas drogas usadas para doenças humanas podem modificar a biodisponibilidade de radiofármacos. Nós estudamos o efeito de drogas antimaláricas na biodisponibilidade do 99mTc-MDP em ratos. Mefloquina (MQ e artemisinina (AM foram administradas em dois grupos tratados (T e sorbitol no grupo controle (C por 7 dias. Em seguida, 99mTc-MDP foi injetado em todos os grupos e o %ATI foi calculado. Um aumento significativo do %ATI no grupo da MQ, do controle para o tratado, ocorreu no baço (0,35±0,10 para 0,58±0,13, fígado (1,69±0,28 para 3,31±0,07 e sangue (0,79±0,17 para 2,09±0,53. O %ATI aumentou significantemente no grupo da AM: no fêmur (2,76±0,59 para 5,98±0,70, fígado (1,69±0,28 para 4,59±0,68, pulmões (0,29±0,05 para 6,22±0,86, no baço (0,35±0,10 para 0,86±0

  19. The antimalarial drug mefloquine inhibits cardiac inward rectifier K+ channels: evidence for interference in PIP2-channel interaction.

    Science.gov (United States)

    López-Izquierdo, Angélica; Ponce-Balbuena, Daniela; Moreno-Galindo, Eloy G; Aréchiga-Figueroa, Iván A; Rodríguez-Martínez, Martín; Ferrer, Tania; Rodríguez-Menchaca, Aldo A; Sánchez-Chapula, José A

    2011-04-01

    The antimalarial drug mefloquine was found to inhibit the KATP channel by an unknown mechanism. Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers, we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition. We studied the inhibitory effects of mefloquine on Kir2.1, Kir2.3, Kir2.3(I213L), and Kir6.2/SUR2A channels expressed in HEK-293 cells, and on IK1 and IKATP from feline cardiac myocytes. The order of mefloquine inhibition was Kir6.2/SUR2A ≈ Kir2.3 (IC50 ≈ 2 μM) > Kir2.1 (IC50 > 30 μM). Similar results were obtained in cardiac myocytes. The Kir2.3(I213L) mutant, which enhances the strength of interaction with PIP2 (compared to WT), was significantly less sensitive (IC50 = 9 μM). In inside-out patches, continuous application of PIP2 strikingly prevented the mefloquine inhibition. Our results support the idea that mefloquine interferes with PIP2-Kir channels interactions.

  20. Antimalarial activity of azadipeptide nitriles.

    Science.gov (United States)

    Löser, Reik; Gut, Jiri; Rosenthal, Philip J; Frizler, Maxim; Gütschow, Michael; Andrews, Katherine T

    2010-01-01

    Azadipeptide nitriles-novel cysteine protease inhibitors-display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite's hemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of the compounds was observed. These first generation azadipeptide nitriles represent a promising new class of compounds for antimalarial drug development. Copyright 2009 Elsevier Ltd. All rights reserved.

  1. Microwave-Assisted Extraction Studies of Target Analyte Artemisinin from Dried Leaves of Artemisia annua L.

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    Himanshu Misra

    2013-01-01

    Full Text Available Artemisia annua L. (Asteraceae is an annual herb native of Asia. This plant has been used for many centuries in traditional Chinese medicine for the treatment of fever and malaria. Conventional methods for the extraction of artemisinin from A. annua including solvent extraction, Soxhlet extraction, and heat reflux extraction are characterized by long extraction times and the consumption of large volume of solvents. A simple, rapid, and precise microwave-assisted extraction process was optimized for fast sample preparation for the faster quantitative determination of artemisinin, potential new generation antimalarial drug, from dried leaves of Artemisia annua L. A simple experiment was designed for the optimization of the appropriate solvent under same extraction conditions. The selected appropriate solvent was then standardized for various different extraction variables. The major parameters studied showed effects on extraction efficiency including processing time, strength of microwave, moisture content, volume and nature of the solvent. The most favorable conditions were obtained by using plant material of 25 mesh (particle size extracted with acetone for 120 seconds at 160 W (i.e., 20% of total power. Quantitative analysis was performed using thin-layer chromatography coupled with a densitometer (TLC densitometry. The results showed that MAE can be used as an efficient and rapid method for the extraction of the active components from plants.

  2. In Vivo Parasitological Measures of Artemisinin Susceptibility

    Science.gov (United States)

    Stepniewska, Kasia; Ashley, Elizabeth; Lee, Sue J.; Anstey, Nicholas; Barnes, Karen I.; Binh, Tran Quang; D’Alessandro, Umberto; Day, Nicholas P. J.; de Vries, Peter J.; Dorsey, Grant; Guthmann, Jean-Paul; Mayxay, Mayfong; Newton, Paul N.; Olliaro, Piero; Osorio, Lyda; Price, Ric N.; Rowland, Mark; Smithuis, Frank; Taylor, Walter R. J.; Nosten, François; White, Nicholas J.

    2015-01-01

    Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n = 14,539), moderate (n = 2077), and high (n = 2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/μL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24. PMID:20085495

  3. Development and validation of a generic liquid chromatographic method for the simultaneous determination of five commonly used antimalarial drugs: Application to pharmaceutical formulations and human plasma.

    Science.gov (United States)

    Mannemala, Sai Sandeep; Nagarajan, Janaki Sankarachari Krishnan

    2015-05-01

    A simple, sensitive, and rapid liquid chromatographic method was developed and validated using diode array detection for the determination of five commonly used antimalarial drugs in pharmaceutical formulations and in human plasma. Chromatographic separation of antimalarial drugs and internal standard (ibuprofen) was achieved on a C18 column with a mobile phase composed of 10 mM dipotassium orthophosphate at pH 3.0, methanol, and acetonitrile in a ratio of 20:38:42 v/v, at a flow rate of 1 mL/min. The analytes were monitored at 220 nm and separated in ˂10 min. The method was validated for linearity, accuracy, precision, limit of quantification, and robustness. Both intra- and interday precisions (in terms of %RSD) were lower than 3% and accuracy ranged from 98.1 to 104.5%. Extraction recoveries were ≥96% in plasma. The limits of quantitation for artemether, lumefantrine, pyrimethamine, sulfadoxine, and mefloquine were 0.3, 0.03, 0.06, 0.15, and 0.15 μg/mL in human plasma. Stability under various conditions was also investigated. The method was successfully applied for quantification of antimalarial drugs in marketed formulations and in spiked human plasma. The method can be employed for routine QC purposes and in pharmacokinetic investigations.

  4. Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase.

    Science.gov (United States)

    Sonoiki, Ebere; Palencia, Andres; Guo, Denghui; Ahyong, Vida; Dong, Chen; Li, Xianfeng; Hernandez, Vincent S; Zhang, Yong-Kang; Choi, Wai; Gut, Jiri; Legac, Jennifer; Cooper, Roland; Alley, M R K; Freund, Yvonne R; DeRisi, Joseph; Cusack, Stephen; Rosenthal, Philip J

    2016-08-01

    There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

  5. Qinghaosu (artemisinin): Chemistry and pharmacology

    Institute of Scientific and Technical Information of China (English)

    Ying LI

    2012-01-01

    Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug.Up to now,some important progresses of Qinghaosu research have been made,including synthesis of new Qinghaosu derivatives and analogs,investigation on their bioactivities and mode of actions.The present review briefly describes these efforts made by researchers in China,particularly in this Institute.

  6. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    Directory of Open Access Journals (Sweden)

    Ronn Anita

    2011-08-01

    antibodies for the drugs used in artemisinin-based combination therapy (ACT.

  7. Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate.

    Science.gov (United States)

    Dechy-Cabaret, Odile; Benoit-Vical, Françoise

    2012-12-13

    Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development of efficient molecules against gametocytes. Knowledge of the pharmacological properties of antiplasmodials is helpful in term of using relevant molecules to treat malaria and to eradicate this dramatic public health problem. The effects of the major antiplasmodial drugs including artemisinin-based combination therapies on gametocyte load are thus reviewed herein, making the difference whenever possible between the effects on gametocytogenesis and the gametocytocidal activity. Current status on the portfolio of the most promising anti-gametocytes compounds is also presented. A close analysis of the relationship between chemical structure and antiplasmodial activity should help the design of novel antimalarial drugs targeting Plasmodium sexual stages.

  8. The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites

    Science.gov (United States)

    Delves, Michael; Plouffe, David; Scheurer, Christian; Meister, Stephan; Wittlin, Sergio; Winzeler, Elizabeth A.; Sinden, Robert E.; Leroy, Didier

    2012-01-01

    Background Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance. Methods and Findings Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony. Conclusions These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life cycles. Please see later in the article for the Editors' Summary PMID

  9. Clinical development of new prophylactic antimalarial drugs after the 5th Amendment to the Declaration of Helsinki

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    Geoffrey S Dow

    2008-09-01

    Full Text Available Geoffrey S Dow, Alan J Magill, Colin OhrtDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USAAbstract: Malaria is of continuing concern in nonimmune traveling populations. Traditionally, antimalarial drugs have been developed as agents for dual indications (treatment and prophylaxis. However, since 2000, when the 5th Amendment to the Declaration of Helsinki (DH2000 was adopted, development of new malaria prophylaxis drugs in this manner has ceased. As a consequence, there may not be any new drugs licensed for this indication in the foreseeable future. Major pharmaceutical companies have interpreted DH2000 to mean that the traditional development paradigm may be considered unethical because of doubt over the likelihood of benefit to endemic populations participating in clinical studies, the use of placebo, and the sustainability of post-trial access to study medications. In this article, we explore the basis of these concerns and suggest that the traditional development paradigm remains ethical under certain circumstances. We also consider alternative approaches that may be more attractive to sponsors as they either do not use placebo, or utilize populations in endemic countries who may unambiguously benefit. These approaches represent the way forward in the future, but are at present unproven in clinical practice, and face numerous regulatory, logistical and technical challenges. Consequently, in the short term, we argue that the traditional clinical development paradigm remains the most feasible approach and is ethical and consistent with the spirit of DH2000 under the appropriate circumstances.Keywords: malaria, prophylaxis, treatment, Declaration of Helsinki, DH2000, ethics

  10. The Mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine.

    Science.gov (United States)

    Henriques, Gisela; van Schalkwyk, Donelly A; Burrow, Rebekah; Warhurst, David C; Thompson, Eloise; Baker, David A; Fidock, David A; Hallett, Rachel; Flueck, Christian; Sutherland, Colin J

    2015-05-01

    The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis of resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance, ap2-mu (encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent malaria parasite Plasmodium chabaudi (pcap2-mu). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the Plasmodium falciparum ap2-mu homologue, pfap2-mu, found evidence that differences in the amino acid encoded by codon 160 are associated with enhanced parasite survival in vivo following combination treatments which included artemisinin derivatives. Here, we characterize the role of pfap2-mu in mediating the in vitro antimalarial drug response of P. falciparum by generating transgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant (160Asn) form of pfap2-mu. Transgenic parasites carrying the pfap2-mu 160Asn allele were significantly less sensitive to dihydroartemisinin using a standard 48-h in vitro test, providing direct evidence of an altered parasite response to artemisinin. Our data also provide evidence that pfap2-mu variants can modulate parasite sensitivity to quinine. No evidence was found that pfap2-mu variants contribute to the slow-clearance phenotype exhibited by P. falciparum in Cambodian patients treated with artesunate monotherapy. These findings provide compelling evidence that pfap2-mu can modulate P. falciparum responses to multiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance.

  11. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

    Science.gov (United States)

    Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

    2013-01-01

    Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

  12. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: A structure-based drug designing approach

    Directory of Open Access Journals (Sweden)

    Rajesh Kumar Kesharwani

    2013-04-01

    Full Text Available Background & objectives: Cysteine proteases (falcipains, a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Methods: Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64 and leupeptin respectively were retrieved from protein data bank (PDB and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. Results: The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in

  13. Elucidating antimalarial drug targets/mode-of-action by application of system biology technologies

    CSIR Research Space (South Africa)

    Becker, J

    2008-11-01

    Full Text Available . In this regard, the researchers chose the polymine metabolic pathway in P. falciparum as a proof of concept project, to validate the pathway as a drug target and elucidate the (MoA) of cyclohexylamine in P. falciparum 3D7. Drug effects were examined through...

  14. Antimalarial drug prescribing practice in private and public health facilities in South-east Nigeria: a descriptive study

    Directory of Open Access Journals (Sweden)

    Okebe Joseph

    2007-05-01

    Full Text Available Abstract Background Nigeria's national standard has recently moved to artemisinin combination treatments for malaria. As clinicians in the private sector are responsible for attending a large proportion of the population ill with malaria, this study compared prescribing in the private and public sector in one State in Nigeria prior to promoting ACTs. Objective To assess prescribing for uncomplicated malaria in government and private health facilities in Cross River State. Method Audit of 665 patient records at six private and seven government health facilities in 2003. Results Clinicians in the private sector were less likely to record history or physical examination than those in public facilities, but otherwise practice and prescribing were similar. Overall, 45% of patients had a diagnostic blood slides; 77% were prescribed monotherapy, either chloroquine (30.2%, sulphadoxine-pyrimethamine (22.7% or artemisinin derivatives alone (15.8%. Some 20.8% were prescribed combination therapy; the commonest was chloroquine with sulphadoxine-pyrimethamine. A few patients (3.5% were prescribed sulphadoxine-pyrimethamine-mefloquine in the private sector, and only 3.0% patients were prescribed artemisinin combination treatments. Conclusion Malaria treatments were varied, but there were not large differences between the public and private sector. Very few are following current WHO guidelines. Monotherapy with artemisinin derivatives is relatively common.

  15. CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine

    Directory of Open Access Journals (Sweden)

    Pybus Brandon S

    2012-08-01

    Full Text Available Abstract Background The 8-aminoquinoline (8AQ drug primaquine (PQ is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum. To date, several groups have investigated the toxicity observed in the 8AQ class, however, exact mechanisms and/or metabolic species responsible for PQ’s haemotoxic and anti-malarial properties are not fully understood. Methods In the present study, the metabolism of PQ was evaluated using in vitro recombinant metabolic enzymes from the cytochrome P450 (CYP and mono-amine oxidase (MAO families. Based on this information, metabolite identification experiments were performed using nominal and accurate mass measurements. Results Relative activity factor (RAF-weighted intrinsic clearance values show the relative role of each enzyme to be MAO-A, 2C19, 3A4, and 2D6, with 76.1, 17.0, 5.2, and 1.7% contributions to PQ metabolism, respectively. CYP 2D6 was shown to produce at least six different oxidative metabolites along with demethylations, while MAO-A products derived from the PQ aldehyde, a pre-cursor to carboxy PQ. CYPs 2C19 and 3A4 produced only trace levels of hydroxylated species. Conclusions As a result of this work, CYP 2D6 and MAO-A have been implicated as the key enzymes associated with PQ metabolism, and metabolites previously identified as potentially playing a role in efficacy and haemolytic toxicity have been attributed to production via CYP 2D6 mediated pathways.

  16. A non-radioactive DAPI-based high-throughput in vitro assay to assess Plasmodium falciparum responsiveness to antimalarials--increased sensitivity of P. falciparum to chloroquine in Senegal.

    Science.gov (United States)

    Ndiaye, Daouda; Patel, Vishal; Demas, Allison; LeRoux, Michele; Ndir, Omar; Mboup, Souleymane; Clardy, Jon; Lakshmanan, Viswanathan; Daily, Johanna P; Wirth, Dyann F

    2010-02-01

    The spread of Plasmodium falciparum drug resistance is outpacing new antimalarial development and compromising effective malaria treatment. Combination therapy is widely implemented to prolong the effectiveness of currently approved antimalarials. To maximize utility of available drugs, periodic monitoring of drug efficacy and gathering of accurate information regarding parasite-sensitivity changes are essential. We describe a high-throughput, non-radioactive, field-based assay to evaluate in vitro antimalarial drug sensitivity of P. falciparum isolates from 40 Senegalese patients. Compared with earlier years, we found a significant decrease in chloroquine in vitro and in genotypic resistances (> 50% and > 65%, respectively, in previous studies) with only 23% of isolates showing resistance. This is possibly caused by a withdrawal of chloroquine from Senegal in 2002. We also found a range of artemisinin responses. Prevalence of drug resistance is dynamic and varies by region. Therefore, the implementation of non-radioactive, robust, high-throughput antimalarial sensitivity assays is critical for defining region-specific prophylaxis and treatment guidelines.

  17. Assessment of the Worldwide Antimalarial Resistance Network Standardized Procedure for In Vitro Malaria Drug Sensitivity Testing Using SYBR Green Assay for Field Samples with Various Initial Parasitemia Levels.

    Science.gov (United States)

    Cheruiyot, Agnes C; Auschwitz, Jennifer M; Lee, Patricia J; Yeda, Redemptah A; Okello, Charles O; Leed, Susan E; Talwar, Mayank; Murthy, Tushar; Gaona, Heather W; Hickman, Mark R; Akala, Hoseah M; Kamau, Edwin; Johnson, Jacob D

    2016-04-01

    The malaria SYBR green assay, which is used to profilein vitrodrug susceptibility ofPlasmodium falciparum, is a reliable drug screening and surveillance tool. Malaria field surveillance efforts provide isolates with various low levels of parasitemia. To be advantageous, malaria drug sensitivity assays should perform reproducibly among various starting parasitemia levels rather than at one fixed initial value. We examined the SYBR green assay standardized procedure developed by the Worldwide Antimalarial Resistance Network (WWARN) for its sensitivity and ability to accurately determine the drug concentration that inhibits parasite growth by 50% (IC50) in samples with a range of initial parasitemia levels. The initial sensitivity determination of the WWARN procedure yielded a detection limit of 0.019% parasitemia.P. falciparumlaboratory strains and field isolates with various levels of initial parasitemia were then subjected to a range of doses of common antimalarials. The IC50s were comparable for laboratory strains with between 0.0375% and 0.6% parasitemia and for field isolates with between 0.075% and 0.6% parasitemia for all drugs tested. Furthermore, assay quality (Z') analysis indicated that the WWARN procedure displays high robustness, allowing for drug testing of malaria field samples within the derived range of initial parasitemia. The use of the WWARN procedure should allow for the inclusion of more malaria field samples in malaria drug sensitivity screens that would have otherwise been excluded due to low initial parasitemia levels.

  18. Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in urban health facilities in Yaoundé, central province, Cameroon

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    Bley Daniel

    2009-07-01

    Full Text Available Abstract Background After adoption of artesunate-amodiaquine (AS/AQ as first-line therapy for the treatment of uncomplicated malaria by the malaria control programme, this study was designed to assess the availability of anti-malarial drugs, treatment practices and acceptability of the new protocol by health professionals, in the urban health facilities and drugstores of Yaoundé city, Cameroon. Methods Between April and August 2005, retrospective and current information was collected by consulting registers and interviewing health practitioners in urban health facilities using a structured questionnaire. Results In 2005, twenty-seven trade-named drugs have been identified in drugstores; quinine tablets (300 mg were the most affordable anti-malarial drugs. Chloroquine was restricted to food market places and no generic artemisinin derivative was available in public health centres. In public health facilities, 13.6% of health professionals were informed about the new guidelines; 73.5% supported the use of AS-AQ as first-line therapy. However, 38.6% apprehended its use due to adverse events attributed to amodiaquine. Malaria treatment was mainly based on the diagnosis of fever. Quinine (300 mg tablets was the most commonly prescribed first-line anti-malarial drug in adults (44.5% and pregnant women (52.5%. Artequin® was the most cited artemsinin-based combination therapy (ACT (9.9%. Medical sales representatives were the main sources of information on anti-malarials. Conclusion The use of AS/AQ was not implemented in 2005 in Yaoundé, despite the wide range of anti-malarials and trade-named artemisinin derivatives available. Nevertheless, medical practitioners will support the use of this combination, when it is available in a paediatric formulation, at an affordable price. Training, information and participation of health professionals in decision-making is one of the key elements to improve adherence to new protocol guidelines. This baseline

  19. A Novel Semi-biosynthetic Route for Artemisinin Production Using Engineered Substrate-Promiscuous P450BM3

    Energy Technology Data Exchange (ETDEWEB)

    Dietrich, Jeffrey; Yoshikuni, Yasuo; Fisher, Karl; Woolard, Frank; Ockey, Denise; McPhee, Derek; Renninger, Neil; Chang, Michelle; Baker, David; Keasling, Jay

    2009-11-30

    Production of fine heterologus pathways in microbial hosts is frequently hindered by insufficient knowledge of the native metabolic pathway and its cognate enzymes; often the pathway is unresolved and enzymes lack detailed characterization. An alternative paradigm to using native pathways is de novo pathway design using well-characterized, substrate-promiscuous enzymes. We demonstrate this concept using P450BM3 from Bacillus megaterium. Using a computer model, we illustrate how key P450BM3 activ site mutations enable binding of non-native substrate amorphadiene, incorporating these mutations into P450BM3 enabled the selective oxidation of amorphadiene arteminsinic-11s,12-epoxide, at titers of 250 mg L"1 in E. coli. We also demonstrate high-yeilding, selective transformations to dihydroartemisinic acid, the immediate precursor to the high value anti-malarial drug artemisinin.

  20. Determination of log P values of new cyclen based antimalarial drug leads using RP-HPLC.

    Science.gov (United States)

    Rudraraju, A V; Amoyaw, P N A; Hubin, T J; Khan, M O F

    2014-09-01

    Lipophilicity, expressed by log P, is an important physicochemical property of drugs that affects many biological processes, including drug absorption and distribution. The main purpose of this study to determine the log P values of newly discovered drug leads using reversed-phase high-performance liquid chromatography (RP-HPLC). The reference standards, with varying polarity ranges, were dissolved in methanol and analyzed by RP-HPLC using a C18 column. The mobile phase consisted of a mixture of acetonitrile, methanol and water in a gradient elution mode. A calibration curve was plotted between the experimental log P values and obtained log k values of the reference standard compounds and a best fit line was obtained. The log k values of the new drug leads were determined in the same solvent system and were used to calculate the respective log P values by using the best fit equation. The log P vs. log k data gave a best fit linear curve that had an R2 of 0.9786 with Pvalues of the intercept and slope of 1.19 x 10(-6) and 1.56 x 10(-10), respectively, at 0.05 level of significance. Log P values of 15 new drug leads and related compounds, all of which are derivatives of macrocyclic polyamines and their metal complexes, were determined. The values obtained are closely related to the calculated log P (Clog P) values using ChemDraw Ultra 12.0. This experiment provided efficient, fast and reasonable estimates of log P values of the new drug leads by using RP-HPLC.

  1. Antimalarial sesquiterpene lactones from oncosiphon piluliferum

    CSIR Research Space (South Africa)

    Pillay, P

    2006-02-01

    Full Text Available With the emergence and spread of drug- resistant parasites, there is a need for new chemically diverse, effective antimalarial drugs. A national multidisciplinary consortium was established to validate scientifically South African medicinal plants...

  2. Accessibility, availability and affordability of anti-malarials in a rural district in Kenya after implementation of a national subsidy scheme

    Directory of Open Access Journals (Sweden)

    Simiyu Chrispinus

    2011-10-01

    Full Text Available Abstract Background Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity. In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours. The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist. The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide. Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT. One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector. The goal of this strategy is to make ACT as affordable as ineffective alternatives. The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010. Methods In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area. Availability, types, and prices of anti-malarials were assessed. There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered. Results The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that. Quinine is the most frequently stocked anti-malarial (61% of retailers. More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57% than ACT (44%. Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL. No retailers had chloroquine in stock and only five were selling artemisinin

  3. Identification of the Schistosoma mansoni Molecular Target for the Antimalarial Drug Artemether

    KAUST Repository

    Lepore, Rosalba

    2011-11-28

    Plasmodium falciparum and Schistosoma mansonii are the parasites responsible for most of the malaria and schistosomiasis cases in the world. Notwithstanding their many differences, the two agents have striking similarities in that they both are blood feeders and are targets of an overlapping set of drugs, including the well-known artemether molecule. Here we explore the possibility of using the known information about the mode of action of artemether in Plasmodium to identify the molecular target of the drug in Schistosoma and provide evidence that artemether binds to SmSERCA, a putative Ca2+-ATPase of Schistosoma. We also predict the putative binding mode of the molecule for both its Plasmodium and Schistosoma targets. Our analysis of the mode of binding of artemether to Ca2+-ATPases also provides an explanation for the apparent paradox that, although the molecule has no side effect in humans, it has been shown to possess antitumoral activity. © 2011 American Chemical Society.

  4. Anti-malarial drug quality in Lagos and Accra - a comparison of various quality assessments

    OpenAIRE

    2010-01-01

    Abstract Background Two major cities in West Africa, Accra, the capital of Ghana, and Lagos, the largest city of Nigeria, have significant problems with substandard pharmaceuticals. Both have actively combated the problem in recent years, particularly by screening products on the market using the Global Pharma Health Fund e.V. Minilab® protocol. Random sampling of medicines from the two cities at least twice over the past 30 months allows a tentative assessment of whether improvements in drug...

  5. Prescription pattern of anti-malarial drugs in a tertiary care hospital

    Institute of Scientific and Technical Information of China (English)

    Santoshkumar R Jeevangi; Manjunath S; Sharanabasappa M Awanti

    2010-01-01

    Objective:To evaluate the prescribing pattern of anti malarial drugs in a tertiary care hospital. Methods:A prospective cross-sectional study was conducted for 6 months of patients visiting in Basaveshwar Teaching and General Hospital, Gulbarga. Data were analyzed for various drug use indicators. Results: A total of 212 prescriptions were collected, with 136 (64.15%) male and 76 (35.85%) female. There were 128 (60.37%) Plasmodium vivax cases and 84 (39.63%) Plasmodium falciparum cases. All Plasmodium vivax cases were treated with chloroquine alone and among these 16 (12.5%) recieved radical treatment with primaquine along with chloroquine. Among 84 patients with Pasmodium falciparum, 40 patients received single drug such as quinine/mefloquinine/artesunate/arteether. Another 44 patients received multidrug regime like, quinine+artesunate (54.54%), quinine+mefloquine (27.27%) and quinine+arteether (18.18%). Chloroquine was not administered to any of the patients with Plasmodium falciparum malaria. The most common adverse effects with chloroquine were anorexia, nausea, vomiting and tinnitus in 9.37%of the cases. With quinine it was nausea and vomiting in 17.64%, tinnitus in 11.76%and hypoglycemia in 2.1%of cases. Conclusions: Our study found the perennial favorites like chloroquine for Plasmodium vivax and quinine for Plasmodium falciparum were the most effective drug. In the severe Plasmodium falciparum cases the artesunate derivatives and combination of artesunate with quinine/mefloquine were most effective with fewer incidences of side effects.

  6. A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    James S McCarthy

    Full Text Available BACKGROUND: Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP. The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection. METHODS AND FINDINGS: A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether-lumefantrine (A/L or atovaquone-proguanil (A/P. In the first cohort (n = 6 where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6. In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7 The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120-4786 and 7-40 respectively; p<0.01. CONCLUSIONS: This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055002.

  7. Inhibition of native 5-HT3 receptor-evoked contractions in guinea pig and mouse ileum by antimalarial drugs.

    Science.gov (United States)

    Kelley, Stephen P; Walsh, Jacqueline; Kelly, Mark C; Muhdar, Simerjyot; Adel-Aziz, Mohammed; Barrett, Iain D; Wildman, Scott S

    2014-09-05

    Quinine, chloroquine and mefloquine are commonly used to treat malaria, however, with associated gastrointestinal (GI) side-effects. These drugs act as antagonists at recombinant 5-HT3 receptors and modulate gut peristalsis. These gastrointestinal side effects may be the result of antagonism at intestinal 5-HT3 receptors. Ileum from male C57BL/6 mice and guinea pigs was mounted longitudinally in organ baths. The concentration-response curves for 5-HT and the selective 5-HT3 agonist 2-Me-5-HT were obtained with 5-HT (pEC50 = 7.57 ± 0.33, 12) more potent (P = 0.004) than 2-Me-5-HT (pEC50 = 5.45 ± 0.58, n = 5) in mouse ileum. There was no difference in potency of 5-HT (pEC50 = 5.42 ± 0.15, n = 8) and 2-Me-5-HT (pIC50 = 5.01 ± 0.55, n = 11) in guinea pig ileum (P > 0.05). Quinine, chloroquine or mefloquine was applied for 10 min and inhibitions prior to submaximal agonist application. In mouse ileum, quinine, chloroquine and mefloquine antagonised 5-HT-induced contractions (pIC50 = 4.9 ± 0.17, n = 7; 4.76 ± 0.14, n = 5; 6.21 ± 0.2, n = 4, correspondingly) with mefloquine most potent (P contractions (pIC50 = 6.35 ± 0.11, n = 8; 4.64 ± 0.2, n = 7; 5.11 ± 0.22, n = 6, correspondingly) with quinine most potent (P contractions (pIC50 = 5.02 ± 0.15, n = 6; 4.54 ± 0.1, n = 7; 5.32 ± 0.13, n = 5) and 2-me-5-HT-induced contractions (pIC50 = 4.62 ± 0.25, n = 5; 4.56 ± 0.14, n = 6; 5.67 ± 0.12, n = 4) with chloroquine least potent against 5-HT and mefloquine most potent against 2-me-5-HT (P < 0.05). These results support previous studies identifying anti-malarial drugs as antagonists at recombinant 5-HT3 receptors and may also demonstrate the ability of these drugs to influence native 5-HT3 receptor-evoked contractile responses which may account for their associated GI side-effects.

  8. Differential speciation of ferriprotoporphyrin IX in the presence of free base and diprotic 4-aminoquinoline antimalarial drugs

    Science.gov (United States)

    Gildenhuys, Johandie; Müller, Ronel; le Roex, Tanya; de Villiers, Katherine A.

    2017-03-01

    The crystal structures of the μ-propionato dimer and π-π dimer of ferriprotoporphyrin IX (Fe(III)PPIX) have been determined by single crystal X-ray diffraction (SCD). Both species were obtained in the presence of the synthetic 4-aminoquinoline antimalarial drug, amodiaquine (AQ). The solution that afforded the μ-propionato dimer contained AQ as a free base (i.e. with both quinoline and terminal amine nitrogen atoms neutral). On the other hand, when the diprotic salt of AQ was included in the crystallization medium, the Fe(III)PPIX π-π dimer was obtained. The structure of the μ-propionato dimer, which is the discrete structural unit that constitutes haemozoin (malaria pigment), is identical to that obtained previously in presence of chloroquine free base. We suspect that the drug, via its two available basic sites, facilitates dissociation of one of the two Fe(III)PPIX propionic acid groups to yield a propionate group that is required for reciprocal coordination of the metal centre to form the centrosymmetric dimer. On the other hand, this proton transfer is not possible when the drug is present as a diprotic salt. In this case, the π-π dimer of Fe(III)PPIX is obtained. In the current study, the π-π dimer of haemin (chloro-Fe(III)PPIX) was obtained as a DMF solvate from non-aqueous aprotic solution (dimethyl formamide and chloroform), however the π-π dimer is also known to exist in aqueous solution (as aqua- or hydroxo-Fe(III)PPIX), where it is purportedly involved in the nucleation of haemozoin. We have been able to unambiguously determine the positions of all non-hydrogen atoms, as well as locate or assign all hydrogen atoms in the structure of the π-π dimer, which was not possible in the SCD structure of haemin reported by Koenig in 1965 owing to disorder in the vinyl and methyl substituents. Interestingly, no disorder in the methyl and vinyl groups is observed in the current structure. Both the π-π and μ-propionato dimers of Fe(III)PPIX are

  9. Expanding the Therapeutic Spectrum of Artemisinin: Activity Against Infectious Diseases Beyond Malaria and Novel Pharmaceutical Developments

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    Thomas Efferth

    2016-08-01

    Full Text Available The interest of Western medicine in Traditional Chinese Medicine (TCM as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin (qinghaosu, which is extracted from the medicinal plant Artemisia annua L. (qinghao. The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives (artemisinins exert profound activities towards other protozoans (Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella, trematodes (Schistosoma, liver flukes, and viruses (human cytomegalovirus, hepatitis B and C viruses. Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives (artesunate, artemether, arteether, novel drug development strategies have been pursued. These included the synthesis of acetal- and non-acetal-type artemisinin dimeric molecules as well as developing nanotechnological approaches, e.g. artemisinin-based liposomes, niosomes, micelles, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in

  10. Artemisinin inhibits chloroplast electron transport activity: mode of action.

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    Adyasha Bharati

    Full Text Available Artemisinin, a secondary metabolite produced in Artemisia plant species, besides having antimalarial properties is also phytotoxic. Although, the phytotoxic activity of the compound has been long recognized, no information is available on the mechanism of action of the compound on photosynthetic activity of the plant. In this report, we have evaluated the effect of artemisinin on photoelectron transport activity of chloroplast thylakoid membrane. The inhibitory effect of the compound, under in vitro condition, was pronounced in loosely and fully coupled thylakoids; being strong in the former. The extent of inhibition was drastically reduced in the presence of uncouplers like ammonium chloride or gramicidin; a characteristic feature described for energy transfer inhibitors. The compound, on the other hand, when applied to plants (in vivo, behaved as a potent inhibitor of photosynthetic electron transport. The major site of its action was identified to be the Q(B; the secondary quinone moiety of photosystemII complex. Analysis of photoreduction kinetics of para-benzoquinone and duroquinone suggest that the inhibition leads to formation of low pool of plastoquinol, which becomes limiting for electron flow through photosystemI. Further it was ascertained that the in vivo inhibitory effect appeared as a consequence of the formation of an unidentified artemisinin-metabolite rather than by the interaction of the compound per se. The putative metabolite of artemisinin is highly reactive in instituting the inhibition of photosynthetic electron flow eventually reducing the plant growth.

  11. Treatment of falciparum malaria in the age of drug resistance

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    Shanks G

    2006-01-01

    Full Text Available The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rather than curing them, leading to increasedtransmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs.Antifolate drug resistance (i.e. pyrimethamine means that new combinations are urgently needed particularlybecause addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance toeach having been documented soon after drug introduction. Drug combinations delay further transmission ofresistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currentlyrecommended drug combinations for falciparum malaria are variants of artemisinin combination therapy wherea rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisininsused include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard ofcare must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only tothe successful treatment of individual patients but also for public health control of malaria.

  12. A Redox-Active Fluorescent pH Indicator for Detecting Plasmodium falciparum Strains with Reduced Responsiveness to Quinoline Antimalarial Drugs.

    Science.gov (United States)

    Jida, Mouhamad; Sanchez, Cecilia P; Urgin, Karène; Ehrhardt, Katharina; Mounien, Saravanan; Geyer, Aurelia; Elhabiri, Mourad; Lanzer, Michael; Davioud-Charvet, Elisabeth

    2017-02-10

    Mutational changes in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) have been associated with differential responses to a wide spectrum of biologically active compounds including current and former quinoline and quinoline-like antimalarial drugs. PfCRT confers altered drug responsiveness by acting as a transport system, expelling drugs from the parasite's digestive vacuole where these drugs exert, at least part of, their antiplasmodial activity. To preserve the efficacy of these invaluable drugs, novel functional tools are required for epidemiological surveys of parasite strains carrying mutant PfCRT variants and for drug development programs aimed at inhibiting or circumventing the action of PfCRT. Here we report the synthesis and characterization of a pH-sensitive fluorescent chloroquine analogue consisting of 7-chloro-N-{2-[(propan-2-yl)amino]ethyl}quinolin-4-amine functionalized with the fluorochrome 7-nitrobenzofurazan (NBD) (henceforth termed Fluo-CQ). In the parasite, Fluo-CQ accumulates in the digestive vacuole, giving rise to a strong fluorescence signal but only in parasites carrying the wild type PfCRT. In parasites carrying the mutant PfCRT, Fluo-CQ does not accumulate. The differential handling of the fluorescent probe, combined with live cell imaging, provides a diagnostic tool for quick detection of those P. falciparum strains that carry a PfCRT variant associated with altered responsiveness to quinoline and quinoline-like antimalarial drugs. In contrast to the accumulation studies, chloroquine (CQ)-resistant parasites were observed cross-resistant to Fluo-CQ when the chemical probe was tested in various CQ-sensitive and -resistant parasite strains. NBD derivatives were found to act as redox cyclers of two essential targets, using a coupled assay based on methemoglobin and the NADPH-dependent glutathione reductase (GRs) from P. falciparum. This redox activity is proposed to contribute to the dual action of Fluo-CQ on redox

  13. Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia

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    Satimai Wichai

    2012-08-01

    Full Text Available Abstract Background The area along the Thai-Cambodian border is considered an epicenter of anti-malarial drug resistance. Recently, parasite resistance to artemisinin-based therapies has been reported in the area. The artemisinin resistance containment project was initiated in November 2008, with the aim to limit resistant parasites and eliminate malaria in this region. This study describes the response to artemisinin-based therapy among falciparum malaria patients in the area, using data from the malaria surveillance programmed under the containment project. Methods The study was conducted in seven provinces of Thailand along the Thai-Cambodian border. Data of Plasmodium falciparum-positive patients during January 2009 to December 2011 were obtained from the electronic malaria information system (eMIS Web-based reporting system. All P. falciparum cases were followed for 42 days, as the routine case follow-up protocol. The demographic characteristics of the patients were described. Statistical analysis was performed to determine the cure rate of the current standard anti-malarial drug regimen--mefloquine-artesunate combination therapy (MAS. The proportion of patients who remained parasite-positive at each follow-up day was calculated. In addition, factors related to the delayed parasite clearance on day-3 post-treatment, were explored. Results A total of 1,709 P. falciparum-positive cases were reported during the study period. Almost 70% of falciparum cases received MAS therapy (n = 1,174. The majority of cases were males, aged between 31 and 50 years. The overall MAS cure rate was >90% over the three-year period. Almost all patients were able to clear the parasite within 7 to 14 days post-treatment. Approximately 14% of patients undergoing MAS remained parasite-positive on day-3. Delayed parasite clearance was not significantly associated with patient gender, age, or citizenship. However, delayed parasite clearance varied across the

  14. Molecular diagnosis of resistance to antimalarial drugs during epidemics and in war zones.

    Science.gov (United States)

    Djimdé, Abdoulaye A; Dolo, Amagana; Ouattara, Amed; Diakité, Sira; Plowe, Christopher V; Doumbo, Ogobara K

    2004-08-15

    Plasmodium falciparum mutations pfcrt K76T and the dhfr/dhps "quintuple mutant" are molecular markers of resistance to chloroquine and sulfadoxine-pyrimethamine, respectively. During an epidemic of P. falciparum malaria in an area of political unrest in northern Mali, where standard efficacy studies have been impossible, we measured the prevalence of these markers in a cross-sectional survey. In 80% of cases of infection, pfcrt K76T was detected, but none of the cases carried the dhfr/dhps quintuple mutant. On the basis of these results, chloroquine was replaced by sulfadoxine-pyrimethamine in control efforts. This example illustrates how molecular markers for drug resistance can provide timely data that inform malaria-control policy during epidemics and other emergency situations.

  15. Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.

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    Adoke Yeka

    2005-07-01

    Full Text Available BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ + sulfadoxine-pyrimethamine (SP; amodiaquine (AQ + SP; or AQ + artesunate (AS. Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84% were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01 after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively. Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003. CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN

  16. Plants as Sources of Antimalarial Drugs Part. 1. In vitro Test Method for the Evaluation of Crude Extracts from Plants.

    Science.gov (United States)

    O'neill, M J; Bray, D H; Boardman, P; Phillipson, J D; Warhurst, D C

    1985-10-01

    An IN VITRO antimalarial test, utilising the inhibition of uptake of [G- (3)H]-hypoxanthine into PLASMODIUM FALCIPARUM cultured in human blood, has been used to assess the activity of crude extracts of ARTEMISIA ANNUA and A. VULGARIS (Compositae) and of BRUCEA JAVANICA, AILANTHUS ALTISSIMA, and SIMABA CEDRON (Simaroubaceae).

  17. Artemisinin-based combination therapies (ACTs): best hope for malaria treatment but inaccessible to the needy!

    Science.gov (United States)

    Mutabingwa, T K

    2005-09-01

    Artemisinin-based combination therapies (ACTs) are the best anti-malarial drugs available now. Artemisinin enhances efficacy and has the potential of lowering the rate at which resistance emerges and spreads. Under low transmission intensity, ACTs have an additional public health benefit of reducing the overall malaria transmission and studies are urgently needed to investigate modalities of attaining similar benefits under high transmission. Despite being recommended by WHO since 2001, overall deployment of ACT has been slow. Limiting factors are high cost, limited knowledge and public awareness on the concept of combination therapy (CT) and ACT in particular, limited knowledge on safety of ACTs in pregnancy, operational issue such as inappropriate drug use, lack of suitable drug formulations, lack of post-marketing surveillance (PMS) systems, and the imbalance between demand and supply. Through concerted efforts of multilateral organizations, the local scientific community with involvement of policy-makers progress has been on several fonts leading to improved ACT uptake rates in the last 2 years. Of 43 countries that had adopted ACT by February 2005, 18 (42%) adopted the policy in 2004. Preference to co-formulated Coartem has led to a surge in its demand with consequent shortage. Alternative ways for increased production of ACTs are urgently needed otherwise most policies will remain adopted on paper. Despite limitations, opportunities are opening up for effective malaria control. Insecticides, insecticide-treated nets (ITNs) and ACTs are proven efficacious controls available that should be accessed by many. Substantial funding is now available for biomedical malaria research and for policy implementation. While the Global Fund is the financial engine behind the scaling up of ACT uptake, delays in cash flow after grant approval has led to many countries adopting ACT in 2004 but only few (nine) implementing it. Clear policies on granted funds and minimal politics

  18. Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal

    DEFF Research Database (Denmark)

    Ranjitkar, Samir; Schousboe, Mette L; Thomsen, Thomas

    2011-01-01

    ABSTRACT: BACKGROUND: Sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been used in treatment of falciparum and vivax malaria in Nepal. Recently, resistance to both drugs have necessitated a change towards artemisinin combination therapy (ACT) against Plasmodium falciparum in highly...... endemic areas. However, SP is still used against P. falciparum infections in low endemic areas while CQ is used in suspected cases in areas with lack of diagnostic facilities. This study examines the prevalence of molecular markers of P. falciparum and Plasmodium vivax CQ and SP resistance to determine...... if high levels of in vivo resistance are reflected at molecular level as well. METHODS: Finger prick blood samples (n=189) were collected from malaria positive patients from two high endemic districts and analysed for single nucleotide polymorphisms (SNPs) in the resistance related genes of P. falciparum...

  19. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies.

    Science.gov (United States)

    Witkowski, Benoit; Amaratunga, Chanaki; Khim, Nimol; Sreng, Sokunthea; Chim, Pheaktra; Kim, Saorin; Lim, Pharath; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Anderson, Jennifer M; Duong, Socheat; Chuor, Char Meng; Taylor, Walter R J; Suon, Seila; Mercereau-Puijalon, Odile; Fairhurst, Rick M; Menard, Didier

    2013-12-01

    Artemisinin resistance in Plasmodium falciparum lengthens parasite clearance half-life during artemisinin monotherapy or artemisinin-based combination therapy. Absence of in-vitro and ex-vivo correlates of artemisinin resistance hinders study of this phenotype. We aimed to assess whether an in-vitro ring-stage survival assay (RSA) can identify culture-adapted P falciparum isolates from patients with slow-clearing or fast-clearing infections, to investigate the stage-dependent susceptibility of parasites to dihydroartemisinin in the in-vitro RSA, and to assess whether an ex-vivo RSA can identify artemisinin-resistant P falciparum infections. We culture-adapted parasites from patients with long and short parasite clearance half-lives from a study done in Pursat, Cambodia, in 2010 (registered with ClinicalTrials.gov, number NCT00341003) and used novel in-vitro survival assays to explore the stage-dependent susceptibility of slow-clearing and fast-clearing parasites to dihydroartemisinin. In 2012, we implemented the RSA in prospective parasite clearance studies in Pursat, Preah Vihear, and Ratanakiri, Cambodia (NCT01736319), to measure the ex-vivo responses of parasites from patients with malaria. Continuous variables were compared with the Mann-Whitney U test. Correlations were analysed with the Spearman correlation test. In-vitro survival rates of culture-adapted parasites from 13 slow-clearing and 13 fast-clearing infections differed significantly when assays were done on 0-3 h ring-stage parasites (10·88% vs 0·23%; p=0·007). Ex-vivo survival rates significantly correlated with in-vivo parasite clearance half-lives (n=30, r=0·74, 95% CI 0·50-0·87; p<0·0001). The in-vitro RSA of 0-3 h ring-stage parasites provides a platform for the molecular characterisation of artemisinin resistance. The ex-vivo RSA can be easily implemented where surveillance for artemisinin resistance is needed. Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH

  20. Phase I randomized dose-ascending placebo-controlled trials of ferroquine - a candidate anti-malarial drug - in adults with asymptomatic Plasmodium falciparum infection

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    Ospina Salazar Carmen L

    2011-03-01

    Full Text Available Abstract Background The development and spread of drug resistant Plasmodium falciparum strains is a major concern and novel anti-malarial drugs are, therefore, needed. Ferroquine is a ferrocenic derivative of chloroquine with proven anti-malarial activity against chloroquine-resistant and -sensitive P. falciparum laboratory strains. Methods Adult young male aged 18 to 45 years, asymptomatic carriers of P. falciparum, were included in two-dose escalation, double-blind, randomized, placebo-controlled Phase I trials, a single dose study and a multiple dose study aiming to evaluate oral doses of ferroquine from 400 to 1,600 mg. Results Overall, 54/66 patients (40 and 26 treated in the single and multiple dose studies, respectively experienced at least one adverse event, 15 were under placebo. Adverse events were mainly gastrointestinal symptoms such as abdominal pain (16, diarrhoea (5, nausea (13, and vomiting (9, but also headache (11, and dizziness (5. A few patients had slightly elevated liver parameters (10/66 including two patients under placebo. Moderate changes in QTc and morphological changes in T waves were observed in the course of the study. However, no adverse cardiac effects with clinical relevance were observed. Conclusions These phase I trials showed that clinically, ferroquine was generally well-tolerated up to 1,600 mg as single dose and up to 800 mg as repeated dose in asymptomatic young male with P. falciparum infection. Further clinical development of ferroquine, either alone or in combination with another anti-malarial, is highly warranted and currently underway.

  1. Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

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    Jambalsuren Bayarmaa

    2008-06-01

    Full Text Available Quantitative structure-activity relationships are based on the construction of predictive models using a set of known molecules and associated activity value. This accurate methodology, developed with adequate mathematical and computational tools, leads to a faster, cheaper and more comprehensive design of new products, reducing the experimental synthesis and testing on animals. Preparation of the QSAR models of artemisinin derivatives was carried out by the genetic function algorithm (GFA method for 91 molecules. The results show some relationships to the observed antimalarial activities of the artemisinin derivatives. The most statistically signi fi cant regression equation obtained from the fi nal GFA relates to two molecular descriptors.

  2. 2011 Lasker Clinical Medical Research Award Honors Prof.TU You-you for the Discovery of Artemisinin

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    The 2011 Lasker Clinical Medical Research Award honors a scientist who discovered artemisinin and its utility for treating malaria.Prof.TU You-you (China Academy of Chinese Medical Sciences,Beijing) transformed an ancient Chinese healing method into the most powerful antimalarial medicine currently available that has saved millions of lives across the globe,especially in the developing world.

  3. Artemisinin and Chinese medicine as Tu science.

    Science.gov (United States)

    Fu, Jia-Chen

    2017-07-07

    The story of discovery of artemisinin highlights the diversity of scientific values across time and space. Resituating artemisinin research within a broader temporal framework allows us to understand how Chinese drugs like qinghao came to articulate a space for scientific experimentation and innovation through its embodiment of alternating clusters of meanings associated with tu and yang within scientific discourse. Tu science, which was associated with terms like native, Chinese, local, rustic, mass, and crude, articulated a radical vision of science in the service of socialist revolutionary ideals. Yang science, which signified foreign, Western, elite, and professional, tended to bear the hallmarks of professionalism, transnational networks in education and training, and an emphasis on basic or foundational research. With respect to medical research, the case of artemisinin highlights how the constitution of socialist science as an interplay of tu and yang engendered different scientific values and parameters for scientific endeavor. Modern medical research in Maoist China could harness the productive energies of mass participation to technical expertise in its investigations of Chinese drugs, and under the banner of tu science, it became possible and scientifically legitimate to research Chinese drugs in ways that had previously provoked resistance and controversy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Evaluation of antimalarial resistance marker polymorphism in returned migrant workers in China.

    Science.gov (United States)

    Feng, Jun; Li, Jun; Yan, He; Feng, Xinyu; Xia, Zhigui

    2015-01-01

    Imported malaria has been a great challenge for public health in China due to decreased locally transmitted cases and frequent exchange worldwide. Plasmodium falciparum has been mainly responsible for the increasing impact. Currently, artesunate plus amodiaquine, one of the artemisinin combination therapies recommended by the World Health Organization, has been mainly used against uncomplicated P. falciparum malaria in China. However, drug resistance marker polymorphism in returning migrant workers has not been demonstrated. Here, we have evaluated the prevalence of pfmdr1 and pfcrt polymorphisms, as well as the K13 propeller gene, a molecular marker of artemisinin resistance, in migrant workers returned from Ghana to Shanglin County, Guangxi Province, China, in 2013. A total of 118 blood samples were randomly selected and used for the assay. Mutations of the pfmdr1 gene that covered codons 86, 184, 1034, and 1246 were found in 11 isolates. Mutations at codon N86Y (9.7%) were more frequent than at others, and Y(86)Y(184)S(1034)D(1246) was the most prevalent (63.6%) of the four haplotypes. Mutations of the pfcrt gene that covered codons 74, 75, and 76 were observed in 17 isolates, and M(74)N(75)T(76) was common (70.6%) in three haplotypes. Eight different genotypes of the K13 propeller were first observed in 10 samples in China, 2 synonymous mutations (V487V and A627A) and 6 nonsynonymous mutations. C580Y was the most prevalent (2.7%) in all the samples. The data presented might be helpful for enrichment of molecular surveillance of antimalarial resistance and will be useful for developing and updating antimalarial guidance in China.

  5. CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.

    Science.gov (United States)

    Ng, Caroline L; Siciliano, Giulia; Lee, Marcus C S; de Almeida, Mariana J; Corey, Victoria C; Bopp, Selina E; Bertuccini, Lucia; Wittlin, Sergio; Kasdin, Rachel G; Le Bihan, Amélie; Clozel, Martine; Winzeler, Elizabeth A; Alano, Pietro; Fidock, David A

    2016-08-01

    Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials.

  6. Natural products as starting points for future anti-malarial therapies: going back to our roots?

    Directory of Open Access Journals (Sweden)

    Wells Timothy NC

    2011-03-01

    Full Text Available Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal

  7. A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine

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    Rath Srikanta

    2011-05-01

    Full Text Available Abstract Background Amodiaquine (AQ along with sulphadoxine-pyrimethamine (SP offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice. Methods The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination. Results The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial hepatotoxicity. Conclusion These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions.

  8. New antimalarial hits from Dacryodes edulis (Burseraceae--part I: isolation, in vitro activity, in silico "drug-likeness" and pharmacokinetic profiles.

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    Denis Zofou

    Full Text Available The aims of the present study were to identify the compounds responsible for the anti-malarial activity of Dacryoedes edulis (Burseraceae and to investigate their suitability as leads for the treatment of drug resistant malaria. Five compounds were isolated from ethyl acetate and hexane extracts of D. edulis stem bark and tested against 3D7 (chloroquine-susceptible and Dd2 (multidrug-resistant strains of Plasmodium falciparum, using the parasite lactate dehydrogenase method. Cytotoxicity studies were carried out on LLC-MK2 monkey kidney epithelial cell-line. In silico analysis was conducted by calculating molecular descriptors using the MOE software running on a Linux workstation. The "drug-likeness" of the isolated compounds was assessed using Lipinski criteria, from computed molecular properties of the geometry optimized structures. Computed descriptors often used to predict absorption, distribution, metabolism, elimination and toxicity (ADMET were used to assess the pharmacokinetic profiles of the isolated compounds. Antiplasmodial activity was demonstrated for the first time in five major natural products previously identified in D. edulis, but not tested against malaria parasites. The most active compound identified was termed DES4. It had IC50 values of 0.37 and 0.55 µg/mL, against 3D7 and Dd2 respectively. In addition, this compound was shown to act in synergy with quinine, satisfied all criteria of "Drug-likeness" and showed considerable probability of providing an antimalarial lead. The remaining four compounds also showed antiplasmodial activity, but were less effective than DES4. None of the tested compounds was cytotoxicity against LLC-MK2 cells, suggesting their selective activities on malaria parasites. Based on the high in vitro activity, low toxicity and predicted "Drug-likeness" DES4 merits further investigation as a possible drug lead for the treatment of malaria.

  9. Efficacy comparison between anti-malarial drugs in Africans presenting with mild malaria in the Central Republic of Africa: a preliminary study

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    Nambei W.S.

    2005-03-01

    Full Text Available Drug resistance to Plasmodium falciparum contributes to major health problems in central Africa and, as a consequence, poverty. We have analyzed the efficacy of three currently available antimalarial drugs to treat symptomatic, uncomplicated P. falciparum malaria in semiimmune adults living in Bangui, Central Republic of Africa. 210 consecutive individuals were enrolled in the survey, of which 45 were excluded. Those having received dihydroartemisin proved significantly less parasitemic than those having received quinine per os or sulfadoxin-pyrimethamin (χ2 = 16.93 ; p < 0.05, and 75 % recovered in two days compared to 57 and 44 %, respectively. The 25 % who did not recover benefited from a second cure with dihydroartemisin, which proved 100 % efficient. The most accurate protocol remains to be established by analyzing clinical and parasitological data and taking into account the economics of the country.

  10. Antimalarial activity and safety assessment of Flueggea virosa leaves and its major constituent with special emphasis on their mode of action.

    Science.gov (United States)

    Singh, Shiv Vardan; Manhas, Ashan; Kumar, Yogesh; Mishra, Sonali; Shanker, Karuna; Khan, Feroz; Srivastava, Kumkum; Pal, Anirban

    2017-03-05

    A clinical emergency stands due to the appearance of drug resistant Plasmodium strains necessitate novel and effective antimalarial chemotypes, where plants seem as the prime option, especially after the discovery of quinine and artemisinin. The present study was aimed towards bioprospecting leaves of Flueggea virosa for its antimalarial efficacy and active principles. Crude hydro-ethanolic extract along with solvent derived fractions were tested in vitro against Plasmodium falciparum CQ sensitive (3D7) and resistant (K1) strains, where all the fractions exhibited potential activity (IC50 values <10μg/mL) against both the strains. Interestingly, under in vivo conditions against P. berghei in Swiss mice, preferential chemo-suppression was recorded for crude hydro-ethanolic extract (77.38%) and ethyl acetate fraction (86.09%) at the dose of 500mg/kg body weight. Additionally, ethyl acetate fraction was found to be capable of normalizing the host altered pharmacological parameters and enhanced oxidative stress augmented during the infection. The bioactivity guided fractionation lead to the isolation of bergenin as a major and active constituent (IC50, 8.07±2.05μM) of ethyl acetate fraction with the inhibition of heme polymerization pathway of malaria parasite being one of the possible chemotherapeutic target. Furthermore, bergenin exhibited a moderate antimalarial activity against P. berghei and also ameliorated parasite induced systemic inflammation in host (mice). Safe toxicity profile elucidated through in vitro cytotoxicity and in silico ADME/T predications evidently suggest that bergenin possess drug like properties. Hence, the present study validates the traditional usage of F. indica as an antimalarial remedy and also insists for further chemical modifications of bergenin to obtain more effective antimalarial chemotypes.

  11. Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in confirmed and unconfirmed malarial patients.

    Science.gov (United States)

    Clark, Robert L

    2012-02-01

    Rat studies suggest that artemisinin-induced decreases in reticulocyte count are a marker for embryotoxicity (in one study, r = 0.82; p embryotoxicity in which case pregnant women without malaria would be at greater risk of artemisinin-induced embryotoxicity. Malaria protection against artesunate toxicity has been observed in rats. No artemisinin-induced embryotoxicity has been identified in limited numbers of women with confirmed malaria in the first trimester. However, in large parts of tropical Africa, malaria treatment is based on fever rather than confirmation of parasitemia and many pregnant women without malaria are exposed to antimalarials. No clinical studies have been conducted on uninfected women for whom pregnancy was identified and then an artemisinin was administered subsequently. Testing in rats and/or humans is needed to determine if malaria protects against reticulocytopenia and embryotoxicity and whether the parasite is a more or less sensitive target than the embryo and reticulocyte.

  12. An Alternative Paradigm for the Role of Antimalarial Plants in Africa

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    Steven Maranz

    2012-01-01

    Full Text Available Most investigations into the antimalarial activity of African plants are centered on finding an indigenous equivalent to artemisinin, the compound from which current frontline antimalarial drugs are synthesized. As a consequence, the standard practice in ethnopharmacological research is to use in vitro assays to identify compounds that inhibit parasites at nanomolar concentrations. This approach fails to take into consideration the high probability of acquisition of resistance to parasiticidal compounds since parasite populations are placed under direct selection for genetic that confers a survival advantage. Bearing in mind Africa's long exposure to malaria and extensive ethnobotanical experimentation with both therapies and diet, it is more likely that compounds not readily overcome by Plasmodium parasites would have been retained in the pharmacopeia and cuisine. Such compounds are characterized by acting primarily on the host rather than directly targeting the parasite and thus cannot be adequately explored in vitro. If Africa's long history with malaria has in fact produced effective plant therapies, their scientific elucidation will require a major emphasis on in vivo investigation.

  13. Antimalarial properties of Artemisia vulgaris L. ethanolic leaf extract in a Plasmodium berghei murine malaria model

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    Gayan S. Bamunuarachchi

    2013-12-01

    Full Text Available Background & objectives: Artemisinin isolated from Artemisia annua is the most potent antimalarial drug against chloroquine-resistant Plasmodium falciparum malaria. Artemisia vulgaris, an invasive weed, is the only Artemisia species available in Sri Lanka. A pilot study was undertaken to investigate the antiparasitic activity of an A. vulgaris ethanolic leaf extract (AVELE in a P. berghei ANKA murine malaria model that elicits pathogenesis similar to falciparum malaria. Methods: A 4-day suppressive and the curative assays determined the antiparasitic activity of AVELE using four doses (250, 500, 750 and 1000 mg/kg, Coartem® as the positive control and 5% ethanol as the negative control in male ICR mice infected with P. berghei. Results: The 500, 750 and 1000 mg/kg doses of AVELE significantly (p ≤0.01 inhibited parasitaemia by 79.3, 79.6 and 87.3% respectively, in the 4-day suppressive assay, but not in the curative assay. Chronic administration of the high dose of AVELE ruled out overt signs of toxicity and stress as well as hepatotoxicity, renotoxicity and haematotoxicity. Interpretation & conclusion: The oral administration of a crude ethonolic leaf extract of A. vulgaris is non-toxic and possesses potent antimalarial properties in terms of antiparasitic activity.

  14. Maximizing antimalarial efficacy and the importance of dosing strategies

    National Research Council Canada - National Science Library

    Beeson, James G; Boeuf, Philippe; Fowkes, Freya J I

    2015-01-01

    .... Without new drugs to replace artemisinins, it is essential to define dosing strategies that maximize therapeutic efficacy, limit the spread of resistance, and preserve the clinical value of ACTs...

  15. Antimalarial Activity of Methanolic Leaf Extract of Piper betle L.

    OpenAIRE

    Amran, Adel A.; Rohela Mahmud; Zurainee M. Nor; Al-Mekhlafi, Hesham M; Al-Adhroey, Abdulelah H

    2010-01-01

    International audience; The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against Plasmodium berghei (NK65) during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial eff...

  16. FlexiChip package: an universal microarray with a dedicated analysis software for high-thoughput SNPs detection linked to anti-malarial drug resistance

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    Dondorp Arjen M

    2009-10-01

    Full Text Available Abstract Background A number of molecular tools have been developed to monitor the emergence and spread of anti-malarial drug resistance to Plasmodium falciparum. One of the major obstacles to the wider implementation of these tools is the absence of practical methods enabling high throughput analysis. Here a new Zip-code array is described, called FlexiChip, linked to a dedicated software program, which largely overcomes this problem. Methods Previously published microarray probes detecting single-nucleotide polymorphisms (SNP associated with parasite resistance to anti-malarial drugs (ResMalChip were adapted for a universal microarray FlexiChip format. To evaluate the overall sensitivity of the FlexiChip package (microarray + software, the results of FlexiChip were compared to ResMalChip microarray, using the same extension probes and with the same PCR products. In both cases, sequence results were used as gold standard to calculate sensitivity and specificity. FlexiChip results obtained with a set of field isolates were then compared to those assessed in an independent reference laboratory. Results The FlexiChip package gave results identical to the ResMalChip results in 92.7% of samples (kappa coefficient 0.8491, with a standard error 0.021 and had a sensitivity of 95.88% and a specificity of 97.68% compared to the sequencing as the reference method. Moreover the method performed well compared to the results obtained in the reference laboratories, with 99.7% of identical results (kappa coefficient 0.9923, S.E. 0.0523. Conclusion Microarrays could be employed to monitor P. falciparum drug resistance markers with greater cost effectiveness and the possibility for high throughput analysis. The FlexiChip package is a promising tool for use in poor resource settings of malaria endemic countries.

  17. A novel way to grow hemozoin-like crystals in vitro and its use to screen for hemozoin inhibiting antimalarial compounds.

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    Vincent Thomas

    Full Text Available BACKGROUND: Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation. In this report we describe new ways to form hemozoin-like crystals that were incidentally discovered during research in the field of prion inactivation. METHODS: We investigated the use of a new assay based on naturally occurring "self-replicating" particles and previously described as presenting resistance to decontamination comparable to prions. The nature of these particles was determined using electron microscopy, Maldi-Tof analysis and X-ray diffraction. They were compared to synthetic hemozoin and to hemozoin obtained from Plasmodium falciparum. We then used the assay to evaluate the capacity of various antimalarial and anti-prion compounds to inhibit "self-replication" (crystallisation of these particles. RESULTS: We identified these particles as being similar to ferriprotoporphyrin IX crystal and confirmed the ability of these particles to serve as nuclei for growth of new hemozoin-like crystals (HLC. HLC are morphologically similar to natural and synthetic hemozoin. Growth of HLC in a simple assay format confirmed inhibition by quinolines antimalarials at potencies described in the literature. Interestingly, artemisinins and tetracyclines also seemed to inhibit HLC growth. CONCLUSIONS: The described HLC assay is simple and easy to perform and may have the potential to be used as an additional tool to screen antimalarial drugs for their hemozoin inhibiting activity. As already described by others, drugs that inhibit hemozoin crystal formation have also the potential to inhibit misfolded proteins

  18. Different Patterns of pfcrt and pfmdr1 Polymorphisms in P. falciparum Isolates from Nigeria and Brazil: The Potential Role of Antimalarial Drug Selection Pressure

    Science.gov (United States)

    Gbotosho, Grace O.; Folarin, Onikepe A.; Bustamante, Carolina; Pereira da Silva, Luis Hildebrando; Mesquita, Elieth; Sowunmi, Akintunde; Zalis, Mariano G.; Oduola, Ayoade M. J.; Happi, Christian T.

    2012-01-01

    The effect of antimalarial drug selection on pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from two distinct geographical locations was determined in 70 and 18 P. falciparum isolates from Nigeria and Brazil, respectively, using nested polymerase chain reaction and direct DNA sequencing approaches. All isolates from Brazil and 72% from Nigeria harbored the mutant SVMNT and CVIET pfcrt haplotype, respectively. The pfcrt CVMNT haplotype was also observed in (7%) of the Nigerian samples. One hundred percent (100%) and 54% of the parasites from Brazil and Nigeria, respectively, harbored wild-type pfmdr1Asn86. We provide first evidence of emergence of the CVMNT haplotype in West Africa. The high prevalence of pfcrt CVIET and SVMNT haplotypes in Nigeria and Brazil, respectively, is indicative of different selective pressure by chloroquine and amodiaquine. Continuous monitoring of pfcrt SVMNT haplotype is required in endemic areas of Africa, where artesunate-amodiaquine combination is used for treatment of acute uncomplicated malaria. PMID:22302850

  19. Expanding the Therapeutic Spectrum of Artemisinin:Activity Against Infectious Diseases Beyond Malaria and Novel Pharmaceutical Developments

    Institute of Scientific and Technical Information of China (English)

    Thomas Efferth; Jose J.G. Marin; Marta R. Romero; Anna Rita Bilia; Ahmed Galal Osman; Mahmoud ElSohly; Michael Wink; Rudolf Bauer; Ikhlas Khan; Maria Camilla Bergonzi

    2016-01-01

    The interest of Western medicine in Traditional Chinese Medicine (TCM) as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatical y augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin (qinghaosu), which is extracted from the medicinal plant Artemisia annua L. (qinghao). The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives (artemisinins) exert profound activities towards other protozoans (Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella), trematodes (Schistosoma, liver flukes), and viruses (human cytomegalovirus, hepatitis B and C viruses). Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives (artesunate, artemether, arteether), novel drug development strategies have been pursued. These included the synthesis of acetal-and non-acetal-type artemisinin dimeric molecules as wel as developing nanotechnological approaches, e.g. artemisinin-based liposomes, niosomes, micel es, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in addition to the

  20. Exposure to anti-malarial drugs and monitoring of adverse drug reactions using toll-free mobile phone calls in private retail sector in Sagamu, Nigeria: implications for pharmacovigilance

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    Ogunwande Isiaka A

    2011-08-01

    Full Text Available Abstract Background Adverse drug reactions (ADRs contribute to ill-health or life-threatening outcomes of therapy during management of infectious diseases. The exposure to anti-malarial and use of mobile phone technology to report ADRs following drug exposures were investigated in Sagamu - a peri-urban community in Southwest Nigeria. Methods Purchase of medicines was actively monitored for 28 days in three Community Pharmacies (CP and four Patent and Proprietary Medicine Stores (PPMS in the community. Information on experience of ADRs was obtained by telephone from 100 volunteers who purchased anti-malarials during the 28-day period. Results and Discussion A total of 12,093 purchases were recorded during the period. Antibiotics, analgesics, vitamins and anti-malarials were the most frequently purchased medicines. A total of 1,500 complete courses of anti-malarials were purchased (12.4% of total purchases; of this number, purchases of sulphadoxine-pyrimethamine (SP and chloroquine (CQ were highest (39.3 and 25.2% respectiuvely. Other anti-malarials purchased were artesunate monotherapy (AS - 16.1%, artemether-lumefantrine (AL 10.0%, amodiaquine (AQ - 6.6%, quinine (QNN - 1.9%, halofantrine (HF - 0.2% and proguanil (PR - 0.2%. CQ was the cheapest (USD 0.3 and halofantrine the most expensive (USD 7.7. AL was 15.6 times ($4.68 more expensive than CQ. The response to mobile phone monitoring of ADRs was 57% in the first 24 hours (day 1 after purchase and decreased to 33% by day 4. Participants in this monitoring exercise were mostly with low level of education (54%. Conclusion The findings from this study indicate that ineffective anti-malaria medicines including monotherapies remain widely available and are frequently purchased in the study area. Cost may be a factor in the continued use of ineffective monotherapies. Availability of a toll-free telephone line may facilitate pharmacovigilance and follow up of response to medicines in a resource

  1. Polymorphisms of the oxidant enzymes glutathione S-transferase and glutathione reductase and their association with resistance ofPlasmodium falciparum isolates to antimalarial drugs

    Institute of Scientific and Technical Information of China (English)

    Raewadee Wisedpanichkij; Wanna Chaicharoenkul; Poonuch Mahamad; Prapichaya Prompradit; Kesara Na-Bangchang

    2010-01-01

    Objective:To investigate the association between amplification of the two regulatory genes controlling glutathione(GSH)levels, glutathione reductase(PfGR)and glutathione S-transferase (PfGST) genes and sensitivity ofPlasmodium falciparum (P. falciparum)isolates collected from different malaria endemic areas of Thailand to standard antimalarial drugs.Methods: A total of70P. falciparum isolates were collected from endemic areas of multi-drug resistance (Tak, Chantaburi and Ranong Provinces) during the year2008-2009. The in vitro assessment of antimalarial activity ofP. falciparumclones (K1- and Dd2 chloroquine resistant and3D7-chloroquine sensitive) and isolates to chloroquine, quinine, mefloquine and arteusnate was performed based onSYBR Green modified assay.Results:68 (97.14%), 11 (15.71%) and28 (40%) isolates respectively were classified as chloroquine-, quinine- and mefloquine-resistant isolates. With this limited number ofP. falciparum isolates included in the analysis, no significant association between amplification ofPfGST gene and sensitivity of the parasite to chloroquine, quinine, mefloquine and quinine was found. Based onPCR analysis,Dd2, K1 and3D7clones all contained only one copy of thePfGST gene. All isolates (70) also carried only one copy number of PfGST gene. There appears to be an association between amplification ofPfGR gene and chloroquine resistance. The3D7and Dd2 clones were found to carry only onePfGR gene copy, whereas the K1 clone carried two gene copies.Conclusions: Chloroquine resistance is likely to be a consequence of multi-factors and enzymes in theGSH system may be partly involved. Larger number of parasite isolates are required to increase power of the hypothesis testing in order to confirm the involvement of both genes as well as other genes implicated in glutathione metabolism in conferring chloroquine resistance.

  2. Development of a transgenic Plasmodium berghei line (Pb pfpkg expressing the P. falciparum cGMP-dependent protein kinase, a novel antimalarial drug target.

    Directory of Open Access Journals (Sweden)

    Rita Tewari

    Full Text Available With the inevitable selection of resistance to antimalarial drugs in treated populations, there is a need for new medicines to enter the clinic and new targets to progress through the drug discovery pipeline. In this study we set out to develop a transgenic rodent model for testing inhibitors of the Plasmodium falciparum cyclic GMP-dependent kinase in vivo. A model was needed that would allow us to investigate whether differences in amino acid sequence of this enzyme between species influences in vivo efficacy. Here we report the successful development of a transgenic P. berghei line in which the cyclic GMP-dependent protein kinase (PKG was replaced by the P. falciparum orthologue. We demonstrate that the P. falciparum orthologue was able to functionally complement the endogenous P. berghei pkg gene throughout blood stage development and early sexual development. However, subsequent development in the mosquito was severely compromised. We show that this is due to a defect in the female lineage of the transgenic by using genetic crosses with both male and female deficient P. berghei lines. This defect could be due to expression of a female-specific target in the mosquito stages of P. berghei that cannot be phosphorylated by the P. falciparum kinase. Using a previously reported anti-coccidial inhibitor of the cyclic GMP-dependent protein kinase, we show no difference in in vivo efficacy between the transgenic and control P. berghei lines. This in vivo model will be useful for screening future generations of cyclic GMP-dependent protein kinase inhibitors and allowing us to overcome any species-specific differences in the enzyme primary sequence that would influence in vivo efficacy in the rodent model. The approach will also be applicable to in vivo testing of other antimalarial compounds where the target is known.

  3. Development of a transgenic Plasmodium berghei line (Pb pfpkg) expressing the P. falciparum cGMP-dependent protein kinase, a novel antimalarial drug target.

    Science.gov (United States)

    Tewari, Rita; Patzewitz, Eva-Maria; Poulin, Benoit; Stewart, Lindsay; Baker, David A

    2014-01-01

    With the inevitable selection of resistance to antimalarial drugs in treated populations, there is a need for new medicines to enter the clinic and new targets to progress through the drug discovery pipeline. In this study we set out to develop a transgenic rodent model for testing inhibitors of the Plasmodium falciparum cyclic GMP-dependent kinase in vivo. A model was needed that would allow us to investigate whether differences in amino acid sequence of this enzyme between species influences in vivo efficacy. Here we report the successful development of a transgenic P. berghei line in which the cyclic GMP-dependent protein kinase (PKG) was replaced by the P. falciparum orthologue. We demonstrate that the P. falciparum orthologue was able to functionally complement the endogenous P. berghei pkg gene throughout blood stage development and early sexual development. However, subsequent development in the mosquito was severely compromised. We show that this is due to a defect in the female lineage of the transgenic by using genetic crosses with both male and female deficient P. berghei lines. This defect could be due to expression of a female-specific target in the mosquito stages of P. berghei that cannot be phosphorylated by the P. falciparum kinase. Using a previously reported anti-coccidial inhibitor of the cyclic GMP-dependent protein kinase, we show no difference in in vivo efficacy between the transgenic and control P. berghei lines. This in vivo model will be useful for screening future generations of cyclic GMP-dependent protein kinase inhibitors and allowing us to overcome any species-specific differences in the enzyme primary sequence that would influence in vivo efficacy in the rodent model. The approach will also be applicable to in vivo testing of other antimalarial compounds where the target is known.

  4. Plasmodium falciparum malaria: Convergent evolutionary trajectories towards delayed clearance following artemisinin treatment.

    Science.gov (United States)

    Wilairat, Prapon; Kümpornsin, Krittikorn; Chookajorn, Thanat

    2016-05-01

    Malaria is a major global health challenge with 300million new cases every year. The most effective regimen for treating Plasmodium falciparum malaria is based on artemisinin and its derivatives. The drugs are highly effective, resulting in rapid clearance of parasites even in severe P. falciparum malaria patients. During the last five years, artemisinin-resistant parasites have begun to emerge first in Cambodia and now in Thailand and Myanmar. At present, the level of artemisinin resistance is relatively low with clinical presentation of delayed artemisinin clearance (a longer time to reduce parasite load) and a small decrease in artemisinin sensitivity in cultured isolates. Nevertheless, multiple genetic loci associated with delayed parasite clearance have been reported, but they cannot account for a large portion of cases. Even the most well-studied kelch 13 propeller mutations cannot always predict the outcome of artemisinin treatment in vitro and in vivo. Here we propose that delayed clearance by artemisinin could be the result of convergent evolution, driven by multiple trajectories to overcome artemisinin-induced stress, but precluded to become full blown resistance by high fitness cost. Genetic association studies by several genome-wide approaches reveal linkage disequilibrium between multiple loci and delayed parasite clearance. Genetic manipulations at some of these loci already have resulted in loss in artemisinin sensitivity. The notion presented here is by itself consistent with existing evidence on artemisinin resistance and has the potential to be explored using available genomic data. Most important of all, molecular surveillance of artemisinin resistance based on multi-genic markers could be more informative than relying on any one particular molecular marker. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal

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    Faye Oumar

    2007-06-01

    Full Text Available Abstract Background In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam®, artesunate plus mefloquine (Artequin®, artemether plus lumefantrine (Coartem®; four doses and six doses, and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. Methods This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. Results All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%. Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%. The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. Conclusion The four combinations are effective and well-tolerated.

  6. Chemotherapy and drug resistance status of malaria parasite in northeast India

    Institute of Scientific and Technical Information of China (English)

    Diganta Goswami; Indra Baruah; Sunil Dhiman; Bipul Rabha; Vijay Veer; Lokendra Singh; Dhirendra Kumar Sharma

    2013-01-01

    India reports the highest number of malaria cases in Southeast Asia, of which Plasmodiumfalciparum contribute more than half of the cases every year. North eastern states of India contribute only 3.96% of country’s population but account for >10% of total reported malaria cases, 11% of Plasmodium falciparum cases and 20% of malaria related deaths annually. In India, chloroquine resistance was reported for the first time from northeast region and since then chloroquine treatment failure is being reported from many parts of the region. Increased chloroquine treatment failure has led to change of the drug policy to artemisinin combination therapy as first line of malaria treatment in the region. However, replacing chloroquine to artemisinin combination therapy has not shown significant difference in the overall malaria incidence in the region. The present review addresses the current malaria situation of northeastern region of India in the light of antimalarials drug resistance.

  7. Optimization of propafenone analogues as antimalarial leads.

    Science.gov (United States)

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  8. Challenges Associated with Scaling up Artemisinin Combination Therapy in Sub-Saharan Africa ; A Review Article

    Directory of Open Access Journals (Sweden)

    Qader SS

    2008-01-01

    Full Text Available Malaria is the leading cause of morbidity and mortality in Sub-Saharan Africa. One key strategic intervention is provision of early diagnosis and prompt effective treatment. A major setback has been the development of drug resistance to commonly used antimalarials. To overcome this, most countries in Sub-Saharan Africa have adopted Artemisinin Combination Therapy (ACT as a first line treatment for uncomplicated malaria. Artemether Lumefantrine (AL and Artesunate Amodiaquine (ASAQ are the main drugs of choice. There are key implementation issues, which may have a bearing on the scaling up of this new treatment. This article reviewed the published papers on ACT with focus on sustainability, compliance, and diagnosis. ACTs are costly, but highly effective. Their scaling up is the most cost effective malaria intervention currently available. Most countries rely heavily on the Global Fund for their scaling up. AL has a short shelf life, a complicated six-dose regimen that requires intake with fat to ensure sufficient bioavailability. High rates of adherence have been reported. Use of parasitic diagnosis is advocated to ensure rational use. Parasitic diagnostics like rapid test and microscopy are currently inadequate. The majority of malaria cases may continue to be diagnosed clinically leading to over prescription of drugs. ACTs are currently not available at the community level for home based management of malaria. Issues related to safety and rational use need to be addressed before their use in the informal health sector like community drug sellers and community health workers. The majority of malaria cases at the community level could go untreated or continue to be treated using less effective drugs.We conclude that ACTs are highly effective. A major challenge is ensuring rational use and access at the household level. It is hoped that addressing these issues will increase the likelihood that ACT achieves its intended goals of reducing morbidity

  9. Rifabutin reduces systemic exposure of an antimalarial drug 97/78 upon co- administration in rats:anin-vivo & in-vitro analysis

    Institute of Scientific and Technical Information of China (English)

    Yeshwant Singh; Mahendra Kumar Hidau; Shio Kumar Singh

    2015-01-01

    Objective:To determine the potential drug-drug interactions between anti-malarial candidate 97/78 and anti-tubercular drug rifabutin in-vivo in rats followed byin-vitro investigation of the underlying mechanisms of drug interaction.Methods: Single oral dose study was conducted in male and female rats at 40 mg/kg and 70 mg/kg for 97/78 and rifabutin respectively. Results:It was reported that rifabutin co-administration altered pharmacokinetics of 97/63 (active metabolite of 97/78). A significant decrease was reported in the systemic exposure of 97/63 by a factor of 3-4. The AUC0-last values were (4.03 ± 0.60) and (5.44 ± 1.15) μg•h•mL-1 upon 97/78 administration alone, while the values were decreased to (1.13 ± 0.10) and (1.23 ± 1.13) μg•h•mL-1 upon rifabutin co-administration in male and female rats respectively. Statistically significant differences were also reported in Cmaxand Tmax values upon rifabutin co-administration.In-vitro drug metabolism study in rat liver microsomes has shown that the metabolism of 97/63 was increased by 10%-12% upon rifabutin co-incubation. The extent of plasma protein binding of 97/63 was found to be decreased from 54%-55% to 6%-8% upon rifabutin addition.Conclusions:It was concluded that rifabutin co-administration altered PK parameters of 97/63 in SD rats. However, no intersex influences were reported in the interaction pattern. The results obtained in the in-vivo study were well correlated with thein-vitro findings and can further be applied to explore other aspects of potential drug interactions between these two drugs.

  10. Predicting Global Fund grant disbursements for procurement of artemisinin-based combination therapies

    Directory of Open Access Journals (Sweden)

    O'Brien Megan E

    2008-10-01

    Full Text Available Abstract Background An accurate forecast of global demand is essential to stabilize the market for artemisinin-based combination therapy (ACT and to ensure access to high-quality, life-saving medications at the lowest sustainable prices by avoiding underproduction and excessive overproduction, each of which can have negative consequences for the availability of affordable drugs. A robust forecast requires an understanding of the resources available to support procurement of these relatively expensive antimalarials, in particular from the Global Fund, at present the single largest source of ACT funding. Methods Predictive regression models estimating the timing and rate of disbursements from the Global Fund to recipient countries for each malaria grant were derived using a repeated split-sample procedure intended to avoid over-fitting. Predictions were compared against actual disbursements in a group of validation grants, and forecasts of ACT procurement extrapolated from disbursement predictions were evaluated against actual procurement in two sub-Saharan countries. Results Quarterly forecasts were correlated highly with actual smoothed disbursement rates (r = 0.987, p Conclusion This analysis derived predictive regression models that successfully forecasted disbursement patterning for individual Global Fund malaria grants. These results indicate the utility of this approach for demand forecasting of ACT and, potentially, for other commodities procured using funding from the Global Fund. Further validation using data from other countries in different regions and environments will be necessary to confirm its generalizability.

  11. Chemical and biological stability of artemisinin in bovine rumen fluid and its kinetics in goats (Capra hircus).

    Science.gov (United States)

    Ferreira, Jorge F S; Gonzalez, Javier M

    2008-09-01

    There is a pressing need to develop alternative, natural anthelmintics to control widespread drug-resistant gastrointestinal nematodes in ruminants, such as Haemonchus contortus. Artemisinin and its semi-synthetic derivatives are widely used against drug-resistant Plasmodium falciparum, but their role in veterinary medicine is only emerging. Artemisinin may be useful in controlling gastrointestinal parasites including Haemonchus. However, no ruminant studies involving artemisinin have been reported. The stability of artemisinin in capsules, crystals, or stock solutions in ethanol and dimethyl sulfoxide was evaluated in bovine rumen culture medium incubated for 24 hours at 39 degrees C. A second study established artemisinin kinetics in goats after oral administration of artemisinin capsules at 23 mg/kg of body weight. Artemisinin recovered from rumen culture ranged from 67 to 92% at pH 6.8 and was 95% at pH 3.0. The kinetics data showed that artemisinin was metabolized to dihydroartemisinin by goats, while unabsorbed artemisinin was eliminated in feces. Dihydroartemisinin peaked in the blood (0.7 mug/mL) at 12 hours, and decreased to 0.18 mug/mL at 24 hours. At 24 hours, artemisinin concentration in feces was 2.4 mug/g, indicating its poor bioavailability in goats when provided orally and as capsules. These results suggest that the bioavailability of artemisinin to goats can improve by dissolving capsules in ethanol or dimethyl sulfoxide, by using more stable and bioavailable artemisinin-derived drugs, and by using routes of delivery other than oral.

  12. Survey of artemisinin production by diverse Artemisia species in northern Pakistan

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    Asim Muhammad F

    2010-11-01

    Full Text Available Abstract Background Artemisinin is the current drug of choice for treatment of malaria and a number of other diseases. It is obtained from the annual herb, Artemisia annua and some microbial sources by genetic engineering. There is a great concern that the artemisinin production at current rate will not meet the increasing demand by the pharmaceutical industry, so looking for additional sources is imperative. Methods In current study, artemisinin concentration was analysed and compared in the flowers, leaves, roots and stems of Artemisia annua and 14 other Artemisia species including two varieties each for Artemisia roxburghiana and Artemisia dracunculus using high performance liquid chromatography (HPLC. Results The highest artemisinin concentration was detected in the leaves (0.44 ± 0.03% and flowers (0.42 ± 0.03% of A. annua, followed by the flowers (0.34 ± .02% of A. bushriences and leaves (0.27 ± 0% of A. dracunculus var dracunculus. The average concentration of artemisinin varied in the order of flowers > leaves > stems > roots. Conclusion This study identifies twelve novel plant sources of artemisinin, which may be helpful for pharmaceutical production of artemisinin. This is the first report of quantitative comparison of artemisinin among a large number of Artemisia species.

  13. Molecular monitoring of Plasmodium falciparum resistance to artemisinin in Tanzania

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    Genton Blaise

    2006-12-01

    Full Text Available Abstract Artemisinin-based combination therapies (ACTs are recommended for use against uncomplicated malaria in areas of multi-drug resistant malaria, such as sub-Saharan Africa. However, their long-term usefulness in these high transmission areas remains unclear. It has been suggested that documentation of the S769N PfATPase6 mutations may indicate an emergence of artemisinin resistance of Plasmodium falciparum in the field. The present study assessed PfATPase6 mutations (S769N and A623E in 615 asymptomatic P. falciparum infections in Tanzania but no mutant genotype was detected. This observation suggests that resistance to artemisinin has not yet been selected in Tanzania, supporting the Ministry of Health's decision to adopt artemether+lumefantrine as first-line malaria treatment. The findings recommend further studies to assess PfATPase6 mutations in sentinel sites and verify their usefulness in monitoring emergency of ACT resistance.

  14. A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

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    Oyoo George O

    2011-03-01

    Full Text Available Abstract Background Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product were reported. The maximum concentration (Cmax was 160-200 nM and after 6 hours, the effective concentration (Ceff was Conclusion Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

  15. A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers.

    Science.gov (United States)

    Chilengi, Roma; Juma, Rashid; Abdallah, Ahmed M; Bashraheil, Mahfudh; Lodenyo, Hudson; Nyakundi, Priscilla; Anabwani, Evelyn; Salim, Amina; Mwambingu, Gabriel; Wenwa, Ednah; Jemutai, Julie; Kipkeu, Chemtai; Oyoo, George O; Muchohi, Simon N; Kokwaro, Gilbert; Niehues, Tim; Lang, Trudie; Nzila, Alexis

    2011-03-16

    Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was drug as an anti-malarial agent.

  16. Chitosan oligosaccharide and salicylic acid up-regulate gene expression differently in relation to the biosynthesis of artemisinin in Artemisia annua L

    DEFF Research Database (Denmark)

    Yin, Heng; Kjær, Anders; Fretté, Xavier

    2012-01-01

    Artemisia annua L. is a traditional Chinese medicinal plant used for treating fevers and malaria. The primary anti-malarial component is the sesquiterpene lactone peroxide artemisinin, which is accumulated in glandular trichomes. This study investigated the effect of treating plants with chitosan...

  17. Risk of drug resistance in Plasmodium falciparum malaria therapy-a systematic review and meta-analysis.

    Science.gov (United States)

    Zhou, Li-Juan; Xia, Jing; Wei, Hai-Xia; Liu, Xiao-Jun; Peng, Hong-Juan

    2017-02-01

    Plasmodium falciparum is responsible for the vast majority of the morbidity and mortality associated with malaria infection globally. Although a number of studies have reported the emergence of drug resistance in different therapies for P. falciparum infection, the degree of the drug resistance in different antimalarials is still unclear. This research investigated the risk of drug resistance in the therapies with different medications based on meta-analyses. Relevant original randomized control trials (RCTs) were searched in all available electronic databases. Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were used to evaluate the risk of drug resistance resulting from different treatments. Seventy-eight studies were included in the meta-analysis to compare drug resistance in the treatment of P. falciparum infections and yielded the following results: chloroquine (CQ) > sulfadoxine-pyrimethamine (SP) (RR = 3.67, p  artemether + lumefantrine (AL) (RR = 2.94, p  artemisinin-based combination therapies (ACTs) (RR = 1.93, p < 0.001); no significant difference was found in amodiaquine (AQ) vs. SP, AS + AQ vs. AS + SP, AS + AQ vs. AL, or AS + MQ vs. AL. These results presented a global view for the current status of antimalarial drug resistance and provided a guidance for choice of antimalarials for efficient treatment and prolonging the life span of the current effective antimalarial drugs.

  18. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    Science.gov (United States)

    Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

    2016-01-01

    Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

  19. The use of paediatric artemisinin combinations in sub-Saharan Africa: a snapshot questionnaire survey of health care personnel

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    Agnandji Selidji T

    2011-12-01

    Full Text Available Abstract Background Paediatric drug formulations for artemisinin combination therapy (P-ACT have been developed over the past few years and have been shown to improve the therapeutic management of young children with uncomplicated falciparum malaria. This process was however not equally paralleled by a timely adoption of P-ACT in national and international treatment recommendations. National malaria programmes in sub-Saharan Africa have not yet widely embraced this new therapeutic tool. To which extent P-ACT is used in the field in sub-Saharan Africa is not known to date. Methods This snapshot questionnaire survey aimed to provide an overview on the current routine practices for the availability and use of P-ACT as anti-malarial treatment for young children in sub-Saharan Africa. Health care personnel in seven countries in West-, Central, and East-Africa were invited to answer a structured questionnaire assessing use and availability of P-ACT. Results A total of 71 respondents including doctors, nurses and pharmacy personnel responsible for the anti-malarial treatment of young children were interviewed. P-ACT was used by 83% (95% confidence interval: 73-90%; n = 59 as first-line treatment for young children. Use of 15 different P-ACT products was reported among which only two have received WHO prequalification status and approval by a stringent registration authority. Use of a specific P-ACT product was not linked to consumer prices or availability of supporting clinical trial data, but may depend more on the marketing capacity of the manufacturer. Major differences in frequency and dosing of anti-malarial regimens with identical anti-malarial compounds and the marketing of loose combinations were recorded. Conclusion Paediatric ACT is widely used for the treatment of uncomplicated malaria in young children. However, the majority of P-ACT formulations in use do not meet highest international quality standards evoking concerns for patients

  20. Spatial distribution, work patterns, and perception towards malaria interventions among temporary mobile/migrant workers in artemisinin resistance containment zone.

    Science.gov (United States)

    Wai, Khin Thet; Kyaw, Myat Phone; Oo, Tin; Zaw, PeThet; Nyunt, Myat Htut; Thida, Moe; Kyaw, Thar Tun

    2014-05-17

    Mobile populations are at a high risk of malaria infection and suspected to carry and spread resistant parasites. The Myanmar National Malaria Control Programme focuses on preventive interventions and vector control measures for the temporary mobile/migrant workers in Myanmar Artemisinin Resistance Containment Zones. A prospective cross-sectional study was conducted in 2012 in Kawthaung and Bokepyin townships of Tanintharyi Region, Myanmar, covering 192 mobile/migrant aggregates. The objectives were to identify the spatial distribution of the mobile/migrant populations, and to assess knowledge, attitudes, perceptions, and practices concerning malaria prevention and control, and their preferred methods of interventions. The structure of the 192 migrant aggregates was investigated using a migrant mapping tool. Individual and household information was collected by structured interviews of 408 respondents from 39 aggregates, supplemented by 12 in-depth interviews of health care providers, authorities, volunteers, and employers. Data were analyzed by triangulating quantitative and qualitative data. The primary reasons for the limitation in access to formal health services for suspected malaria within 24 hours were identified to be scattered distribution of migrant aggregates, variable working hours and the lack of transportation. Only 19.6% of respondents reported working at night from dusk to dawn. Among study populations, 73% reported a perceived risk of contracting malaria and 60% reported to know how to confirm a suspected case of malaria. Moreover, only 15% was able to cite correct antimalarial drugs, and less than 10% believed that non-compliance with antimalarial treatment may be related to the risk of drug resistance. About 50% of study population reported to seeking health care from the public sector, and to sleep under ITNs/LLINs the night before the survey. There was a gap in willingness to buy ITNs/LLINs and affordability (88.5% vs. 60.2%) which may affect

  1. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  2. High prevalence of pfdhfr-pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine-pyrimethamine in combination with artesunate as first-line treatment in Iran.

    Science.gov (United States)

    Rouhani, Maryam; Zakeri, Sedigheh; Pirahmadi, Sakineh; Raeisi, Ahmad; Djadid, Navid Dinparast

    2015-04-01

    The spread of anti-malarial drug resistance will challenge any malaria control and elimination strategies, and routine monitoring of resistance-associated molecular markers of commonly used anti-malarial drugs is very important. Therefore, in the present investigation, the extent of mutations/haplotypes in dhfr and dhps genes of Plasmodium falciparum isolates (n=72) was analyzed seven years after the introduction of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) as first-line anti-malarial treatment in Iran using PCR-RFLP methods. The results showed that the majority of the patients (97.2%) carried both 59R and 108N mutations in pure form with wild-type genotype at positions N51 and I164. Additionally, a significant increase (Pdrug for treatment of falciparum patients in these malaria-endemic areas of Iran. However, no quintuple mutations associated with treatment failure were detected. In conclusion, the present results along with in vivo assays suggest that seven years after the adoption of SP-AS as the first-line treatment in Iran, this drug remains efficacious for treatment of uncomplicated falciparum malaria, as a partner drug with AS in these malaria-endemic areas.

  3. Structure-based drug design studies of the interactions of ent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparum sarco/endoplasmic reticulum Ca2+-ATPase PfATP6

    Directory of Open Access Journals (Sweden)

    Daniel Silqueira Martins Guimarães

    2015-04-01

    Full Text Available Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

  4. The Discovery of Artemisinin and Advances in Related Research%青蒿素的发现与研究进展

    Institute of Scientific and Technical Information of China (English)

    卢义钦

    2012-01-01

    1967年北京《5·23抗疟计划》付诸实施,在全国多个研究单位协作下,组织植物化学与药理学等专业200多人,搜寻对抗耐氯喹恶性疟疾的新药.他们追索我国历代抗疟方剂,用约200种草药制成380多种抽提物,再筛查其时小鼠疟疾模型的疗效.最后确定,在60℃用乙醚萃取中药青蒿的黄花蒿所得第191号中性抽提物,对感染鼠疟和猴疟的小鼠与猴以及21例恶性疟、间日疟患者均能奏效.1972年11月,从该抽提物分离出相对分子质量0.282 kD的无色结晶,命名为青蒿素.它属于一种新型的倍半萜内酯.继后青蒿素纯品的胶囊被用于临床数千例疟疾患者.2006年以来,为克服耐药性,世界卫生组织(WHO)宣布改用青蒿素的联合疗法(ACT),挽救了80个国家100多万人的生命.因在发现青蒿素过程中的关键作用,屠呦呦被授予2011年度拉斯克临床医学研究奖.本文对青蒿素发现的争议,如何恰当评价其他科学家的贡献,以及开发植物界以外青蒿素新药源的近况,均作了简要报道.%5·23 Beijing Antimalarial Project was conducted in 1967. In collaboration with several domestic research institutes, more than 200 staff members of phytochemistry and pharmcology specialities etc., were organized to search after the new drugs for anti-chloroquine resistant subtertian malaria. The ancient Chinese anti-malarial prescriptions were collected and reviewed. Exceeding 380 extracts were prepared from approximately 200 items of herbs, their therapeutic effects were detected by the models of mouse malaria. The No. 191 neutral extract obtained by ether extraction of Artemisia annua L at 60 t exhibited distinct curative effects in mice and monkeys infected with malarial parasites as well as in 21 patients with subtertian and tertian malaria. In November of 1972, a colorless crystlline substance with relative molecular mass of 0.282 kD was isolated from No.191 extract, it was named artemisinin

  5. Cost of increasing access to artemisinin combination therapy: the Cambodian experience

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    Socheat Duong

    2008-05-01

    Full Text Available Abstract Background Malaria-endemic countries are switching antimalarial drug policy from cheap ineffective monotherapies to artemisinin combination therapies (ACTs for the treatment of Plasmodium falciparum malaria and the global community are considering setting up a global subsidy to fund their purchase. However, in order to ensure that ACTs are correctly used and are accessible to the poor and remote communities who need them, specific interventions will be necessary and the additional costs need to be considered. Methods This paper presents an incremental cost analysis of some of these interventions in Cambodia, the first country to change national antimalarial drug policy to an ACT of artesunate and mefloquine. These costs include the cost of rapid diagnostic tests (RDTs, the cost of blister-packaging the drugs locally and the costs of increasing access to diagnosis and treatment to remote communities through malaria outreach teams (MOTs and Village Malaria Workers (VMW. Results At optimum productive capacity, the cost of blister-packaging cost under $0.20 per package but in reality was significantly more than this because of the low rate of production. The annual fixed cost (exclusive of RDTs and drugs per capita of the MOT and VMW schemes was $0.44 and $0.69 respectively. However because the VMW scheme achieved a higher rate of coverage than the MOT scheme, the cost per patient treated was substantially lower at $5.14 compared to $12.74 per falciparum malaria patient treated. The annual cost inclusive of the RDTs and drugs was $19.31 for the MOT scheme and $11.28 for the VMW scheme given similar RDT positivity rates of around 22% and good provider compliance to test results. Conclusion In addition to the cost of ACTs themselves, substantial additional investments are required in order to ensure that they reach the targeted population via appropriate delivery systems and to ensure that they are used appropriately. In addition, differences

  6. Preparation and Characterization of Micronized Artemisinin via a Rapid Expansion of Supercritical Solutions (RESS Method

    Directory of Open Access Journals (Sweden)

    Xiaonan Zhang

    2012-04-01

    Full Text Available The particle sizes of pharmaceutical substances are important for their bioavailability. Bioavailability can be improved by reducing the particle size of the drug. In this study, artemisinin was micronized by the rapid expansion of supercritical solutions (RESS. The particle size of the unprocessed white needle-like artemisinin particles was 30 to 1200 µm. The optimum micronization conditions are determined as follows: extraction temperature of 62 °C, extraction pressure of 25 MPa, precipitation temperature 45 °C and nozzle diameter of 1000 μm. Under the optimum conditions, micronized artemisinin with a (mean particle size MPS of 550 nm is obtained. By analysis of variance (ANOVA, extraction temperature and pressure have significant effects on the MPS of the micronized artemisinin. The particle size of micronized artemisinin decreased with increasing extraction temperature and pressure. Moreover, the SEM, LC-MS, FTIR, DSC and XRD allowed the comparison between the crystalline initial state and the micronization particles obtained after the RESS process. The results showed that RESS process has not induced degradation of artemisinin and that processed artemisinin particles have lower crystallinity and melting point. The bulk density of artemisinin was determined before and after RESS process and the obtained results showed that it passes from an initial density of 0.554 to 0.128 g·cm−3 after the processing. The decrease in bulk density of the micronized powder can increase the liquidity of drug particles when they are applied for medicinal preparations. These results suggest micronized powder of artemisinin can be of great potential in drug delivery systems.

  7. Mechanism of Action of Artemisinins: a Long Unsettled Challenge%青蒿素类药物的作用机制:一个长久未决的基础研究挑战

    Institute of Scientific and Technical Information of China (English)

    孙辰; 李坚; 周兵

    2012-01-01

    青蒿素是中国自主研制的抗疟良药,高效、低毒,许多基于青蒿素研发的衍生物具有良好的抗疟效果,近年来已成为抗疟的一线药物,受到世界医疗卫生界的充分肯定,虽然青蒿素结构奇特,抑疟效果显著,但40年来其生物作用机制之谜一直未被彻底破解.针对青蒿素类药物的作用机制,提出了不同的假说,如血红素参与青蒿素的激活并被烷基化从而起到抑疟作用,线粒体参与青蒿素的激活和作用过程,某些特定的蛋白是青蒿素作用靶点等.除抑疟外,青蒿素类药物在杀灭其他种类寄生虫、抑制某些癌症细胞以及抗病毒、治疗类风湿等方面也有一定作用.本文将对青蒿素类药物作用机制的研究进行综述及展望,包括抗疟疾过程中的药物激活、作用靶点以及简要的青蒿素抑制肿瘤细胞作用机制,以期为今后的研究提供帮助.%Artemisinin, discovered by Chinese scientists in the early 1970s, is an effective antimalarial drug with low toxicity. Artemisinins (artemisinin and its derivatives) remain as the gold standard in combating ever increasing drug-resistant malaria. Although intensive efforts have been devoted to explore the mode of action of this class of drugs, its exact mechanism remains an enigma. Many hypotheses have been proposed, such as iron and heme model, mitochondria model, PfATP6 model, and so forth. Recent studies have demonstrated that artemisinin and its analogs also possess potent inhibitory activities on some other parasites, cancer, virus and rheumatism. The aim of this review is to provide a mechanistic overview of the action of artemisinins.

  8. A topological study of the decomposition of 6,7,8-trioxabicyclo[3.2.2]nonane induced by Fe(II): modeling the artemisinin reaction with heme.

    Science.gov (United States)

    Moles, Pamela; Oliva, Mónica; Sánchez-González, Angel; Safont, Vicent S

    2010-01-21

    We report a theoretical study on the electronic and topological aspects of the reaction of dihydrated Fe(OH)(2) with 6,7,8-trioxabicyclo[3.2.2]nonane, as a model for the reaction of heme with artemisinin. A comparison is made with the reaction of dihydrated ferrous hydroxide with O(2), as a model for the heme interaction with oxygen. We found that dihydrated Fe(OH)(2) reacts more efficiently with the artemisinin model than with O(2). This result suggests that artemisinin instead of molecular oxygen would interact with heme, disrupting its detoxification process by avoiding the initial heme to hemin oxidation, and killing in this way the malaria parasite. The ELF and AIM theories provide support for such a conclusion, which further clarifies our understanding on how artemisinin acts as an antimalarial agent.

  9. The quality of antimalarials available in Yemen.

    Science.gov (United States)

    Abdo-Rabbo, Ahmed; Bassili, Amal; Atta, Hoda

    2005-06-29

    Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine) available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only) in comparison to standard specifications for these products in the relevant pharmacopoeia. The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This appears to be due to non-compliance with Good Manufacturing

  10. The quality of antimalarials available in Yemen

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    Atta Hoda

    2005-06-01

    Full Text Available Abstract Background Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. Methods Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only in comparison to standard specifications for these products in the relevant pharmacopoeia. Results The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. Conclusion There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This

  11. Flavonoids from Artemisia annua L. as Antioxidants and Their Potential Synergism with Artemisinin against Malaria and Cancer

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    Jorge F.S. Ferreira

    2010-04-01

    Full Text Available Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin.Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether, arteether, and artesunate. Artemisinin per se has not been used in mainstream clinical practice due to its poor bioavailability when compared to its analogs. In the past decade, the work with artemisinin-based compounds has expanded to their anti-cancer properties. Although artemisinin is a major bioactive component present in the traditional Chinese herbal preparations (tea, leaf flavonoids, also present in the tea, have shown a variety of biological activities and may synergize the effects of artemisinin against malaria and cancer. However, only a few studies have focused on the potential synergistic effects between flavonoids and artemisinin. The resurgent idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACT, instead of the previously used monotherapy with artemisinins. In this critical review we will discuss the possibility that artemisinin and its semi-synthetic analogs might become more effective to treat parasitic diseases (such as malaria and cancer if simultaneously delivered with flavonoids. The flavonoids present in A. annua leaves have been linked to suppression of CYP450 enzymes responsible for altering the absorption and metabolism of artemisinin in the body, but also have been linked to a beneficial immunomodulatory activity in subjects afflicted with parasitic and chronic diseases.

  12. Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis

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    Want MY

    2017-03-01

    Full Text Available Muzamil Y Want,1 Mohammad Islammudin,1 Garima Chouhan,1 Hani A Ozbak,2 Hassan A Hemeg,2 Asoke P Chattopadhyay,3 Farhat Afrin2 1Parasite Immunology Laboratory, Department of Biotechnology, Jamia Hamdard, Hamdard University, New Delhi, India; 2Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia; 3Department of Chemistry, University of Kalyani, Kalyani, India Abstract: Visceral leishmaniasis (VL is a fatal, vector-borne disease caused by the intracellular protozoa of the genus Leishmania. Most of the therapeutics for VL are toxic, expensive, or ineffective. Sesquiterpenes are a new class of drugs with proven antimicrobial and antiviral activities. Artemisinin is a sesquiterpene lactone with potent antileishmanial activity, but with limited access to infected cells, being a highly lipophilic molecule. Association of artemisinin with liposome is a desirable strategy to circumvent the problem of poor accessibility, thereby improving its efficacy, as demonstrated in a murine model of experimental VL. Nanoliposomal artemisinin (NLA was prepared by thin-film hydration method and optimized using Box–Behnken design with a mean particle diameter of 83±16 nm, polydispersity index of 0.2±0.03, zeta potential of -27.4±5.7 mV, and drug loading of 33.2%±2.1%. Morphological study of these nanoliposomes by microscopy showed a smooth and spherical surface. The mechanism of release of artemisinin from the liposomes followed the Higuchi model in vitro. NLA was free from concomitant signs of toxicity, both ex vivo in murine macrophages and in vivo in healthy BALB/c mice. NLA significantly denigrated the intracellular infection of Leishmania donovani amastigotes and the number of infected macrophages ex vivo with an IC50 of 6.0±1.4 µg/mL and 5.1±0.9 µg/mL, respectively. Following treatment in a murine model of VL, NLA demonstrated superior efficacy compared to artemisinin with a

  13. Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia

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    Taylor Walter RJ

    2007-02-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is being widely promoted as a strategy to counteract the increase in Plasmodium falciparum antimalarial drug resistance. Methods A randomized, double-blind, placebo-controlled, clinical trial of the efficacy, effect on gametocytes and safety of the addition of artesunate/placebo (4 mg/kg/day × 3 d to amodiaquine (10 mg/kg/day × 3 d was conducted in Choco department, a low intensity transmission area in northwest Colombia. Results From 2,137 screened subjects, 85 entered the study: 43 in the amodiaquine plus placebo and 42 in the amodiaquine plus artesunate groups. Potentially eligible cases failed to qualify mostly because they were not available for follow-up visits (73%. Based on a per protocol analysis, the therapeutic response to both treatments was high: amodiaquine/placebo 35/36, 97.2% (95% CI 85.5–99.9, and amodiaquine/artesunate 32/32, 100% (89.1–100 after PCR genotyping. The Kaplan-Meier survival estimates based on all eligible patients enrolled (amodiaquine/placebo: n = 42; amodiaquine/artesunate: n = 41 were similar in the two study groups (P = 0.3. The addition of artesunate significantly decreased gametocyte carriage on Day 4 (OR = 0.1 95% CI 0.02–0.6, Day 7 (OR = 0.2 95%CI 0.04–0.9, Day 14 (OR = 0.09 95% CI 0–0.8, and Day 21 (OR95%CI 0–0.9. Most subjects in both groups (81% in amodiaquine/placebo and 75.6% in amodiaquine/artesunate reported at least one drug related adverse event. Symptoms were generally mild and self-limiting and there was no serious adverse event. Two patients on amodiaquine/artesunate voluntarily withdrew from study because they could not tolerate the medication. Conclusion Both drug regimens were effective in this area of Colombia. The addition of artesunate reduced gametocyte carriage and did not adversely affect tolerability. In this set of patients, the rate of adverse events was higher than in other studies. Patients' follow-up is

  14. The anti-malarial drug Mefloquine disrupts central autonomic and respiratory control in the working heart brainstem preparation of the rat

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    Lall Varinder K

    2012-12-01

    Full Text Available Abstract Background Mefloquine is an anti-malarial drug that can have neurological side effects. This study examines how mefloquine (MF influences central nervous control of autonomic and respiratory systems using the arterially perfused working heart brainstem preparation (WHBP of the rat. Recordings of nerve activity were made from the thoracic sympathetic chain and phrenic nerve, while heart rate (HR and perfusion pressure were also monitored in the arterially perfused, decerebrate, rat WHBP. MF was added to the perfusate at 1 μM to examine its effects on baseline parameters as well as baroreceptor and chemoreceptor reflexes. Results MF caused a significant, atropine resistant, bradycardia and increased phrenic nerve discharge frequency. Chemoreceptor mediated sympathoexcitation (elicited by addition of 0.1 ml of 0.03% sodium cyanide to the aortic cannula was significantly attenuated by the application of MF to the perfusate. Furthermore MF significantly decreased rate of return to resting HR following chemoreceptor induced bradycardia. An increase in respiratory frequency and attenuated respiratory-related sympathetic nerve discharge during chemoreceptor stimulation was also elicited with MF compared to control. However, MF did not significantly alter baroreceptor reflex sensitivity. Conclusions These studies indicate that in the WHBP, MF causes profound alterations in autonomic and respiratory control. The possibility that these effects may be mediated through actions on connexin 36 containing gap junctions in central neurones controlling sympathetic nervous outflow is discussed.

  15. Repurposing the anti-malarial drug dihydroartemisinin suppresses metastasis of non-small-cell lung cancer via inhibiting NF-κB/GLUT1 axis.

    Science.gov (United States)

    Jiang, Jie; Geng, Guojun; Yu, Xiuyi; Liu, Hongming; Gao, Jing; An, Hanxiang; Cai, Chengfu; Li, Ning; Shen, Dongyan; Wu, Xiaoqiang; Zheng, Lisheng; Mi, Yanjun; Yang, Shuyu

    2016-12-27

    Non-small-cell lung cancer (NSCLC) is an aggressive malignancy and long-term survival remains unsatisfactory for patients with metastatic and recurrent disease. Repurposing the anti-malarial drug dihydroartemisinin (DHA) has been proved to possess potent antitumor effect on various cancers. However, the effects of DHA in preventing the invasion of NSCLC cells have not been studied. In the present study, we determined the inhibitory effects of DHA on invasion and migration and the possible mechanisms involved using A549 and H1975 cells. DHA inhibited in vitro migration and invasion of NSCLC cells even in low concentration with little cytotoxicity. Additionally, low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA. Our results suggested that DHA can inhibit metastasis of NSCLC by targeting glucose metabolism via inhibiting NF-κB signaling pathway and DHA may deserve further investigation in NSCLC treatment.

  16. Structure of 1-deoxy-d-xylulose 5-phosphate reductoisomerase in a quaternary complex with a magnesium ion, NADPH and the antimalarial drug fosmidomycin

    Energy Technology Data Exchange (ETDEWEB)

    Yajima, Shunsuke, E-mail: yshun@nodai.ac.jp; Hara, Kodai; Iino, Daisuke; Sasaki, Yasuyuki [Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502 (Japan); Kuzuyama, Tomohisa [Biotechnology Research Center, University of Tokyo, Bunkyo-ku, Tokyo 113-8657 (Japan); Ohsawa, Kanju [Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502 (Japan); Seto, Haruo [Department of Applied Biology and Chemistry, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502 (Japan); Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502 (Japan)

    2007-06-01

    The crystal structure of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) from Escherichia coli complexed with Mg{sup 2+}, NADPH and fosmidomycin was determined at 2.2 Å resolution. The structure showed a well defined loop conformation at the active site of DXR. The crystal structure of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) from Escherichia coli complexed with Mg{sup 2+}, NADPH and fosmidomycin was solved at 2.2 Å resolution. DXR is the key enzyme in the 2-C-methyl-d-erythritol 4-phosphate pathway and is an effective target of antimalarial drugs such as fosmidomycin. In the crystal structure, electron density for the flexible loop covering the active site was clearly observed, indicating the well ordered conformation of DXR upon substrate binding. On the other hand, no electron density was observed for the nicotinamide-ribose portion of NADPH and the position of Asp149 anchoring Mg{sup 2+} was shifted by NADPH in the active site.

  17. A cross-sectional analysis of traditional medicine use for malaria alongside free antimalarial drugs treatment amongst adults in high-risk malaria endemic provinces of Indonesia.

    Science.gov (United States)

    Suswardany, Dwi Linna; Sibbritt, David W; Supardi, Sudibyo; Pardosi, Jerico F; Chang, Sungwon; Adams, Jon

    2017-01-01

    The level of traditional medicine use, particularly Jamu use, in Indonesia is substantial. Indonesians do not always seek timely treatment for malaria and may seek self-medication via traditional medicine. This paper reports findings from the first focused analyses of traditional medicine use for malaria in Indonesia and the first such analyses worldwide to draw upon a large sample of respondents across high-risk malaria endemic areas. A sub-study of the Indonesia Basic Health Research/Riskesdas Study 2010 focused on 12,226 adults aged 15 years and above residing in high-risk malaria-endemic provinces. Logistic regression was undertaken to determine the significant associations for traditional medicine use for malaria symptoms. Approximately one in five respondents use traditional medicine for malaria symptoms and the vast majority experiencing multiple episodes of malaria use traditional medicine alongside free antimalarial drug treatments. Respondents consuming traditional medicine for general health/common illness purposes every day (odds ratio: 3.75, 95% Confidence Interval: 2.93 4.79), those without a hospital in local vicinity (odds ratio: 1.31, 95% Confidence Interval: 1.10 1.57), and those living in poorer quality housing, were more likely to use traditional medicine for malaria symptoms. A substantial percentage of those with malaria symptoms utilize traditional medicine for treating their malaria symptoms. In order to promote safe and effective malaria treatment, all providing malaria care in Indonesia need to enquire with their patients about possible traditional medicine use.

  18. Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice

    Science.gov (United States)

    Weathers, Pamela J.; Elfawal, Mostafa A.; Towler, Melissa J.; Acquaah-Mensah, George K.; Rich, Stephen M.

    2014-01-01

    .44 and 4.32 mg L−1, respectively, indicating that the presence of the plant matrix, even that of mouse chow, had a positive impact on the appearance of artemisinin in the blood. Conclusions These results showed that artemisinin and one of its drug metabolites were processed differently in healthy and infected mice. The results have implications for possible therapeutic use of pACT in treating malaria and other artemisinin-susceptible diseases. PMID:24661969

  19. A newly validated high-performance liquid chromatography method with diode array ultraviolet detection for analysis of the antimalarial drug primaquine in the blood plasma.

    Science.gov (United States)

    Carmo, Ana Paula Barbosa do; Borborema, Manoella; Ribeiro, Stephan; De-Oliveira, Ana Cecilia Xavier; Paumgartten, Francisco Jose Roma; Moreira, Davyson de Lima

    2017-01-01

    Primaquine (PQ) diphosphate is an 8-aminoquinoline antimalarial drug with unique therapeutic properties. It is the only drug that prevents relapses of Plasmodium vivax or Plasmodium ovale infections. In this study, a fast, sensitive, cost-effective, and robust method for the extraction and high-performance liquid chromatography with diode array ultraviolet detection (HPLC-DAD-UV ) analysis of PQ in the blood plasma was developed and validated. After plasma protein precipitation, PQ was obtained by liquid-liquid extraction and analyzed by HPLC-DAD-UV with a modified-silica cyanopropyl column (250mm × 4.6mm i.d. × 5μm) as the stationary phase and a mixture of acetonitrile and 10mM ammonium acetate buffer (pH = 3.80) (45:55) as the mobile phase. The flow rate was 1.0mL·min-1, the oven temperature was 50OC, and absorbance was measured at 264nm. The method was validated for linearity, intra-day and inter-day precision, accuracy, recovery, and robustness. The detection (LOD) and quantification (LOQ) limits were 1.0 and 3.5ng·mL-1, respectively. The method was used to analyze the plasma of female DBA-2 mice treated with 20mg.kg-1 (oral) PQ diphosphate. By combining a simple, low-cost extraction procedure with a sensitive, precise, accurate, and robust method, it was possible to analyze PQ in small volumes of plasma. The new method presents lower LOD and LOQ limits and requires a shorter analysis time and smaller plasma volumes than those of previously reported HPLC methods with DAD-UV detection. The new validated method is suitable for kinetic studies of PQ in small rodents, including mouse models for the study of malaria.

  20. The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance

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    Korenromp Eline

    2008-07-01

    Full Text Available Abstract Background HIV-related immune-suppression increases the risk of malaria (infection, disease and treatment failure and probably the circulating parasite biomass, favoring the emergence of drug resistance parasites. Methods The additional malaria parasite biomass related to HIV-1 co-infection in sub-Saharan Africa was estimated by a mathematical model. Parasite biomass was computed as the incidence rate of clinical malaria episodes multiplied by the number of parasites circulating in the peripheral blood of patients at the time symptoms appear. A mathematical model estimated the influence of HIV-1 infection on parasite density in clinical malaria by country and by age group, malaria transmission intensity and urban/rural area. In a multivariate sensitivity analysis, 95% confidence intervals (CIs were calculated using the Monte Carlo simulation. Results The model shows that in 2005 HIV-1 increased the overall malaria parasite biomass by 18.0% (95%CI: 11.6–26.9. The largest relative increase (134.9–243.9% was found in southern Africa where HIV-1 prevalence is the highest and malaria transmission unstable. The largest absolute increase was found in Zambia, Malawi, the Central African Republic and Mozambique, where both malaria and HIV are highly endemic. A univariate sensitivity analysis shows that estimates are sensitive to the magnitude of the impact of HIV-1 infection on the malaria incidence rates and associated parasite densities. Conclusion The HIV-1 epidemic by increasing the malaria parasite biomass in sub-Saharan Africa may also increase the emergence of antimalarial drug resistance, potentially affecting the health of the whole population in countries endemic for both HIV-1 and malaria.

  1. Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target.

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    Shiming Zhang

    Full Text Available Heme (Fe2+ protoporphyrin IX is an essential molecule that has been implicated the potent antimalarial action of artemisinin and its derivatives, although the source and nature of the heme remain controversial. Artemisinins also exhibit selective cytotoxicity against cancer cells in vitro and in vivo. We demonstrate that intracellular heme is the physiologically relevant mediator of the cytotoxic effects of artemisinins. Increasing intracellular heme synthesis through the addition of aminolevulinic acid, protoporphyrin IX, or transferrin-bound iron increased the cytotoxicity of dihydroartemisinin, while decreasing heme synthesis through the addition of succinyl acetone decreased its cytotoxic activity. A simple and robust high throughput assay was developed to screen chemical compounds that were capable of interacting with heme. A natural products library was screened which identified the compound coralyne, in addition to artemisinin, as a heme interacting compound with heme synthesis dependent cytotoxic activity. These results indicate that cellular heme may serve a general target for the development of both anti-parasitic and anti-cancer therapeutics.

  2. On peroxide antimalarials

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    IGOR OPSENICA

    2007-12-01

    Full Text Available Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure–activity relationship of this kind of antimalarials. The tetraoxanes 2–5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

  3. Drugs use pattern for uncomplicated malaria in medicine retail outlets in Enugu urban, southeast Nigeria: implications for malaria treatment policy.

    Science.gov (United States)

    Ezenduka, Charles C; Ogbonna, Brian O; Ekwunife, Obinna I; Okonta, Mathew J; Esimone, Charles O

    2014-06-24

    Malaria treatment policy recommends regular monitoring of drug utilization to generate information for ensuring effective use of anti-malarial drugs in Nigeria. This information is currently limited in the retail sector which constitutes a major source of malaria treatment in Nigeria, but are characterized by significant inappropriate use of drugs. This study analyzed the use pattern of anti-malarial drugs in medicine outlets to assess the current state of compliance to policy on the use of artemisinin-based combination therapy (ACT). A prospective cross-sectional survey of randomly selected medicine outlets in Enugu urban, southeast Nigeria, was conducted between May and August 2013, to determine the types, range, prices, and use pattern of anti-malarial drugs dispensed from pharmacies and patent medicine vendors (PMVs). Data were collected and analyzed for anti-malarial drugs dispensed for self-medication to patients, treatment by retail outlets and prescription from hospitals. A total of 1,321 anti-malarial drugs prescriptions were analyzed. ACT accounted for 72.7%, while monotherapy was 27.3%. Affordable Medicines Facility-malaria (AMFm) drugs contributed 33.9% (326/961) of ACT. Artemether-lumefantrine (AL), 668 (50.6%) was the most used anti-malarial drug, followed by monotherapy sulphadoxine-pyrimethamine (SP), 248 (18.8%). Median cost of ACT at $2.91 ($0.65-7.42) per dose, is about three times the median cost of monotherapy, $0.97 ($0.19-13.55). Total cost of medication (including co-medications) with ACT averaged $3.64 (95% CI; $3.53-3.75) per prescription, about twice the mean cost of treatment with monotherapy, $1.83 (95% CI; $1.57-2.1). Highest proportion 46.5% (614), of the anti-malarial drugs was dispensed to patients for self-treatment. Treatment by retail outlets accounted for 35.8% while 17.7% of the drugs were dispensed from hospital prescriptions. Self-medication, 82%, accounted for the highest source of monotherapy and a majority of prescriptions

  4. In vitro and in vivo treatments of echinococcus protoscoleces and metacestodes with artemisinin and artemisinin derivatives.

    Science.gov (United States)

    Spicher, Martin; Roethlisberger, Carole; Lany, Catharina; Stadelmann, Britta; Keiser, Jennifer; Ortega-Mora, Luis M; Gottstein, Bruno; Hemphill, Andrew

    2008-09-01

    In vitro treatment of Echinococcus multilocularis and Echinococcus granulosus larval stages with the antimalarials dihydroartemisinin and artesunate (10 to 40 microM) exhibited promising results, while 6 weeks of in vivo treatment of mice infected with E. multilocularis metacestodes (200 mg/kg of body weight/day) had no effect. However, combination treatments of both drugs with albendazole led to a substantial but statistically not significant reduction in parasite weight compared to results with albendazole alone.

  5. Therapeutic efficacy of artesunate in the treatment of uncomplicated Plasmodium falciparum malaria and anti-malarial, drug-resistance marker polymorphisms in populations near the China-Myanmar border

    Directory of Open Access Journals (Sweden)

    Huang Fang

    2012-08-01

    Full Text Available Abstract Background The aim of this study was to evaluate the clinical outcome after seven-day artesunate monotherapy for uncomplicated Plasmodium falciparum malaria in Yingjiang County along the China-Myanmar border and investigate genetic polymorphisms in the P. falciparum chloroquine-resistance transporter (pfcrt, multidrug resistance 1 (pfmdr1, dihydrofolate reductase (pfdhfr, dihydropteroate synthase (pfdhps and ATPase (pfatp6 genes. Methods Patients ≥ one year of age with fever (axillary temperature ≥37.5°C or history of fever and P. falciparum mono-infection were included. Patients received anti-malarial treatment with artesunate (total dose of 16 mg/kg over seven days by directly observed therapy. After a 28-day follow-up, treatment efficacy and effectiveness were assessed based on clinical and parasitological outcomes. Treatment failure was defined as recrudescence of the original parasite and distinguished with new infection confirmed by PCR. Analysis of gene mutation and amplification were performed by nested polymerase chain reaction. Results Sixty-five patients were enrolled; 10 withdrew from the study, and six were lost to follow-up. All but two patients demonstrated adequate clinical and parasitological response; 12 had detectable parasitaemia on day 3. These two patients were confirmed to be new infection by PCR. The efficacy of artesunate was 95.9%. The pfcrt mutation in codon 76 was found in all isolates (100%, and mutations in codons 71 and 72 were found in 4.8% of parasite isolates. No mutation of pfmdr1 (codons 86 or 1246 was found. Among all samples, 5.1% were wild type for pfdhfr, whereas the other samples had mutations in four codons (51, 59, 108 and 164, and mutations in pfdhps (codons 436, 437, 540 and 581 were found in all isolates. No samples had mutations in pfatp6 codons 623 or 769, but two new mutations (N683K and R756K were found in 4.6% and 9.2% of parasite isolates, respectively. Conclusion Plasmodium

  6. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies

    DEFF Research Database (Denmark)

    Vestergaard, Lasse S; Ringwald, Pascal

    2007-01-01

    additional information about changing patterns of resistance. However, some of the tests are technically demanding, and thus there is a need for more resources for training and capacity building in endemic countries to be able to adequately respond to the challenge of drug resistance....... of rational and updated malaria treatment policies, but defining and updating such policies requires a sufficient volume of high-quality drug-resistance data collected at national and regional levels. Three main tools are used for drug resistance monitoring, including therapeutic efficacy tests, in vitro...... tests, and analyses of molecular markers. Data obtained with the therapeutic efficacy test conducted according to the standard protocol of the World Health Organization are most useful for updating national treatment policies, while the in vitro test and molecular markers can provide important...

  7. Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon

    Directory of Open Access Journals (Sweden)

    Bley Daniel

    2009-07-01

    Full Text Available Abstract Background One year after the adoption of artesunate-amodiaquine (AS/AQ as first-line therapy for the treatment of uncomplicated malaria, this study was designed to assess the treatment practices regarding anti-malarial drugs at health facilities in four rural areas in southern Cameroon. Methods Between April and August 2005, information was collected by interviewing fifty-two health professionals from twelve rural health facilities, using a structured questionnaire. Results In 2005, only three anti-malarial drugs were used in rural health facilities, including: amodiaquine, quinine and sulphadoxine-pyrimethamine. Only 2.0% of the health professionals prescribed the recommended AS/AQ combination. After reading the treatment guidelines, 75.0% were in favour of the treatment protocol with the following limitations: lack of paediatric formulations, high cost and large number of tablets per day. Up to 21.0% of professionals did not prescribe AS/AQ because of the level of adverse events attributed to the use of amodiaquine as monotherapy. Conclusion The present study indicates that AS/AQ was not available in the public health facilities at the time of the study, and health practitioners were not informed about the new treatment guidelines. Results of qualitative analysis suggest that prescribers should be involved as soon as possible in projects related to the optimization of treatment guidelines and comply with new drugs. Adapted formulations should be made available at the international level and implemented locally before new drugs and treatments are proposed through a national control programme. This baseline information will be useful to monitor progresses in the implementation of artemisinin-based combination therapy in Cameroon.

  8. 7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid derivatives and their antimalarial activity

    Directory of Open Access Journals (Sweden)

    BOGDAN SOLAJA

    2004-11-01

    Full Text Available Several C2 symmetrical mixed tetraoxanes were prepared starting from a gemdihydroperoxide and a ketone. The obtained tetraoxanes showed pronounced antimalarial activity against P. falciparum chloroquine resistant W2 and chloroquine susceptible D6 strains, with N-(2-dimethylaminoethyl-7,8,15,16-tetraoxa-dispiro[5.2.5.2] hexadecane-3-carboxamide being as active as artemisinin.

  9. Genetically Determined Response to Artemisinin Treatment in Western Kenyan Plasmodium falciparum Parasites

    Science.gov (United States)

    Chebon, Lorna J.; Ngalah, Bidii S.; Ingasia, Luicer A.; Juma, Dennis W.; Muiruri, Peninah; Cheruiyot, Jelagat; Opot, Benjamin; Mbuba, Emmanuel; Imbuga, Mabel; Akala, Hoseah M.; Bulimo, Wallace; Andagalu, Ben; Kamau, Edwin

    2016-01-01

    Genetically determined artemisinin resistance in Plasmodium falciparum has been described in Southeast Asia. The relevance of recently described Kelch 13-propeller mutations for artemisinin resistance in Sub-Saharan Africa parasites is still unknown. Southeast Asia parasites have low genetic diversity compared to Sub-Saharan Africa, where parasites are highly genetically diverse. This study attempted to elucidate whether genetics provides a basis for discovering molecular markers in response to artemisinin drug treatment in P. falciparum in Kenya. The genetic diversity of parasites collected pre- and post- introduction of artemisinin combination therapy (ACT) in western Kenya was determined. A panel of 12 microsatellites and 91 single nucleotide polymorphisms (SNPs) distributed across the P. falciparum genome were genotyped. Parasite clearance rates were obtained for the post-ACT parasites. The 12 microsatellites were highly polymorphic with post-ACT parasites being significantly more diverse compared to pre-ACT (p resistance in Kenya. PMID:27611315

  10. Bioguided investigation of the antimalarial activities of Trema orientalis

    African Journals Online (AJOL)

    Aghomotsegin

    2015-10-28

    Oct 28, 2015 ... of the emergence of resistance to nearly all antimalarial drugs (Kim and Schneider, 2013). Trema orientalis ... parasitic disease remains a public health concern which ... cause of under five mortality (20%) and constitutes 10%.

  11. Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin.

    Science.gov (United States)

    Küster, Tatiana; Stadelmann, Britta; Rufener, Reto; Risch, Corina; Müller, Joachim; Hemphill, Andrew

    2015-11-01

    This study investigated the effects of oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine (MEF) and identified proteins that bind to MEF in parasite extracts and human cells by affinity chromatography. In a pilot experiment, MEF treatment was applied 5 days per week and was intensified by increasing the dosage stepwise from 12.5 mg/kg to 200 mg/kg during 4 weeks followed by treatments of 100 mg/kg during the last 7 weeks. This resulted in a highly significant reduction of parasite weight in MEF-treated mice compared with mock-treated mice, but the reduction was significantly less efficacious compared with the standard treatment regimen of albendazole (ABZ). In a second experiment, MEF was applied orally in three different treatment groups at dosages of 25, 50 or 100 mg/kg, but only twice a week, for a period of 12 weeks. Treatment at 100 mg/kg had a profound impact on the parasite, similar to ABZ treatment at 200 mg/kg/day (5 days/week for 12 weeks). No adverse side effects were noted. To identify proteins in E. multilocularis metacestodes that physically interact with MEF, affinity chromatography of metacestode extracts was performed on MEF coupled to epoxy-activated Sepharose(®), followed by SDS-PAGE and in-gel digestion LC-MS/MS. This resulted in the identification of E. multilocularis ferritin and cystatin as MEF-binding proteins. In contrast, when human cells were exposed to MEF affinity chromatography, nicotinamide phosphoribosyltransferase was identified as a MEF-binding protein. This indicates that MEF could potentially interact with different proteins in parasites and human cells.

  12. A cross-sectional analysis of traditional medicine use for malaria alongside free antimalarial drugs treatment amongst adults in high-risk malaria endemic provinces of Indonesia

    Science.gov (United States)

    Suswardany, Dwi Linna; Sibbritt, David W.; Supardi, Sudibyo; Pardosi, Jerico F.; Chang, Sungwon; Adams, Jon

    2017-01-01

    Background The level of traditional medicine use, particularly Jamu use, in Indonesia is substantial. Indonesians do not always seek timely treatment for malaria and may seek self-medication via traditional medicine. This paper reports findings from the first focused analyses of traditional medicine use for malaria in Indonesia and the first such analyses worldwide to draw upon a large sample of respondents across high-risk malaria endemic areas. Methods A sub-study of the Indonesia Basic Health Research/Riskesdas Study 2010 focused on 12,226 adults aged 15 years and above residing in high-risk malaria-endemic provinces. Logistic regression was undertaken to determine the significant associations for traditional medicine use for malaria symptoms. Findings Approximately one in five respondents use traditional medicine for malaria symptoms and the vast majority experiencing multiple episodes of malaria use traditional medicine alongside free antimalarial drug treatments. Respondents consuming traditional medicine for general health/common illness purposes every day (odds ratio: 3.75, 95% Confidence Interval: 2.93 4.79), those without a hospital in local vicinity (odds ratio: 1.31, 95% Confidence Interval: 1.10 1.57), and those living in poorer quality housing, were more likely to use traditional medicine for malaria symptoms. Conclusion A substantial percentage of those with malaria symptoms utilize traditional medicine for treating their malaria symptoms. In order to promote safe and effective malaria treatment, all providing malaria care in Indonesia need to enquire with their patients about possible traditional medicine use. PMID:28329019

  13. Effect of irradiated sodium alginate and phosphorus on biomass and artemisinin production in Artemisia annua.

    Science.gov (United States)

    Aftab, Tariq; Khan, M Masroor A; Naeem, M; Idrees, Mohd; Siddiqi, T O; Moinuddin; Varshney, Lalit

    2014-09-22

    It is now being realized that irradiation products of natural bioactive agents can also be beneficially utilized to impart value addition in agriculture by converting these bioactive agents into more useful form. Polysaccharides, such as sodium alginate, have proven to be wonderful growth promoting substances in their depolymerized form for various plants. Artemisinin has been increasingly popular as an effective and safe alternative therapy against malaria; also proved effective against the highly adaptable malaria parasite, which has already become resistant to many other drugs. The drug artemisinin can be extracted from the leafy tissues of Artemisia annua. Therefore, experiments were conducted with an aim to evaluate artemisinin production and overall plant development though depolymerized sodium alginate application and nutrient supply. In the present study, sodium alginate, irradiated by Co-60 gamma rays together with various phosphorus doses, was used to study their effect on growth, physiological and biochemical processes and production of artemisinin in A. annua. Among various applied doses of phosphorus fertilizer, P40 (40 kg Pha(-1)) together with ISA80 (80 mg L(-1)) significantly improved all the parameters studied. Increase in plant height as well as weight was noted at this treatment. Dry leaf yield, artemisinin concentration in leaves and artemisinin yield was also significantly enhanced by the treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Synergistic Inhibition of Delayed Rectifier K+ and Voltage-Gated Na+ Currents by Artemisinin in Pituitary Tumor (GH3 Cells

    Directory of Open Access Journals (Sweden)

    Edmund Cheung So

    2017-04-01

    Full Text Available Background: Artemisinin (ART is an anti-malarial agent reported to influence endocrine function. Methods: Effects of ART on ionic currents and action potentials (APs in pituitary tumor (GH3 cells were evaluated by patch clamp techniques. Results: ART inhibited the amplitude of delayed-rectifier K+ current (IK(DR in response to membrane depolarization and accelerated the process of current inactivation. It exerted an inhibitory effect on IK(DR with an IC50 value of 11.2 µM and enhanced IK(DR inactivation with a KD value of 14.7 µM. The steady-state inactivation curve of IK(DR was shifted to hyperpolarization by 10 mV. Pretreatment of chlorotoxin (1 µM or iloprost (100 nM did not alter the magnitude of ART-induced inhibition of IK(DR in GH3 cells. ART also decreased the peak amplitude of voltage-gated Na+ current (INa with a concentration-dependent slowing in inactivation rate. Application of KMUP-1, an inhibitor of late INa, was effective at reversing ART-induced prolongation in inactivation time constant of INa. Under current-clamp recordings, ART alone reduced the amplitude of APs and prolonged the duration of APs. Conclusion: Under ART exposure, the inhibitory actions on both IK(DR and INa could be a potential mechanisms through which this drug influences membrane excitability of endocrine or neuroendocrine cells appearing in vivo.

  15. Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

    Science.gov (United States)

    Borrmann, Steffen; Straimer, Judith; Mwai, Leah; Abdi, Abdirahman; Rippert, Anja; Okombo, John; Muriithi, Steven; Sasi, Philip; Kortok, Moses Mosobo; Lowe, Brett; Campino, Susana; Assefa, Samuel; Auburn, Sarah; Manske, Magnus; Maslen, Gareth; Peshu, Norbert; Kwiatkowski, Dominic P.; Marsh, Kevin; Nzila, Alexis; Clark, Taane G.

    2013-01-01

    Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections. PMID:24270944

  16. Factors related to compliance to anti-malarial drug combination: example of amodiaquine/sulphadoxine-pyrimethamine among children in rural Senegal

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    Sow Diarietou

    2009-06-01

    Full Text Available Abstract Background The introduction of new anti-malarial treatment that is effective, but more expensive, raises questions about whether the high level of effectiveness observed in clinical trials can be found in a context of family use. The objective of this study was to determine the factors related to adherence, when using the amodiaquine/sulphadoxine-pyrimethamine (AQ/SP association, a transitory strategy before ACT implementation in Senegal. Methods The study was conducted in five rural dispensaries. Children, between two and 10 years of age, who presented mild malaria were recruited at the time of the consultation and were prescribed AQ/SP. The child's primary caretaker was questioned at home on D3 about treatment compliance and factors that could have influenced his or her adherence to treatment. A logistic regression model was used for the analyses. Results The study sample included 289 children. The adherence rate was 64.7%. Two risks factors for non-adherence were identified: the children's age (8–10 years (ORa = 3.07 [1.49–6.29]; p = 0.004; and the profession of the head of household (retailer/employee versus farmer (ORa = 2.71 [1.34–5.48]; p = 0.006. Previously seeking care (ORa = 0.28 [0.105–0.736], p=0.001] satisfaction with received information (ORa = 0.45 [0.24–0.84]; p = 0.013, and the quality of history taking (ORa = 0.38 [0.21–0.69]; p = 0.001 were significantly associated with good compliance. Conclusion The results of the study show the importance of information and communication between caregivers and health center staff. The experience gained from this therapeutic transition emphasizes the importance of information given to the patients at the time of the consultation and drug delivery in order to improve drug use and thus prevent the emergence of rapid drug resistance.

  17. [Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs].

    Science.gov (United States)

    Piatakova, N V; Severina, I S

    2012-01-01

    The influence of ambroxol--a mucolytic drug--on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 microM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 microM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX. The influence of artemisinin--an antimalarial drug--on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 microM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 microM. Artemisinin (10 microM) also inhibited (by 71 +/- 4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 microM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

  18. Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar

    2013-01-01

    Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children...... on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n=352) were collected from children under 5years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two...... on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant...

  19. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs.

    Science.gov (United States)

    Spillman, Natalie Jane; Kirk, Kiaran

    2015-12-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na(+) concentration and the plasma membrane P-type cation translocating ATPase 'PfATP4' has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's 'Malaria Box'. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na(+). Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field.

  20. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs

    Directory of Open Access Journals (Sweden)

    Natalie Jane Spillman

    2015-12-01

    Full Text Available The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's ‘Malaria Box’. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na+. Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field.

  1. Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal.

    Science.gov (United States)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar; Ndiaye, Jean L; Diouf, Ibrahima; Lo, Aminata C; Sylla, Khadime; Dieng, Yemou; Hallett, Rachel; Alifrangis, Michael; Gaye, Oumar

    2013-01-01

    Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n=352) were collected from children under 5years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant haplotypes (CNRN and CICN) was stable between years atSenegal according to WHO recommendations.

  2. A combined within-host and between-hosts modelling framework for the evolution of resistance to antimalarial drugs.

    Science.gov (United States)

    Legros, Mathieu; Bonhoeffer, Sebastian

    2016-04-01

    The spread of drug resistance represents a significant challenge to many disease control efforts. The evolution of resistance is a complex process influenced by transmission dynamics between hosts as well as infection dynamics within these hosts. This study aims to investigate how these two processes combine to impact the evolution of resistance in malaria parasites. We introduce a stochastic modelling framework combining an epidemiological model of Plasmodium transmission and an explicit within-human infection model for two competing strains. Immunity, treatment and resistance costs are included in the within-host model. We show that the spread of resistance is generally less likely in areas of intense transmission, and therefore of increased competition between strains, an effect exacerbated when costs of resistance are higher. We also illustrate how treatment influences the spread of resistance, with a trade-off between slowing resistance and curbing disease incidence. We show that treatment coverage has a stronger impact on disease prevalence, whereas treatment efficacy primarily affects resistance spread, suggesting that coverage should constitute the primary focus of control efforts. Finally, we illustrate the importance of feedbacks between modelling scales. Overall, our results underline the importance of concomitantly modelling the evolution of resistance within and between hosts.

  3. Factors associated with non-adherence to Artemisinin-based combination therapy (ACT) to malaria in a rural population from holoendemic region of western Kenya.

    Science.gov (United States)

    Onyango, Elizabeth O; Ayodo, George; Watsierah, Carren A; Were, Tom; Okumu, Wilson; Anyona, Samuel B; Raballah, Evans; Okoth, John M; Gumo, Sussy; Orinda, George O; Ouma, Collins

    2012-06-24

    Over the years, reports implicate improper anti-malarial use as a major contributor of morbidity and mortality amongst millions of residents in malaria endemic areas, Kenya included. However, there are limited reports on improper use of Artemisinin-based Combination Therapy (ACT) which is a first-line drug in the treatment of malaria in Kenya. Knowing this is important for ensured sustainable cure rates and also protection against the emergence of resistant malarial parasites. We therefore investigated ACT adherence level, factors associated with non-adherence and accessibility in households (n = 297) in rural location of Southeast Alego location in Siaya County in western Kenya. ACT Adherence level was assessed with reference to the duration of treatment and number of tablets taken. Using systematic random sampling technique, a questionnaire was administered to a particular household member who had the most recent malaria episode ( 9000; OR, 0.340; 95% CI, 0.167-0.694; P = 0.003) were associated with ACT adherence. In addition, about 52.9% of the respondents reported that ACT was not always available at the source and that drug availability (P = 0.020) and distance to drug source (P < 0.01) significantly affected accessibility. This study demonstrates that more than half of those who get ACT prescription do not take recommended dose and that accessibility is of concern. The findings of this study suggest a potential need to improve accessibility and also initiate programmatic interventions to encourage patient-centred care.

  4. Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area

    Directory of Open Access Journals (Sweden)

    Song Jianping

    2011-08-01

    Full Text Available Abstract Background Drug resistance of falciparum malaria is a global problem. Sulphadoxine/pyrimethamine-resistant and mefloquine-resistant strains of falciparum malaria have spread in Southeast Asia at lightning speed in 1980s-1990s, and the Cambodia-Thailand border is one of the malaria epidemic areas with the most severe forms of multi-drug resistant falciparum malaria. Methods Artemisinin-piperaquine (AP, dihydroartemisinin-piperaquine phosphate (DHP and artemether-lumefantrine (AL were used to treat 110, 55 and 55 uncomplicated malaria patients, respectively. The total dosage for adults is 1,750 mg (four tablets, twice over 24 hours of AP, 2,880 mg (eight tablets, four times over two days of DHP, and 3,360 mg (24 tablets, six times over three days of AL. The 28-day cure rate, parasite clearance time, fever clearance time, and drug tolerance of patients to the three drugs were compared. All of the above methods were consistent with the current national guidelines. Results The mean parasite clearance time was similar in all three groups (66.7 ± 21.9 hrs, 65.6 ± 27.3 hrs, 65.3 ± 22.5 hrs in AP, DHP and AL groups, respectively, and there was no remarkable difference between them; the fever clearance time was also similar (31.6 ± 17.7 hrs, 34.6 ± 21.8 hrs and 36.9 ± 15.4 hrs, respectively. After following up for 28-days, the cure rate was 95.1%(97/102, 98.2%(54/55 and 82.4%(42/51; and the recrudescence cases was 4.9%(5/102, 1.8%(1/55 and 17.6%(9/51, respectively. Therefore, the statistical data showed that 28-day cure rate in AP and DHP groups was superior to AL group obviously. The patients had good tolerance to all the three drugs, and some side effects (anoxia, nausea, vomiting, headache and dizziness could be found in every group and they were self-limited; patients in control groups also had good tolerance to DHP and AL, there was no remarkable difference in the three groups. Conclusions AP, DHP and AL all remained efficacious

  5. Modelling the impact of artemisinin combination therapy and long-acting treatments on malaria transmission intensity.

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    Lucy C Okell

    2008-11-01

    Full Text Available BACKGROUND: Artemisinin derivatives used in recently introduced combination therapies (ACTs for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas. METHODS AND FINDINGS: We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%, compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%. Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact

  6. Highly active ozonides selected against drug resistant malaria

    Science.gov (United States)

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  7. Highly active ozonides selected against drug resistant malaria

    Directory of Open Access Journals (Sweden)

    Lis Lobo

    2016-01-01

    Full Text Available Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART, artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.

  8. Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance.

    Science.gov (United States)

    Chaorattanakawee, Suwanna; Saunders, David L; Sea, Darapiseth; Chanarat, Nitima; Yingyuen, Kritsanai; Sundrakes, Siratchana; Saingam, Piyaporn; Buathong, Nillawan; Sriwichai, Sabaithip; Chann, Soklyda; Se, Youry; Yom, You; Heng, Thay Kheng; Kong, Nareth; Kuntawunginn, Worachet; Tangthongchaiwiriya, Kuntida; Jacob, Christopher; Takala-Harrison, Shannon; Plowe, Christopher; Lin, Jessica T; Chuor, Char Meng; Prom, Satharath; Tyner, Stuart D; Gosi, Panita; Teja-Isavadharm, Paktiya; Lon, Chanthap; Lanteri, Charlotte A

    2015-08-01

    Cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure.

  9. Review of pyronaridine anti-malarial properties and product characteristics

    Directory of Open Access Journals (Sweden)

    Croft Simon L

    2012-08-01

    Full Text Available Abstract Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

  10. Use of Model-Based Nutrient Feeding for Improved Production of Artemisinin by Hairy Roots of Artemisia Annua in a Modified Stirred Tank Bioreactor.

    Science.gov (United States)

    Patra, Nivedita; Srivastava, Ashok K

    2015-09-01

    Artemisinin has been indicated to be a potent drug for the cure of malaria. Batch growth and artemisinin production kinetics of hairy root cultures of Artemisia annua were studied under shake flask conditions which resulted in accumulation of 12.49 g/L biomass and 0.27 mg/g artemisinin. Using the kinetic data, a mathematical model was identified to understand and optimize the system behavior. The developed model was then extrapolated to design nutrient feeding strategies during fed-batch cultivation for enhanced production of artemisinin. In one of the fed-batch cultivation, sucrose (37 g/L) feeding was done at a constant feed rate of 0.1 L/day during 10-15 days, which led to improved artemisinin accumulation of 0.77 mg/g. The second strategy of fed-batch hairy root cultivation involved maintenance of pseudo-steady state sucrose concentration (20.8 g/L) during 10-15 days which resulted in artemisinin accumulation of 0.99 mg/g. Fed-batch cultivation (with the maintenance of pseudo-steady state of substrate) of Artemisia annua hairy roots was, thereafter, implemented in bioreactor cultivation, which featured artemisinin accumulation of 1.0 mg/g artemisinin in 16 days of cultivation. This is the highest reported artemisinin yield by hairy root cultivation in a bioreactor.

  11. The Biosynthesis of Artemisinin (Qinghaosu and the Phytochemistry of Artemisia annua L. (Qinghao

    Directory of Open Access Journals (Sweden)

    Geoffrey D. Brown

    2010-10-01

    Full Text Available The Chinese medicinal plant Artemisia annua L. (Qinghao is the only known source of the sesquiterpene artemisinin (Qinghaosu, which is used in the treatment of malaria. Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. The phytochemistry of A. annua is dominated by both sesquiterpenoids and flavonoids, as is the case for many other plants in the Asteraceae family. However, A. annua is distinguished from the other members of the family both by the very large number of natural products which have been characterised to date (almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes, and by the highly oxygenated nature of many of the terpenoidal secondary metabolites. In addition, this species also contains an unusually large number of terpene allylic hydroperoxides and endoperoxides. This observation forms the basis of a proposal that the biogenesis of many of the highly oxygenated terpene metabolites from A. annua – including artemisinin itself – may proceed by spontaneous oxidation reactions of terpene precursors, which involve these highly reactive allyllic hydroperoxides as intermediates. Although several studies of the biosynthesis of artemisinin have been reported in the literature from the 1980s and early 1990s, the collective results from these studies were rather confusing because they implied that an unfeasibly large number of different sesquiterpenes could all function as direct precursors to artemisinin (and some of the experiments also appeared to contradict one another. As a result, the complete biosynthetic pathway to artemisinin could not be stated conclusively at the time. Fortunately, studies which have been published in the last decade are now providing a clearer picture of the biosynthetic pathways in A. annua. By synthesising some of the sesquiterpene natural products

  12. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    OpenAIRE

    Norazsida Ramli; Pakeer Oothuman Syed Ahamed; Hassan Mohamed Elhady; Muhammad Taher

    2014-01-01

    Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral t...

  13. A novel in vitro bioluminescence rate-of-kill (BRoK) assay to study the pharmacodynamic properties of antimalarial drug action in Plasmodium falciparum

    OpenAIRE

    Ullah, Imran

    2016-01-01

    Massive screens of chemical libraries for antimalarial activity have identified thousands of compounds that exhibit sub-micromolar potency against the blood stage of the malaria parasite Plasmodium falciparum. Triaging these compounds to establish priorities to take forward for development requires additional information regarding their activity. Key amongst their pharmacodynamics (PD) properties is the rate of kill– with a rapid cytocidal effect specifically identified as a key requirement f...

  14. Pyrimidines in antimalarial drug design

    CSIR Research Space (South Africa)

    Moleele, SS

    2008-09-01

    Full Text Available .0. Of the initial series of pyrimethamine analogues 3 screened in silico, 3a-c scored well in the docking experiments (Figure 2), with the majority of the compounds scoring better than pyrimethamine 1. In each case, the flexible linker allows for the aromatic... to 1, which is a rigid molecule, is thought to arise from steric clashes with mutant amino acid residues within the PfDHFR active site. In comparison, WR99210 2, which contains a flexible linker between the two rings, maintains binding affinity to all...

  15. Adherence and uptake of artemisinin-based combination treatments for uncomplicated malaria: a qualitative study in northern Ghana.

    Directory of Open Access Journals (Sweden)

    Samuel Chatio

    Full Text Available Based on the recommendations of the World Health Organization in 2004, Ghana changed her antimalarial drug policy from mono-therapy to Artemisinin-based Combination Therapy (ACTs. The country is currently using three first line drugs artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria. Despite this policy, little or no qualitative studies have been conducted to establish the factors influencing adherence to the new treatment for malaria. This study explored factors influencing adherence to the use of ACTs in northern Ghana.This was a qualitative study comprising forty (40 in-depth interviews with patients with malaria who visited selected public and private health facilities and received ACTs. Systematic sampling technique was used to select participants who were given ACTs for the interviews. Nvivo 9 software was used to code the data into themes for further analysis.The study revealed very important differences in knowledge about ACTs. As expected, the less or illiterates could not mention the type of ACT they would prefer to use for treating their malaria. The educated ones had a good knowledge on ACTs and preferred artemether-lumefantrinee in treating their malaria. The reason was that the drug was good and it had minimal or no side effects. Individual attitudes toward the use of medications and the side effects associated with the use of these ACTs were found to be the main factors affecting adherence to the use of ACTs. Perceived cure of illness after the initial dose greatly affected adherence. Other factors such as forgetfulness and lack of information also influenced patient adherence to ACTs use.Individual knowledge, attitudes and behaviors greatly influence patients' adherence to ACTs use. Since ACTs take a number of days to complete, continuous education by health professionals could improve on adherence to ACTs use by patients with malaria.

  16. Comparative embryotoxicity of different antimalarial peroxides: in vitro study using the rat whole embryo culture model (WEC).

    Science.gov (United States)

    Longo, Monica; Zanoncelli, Sara; Brughera, Marco; Colombo, Paolo; Wittlin, Sergio; Vennerstrom, Jonathan L; Moehrle, Joerg; Craft, J Carl

    2010-12-01

    Three groups of compounds: (i) active peroxides (artemisinin and arterolene), (ii) inactive non-peroxidic derivatives (deoxyartemisinin and carbaOZ277) and (iii) inactive peroxide (OZ381) were tested by WEC system to provide insights into the relationship between chemical structure and embryotoxic potential, and to assess the relationship between embryotoxicity and antimalarial activity. Deoxyartemisinin, OZ381 and carbaOZ277 did not affect rat embryonic development. Artemisinin and arterolane affected primarily nucleated red blood cells (RBCs), inducing anemia and subsequent tissue damage in rat embryos, with NOELs for RBC damage at 0.1 and 0.175μg/mL, respectively. These data support the idea that only active antimalarial peroxides are able to interfere with normal embryonic development. In an attempt to establish whether and to what extent activity as antimalarials and embryotoxicity can be divorced, IC(50)s for activity in Plasmodium falciparum strains and the NOELs for RBCs were compared. From this comparison, arterolane showed a better safety margin than artemisinin.

  17. Access to artemisinin-based combination therapy (ACT) and quinine in malaria holoendemic regions of western Kenya.

    Science.gov (United States)

    Watsierah, Carren A; Ouma, Collins

    2014-07-28

    Artemisinin-based combination therapy (ACT) has been adopted as the most effective treatment against malaria in many endemic countries like Kenya while quinine has remained the second line. The objective of the current study was to assess access to Kenya's policy recommended anti-malarials, ACT and quinine in the public, private and not-for-profit drug outlets in western Kenya. A cross-sectional survey using purposive sampling of 288 outlets (126 public, 96 private, 66 not-for-profit) was conducted in western Kenya in two regions with varying Plasmodium falciparum endemicities. Information on access (availability, price, affordability) on ACT and quinine was collected using the WHO and Healthcare Associated Infection (HAI) standardized methodologies for availability, prices and affordability of drugs. From a Ministry of Health database, the following were included in the analyses: one (1) main public hospital, followed by random selection of five hospitals under this main facility. Eight other public outlets under each of the hospitals were selected, to a total of 96. Matching number of private outlets (n = 96), all (66) not-for-profit outlets and additional 30 public health facilities were sampled to get the required sample size of 288. More public 111 (88.1%) and not-for-profit 27 (40.9%) outlets stocked subsidized ACT (artemether-lumefantrine, AL). Other artemisinin-based combinations were widely available for both children 93 (96.9%) and adults 82 (85.0%) in private outlets. Frequent stock-outs were in public in 106 (84%), reporting three times or more stock-outs in three months. Subsidized ACT (AL) was sold at median price of USD 0.94 and 0.75 in private and not-for-profit outlets respectively. The costs was higher than recommended price of USD 0.5 and requiring up to 0.20-0.25 days of disposable income for households in lowest economic status. There is low availability of subsidized ACT (AL) and higher frequency of stock-outs in government facilities, while

  18. Improving uptake and use of malaria rapid diagnostic tests in the context of artemisinin drug resistance containment in eastern Myanmar: an evaluation of incentive schemes among informal private healthcare providers.

    Science.gov (United States)

    Aung, Tin; White, Christopher; Montagu, Dominic; McFarland, Willi; Hlaing, Thaung; Khin, Hnin Su Su; San, Aung Kyaw; Briegleb, Christina; Chen, Ingrid; Sudhinaraset, May

    2015-03-06

    As efforts to contain artemisinin resistance and eliminate Plasmodium falciparum intensify, the accurate diagnosis and prompt effective treatment of malaria are increasingly needed in Myanmar and the Greater Mekong Sub-region (GMS). Rapid diagnostic tests (RDTs) have been shown to be safe, feasible, and effective at promoting appropriate treatment for suspected malaria, which are of particular importance to drug resistance containment. The informal private sector is often the first point of care for fever cases in malaria endemic areas across Myanmar and the GMS, but there is little published information about informal private provider practices, quality of service provision, or potential to contribute to malaria control and elimination efforts. This study tested different incentives to increase RDT use and improve the quality of care among informal private healthcare providers in Myanmar. The study randomized six townships in the Mon and Shan states of rural Myanmar into three intervention arms: 1) RDT price subsidies, 2) price subsidies with product-related financial incentives, and 3) price subsidies with intensified information, education and counselling (IEC). The study assessed the uptake of RDT use in the communities by cross-sectional surveys of 3,150 households at baseline and six months post-intervention (6,400 households total, 832 fever cases). The study also used mystery clients among 171 providers to assess quality of service provision across intervention arms. The pilot intervention trained over 600 informal private healthcare providers. The study found a price subsidy with intensified IEC, resulted in the highest uptake of RDTs in the community, as compared to subsidies alone or merchandise-related financial incentives. Moreover, intensified IEC led to improvements in the quality of care, with mystery client surveys showing almost double the number of correct treatment following diagnostic test results as compared to a simple subsidy. Results show

  19. Metabolic engineering of E.coli for the production of a precursor to artemisinin, an anti-malarial drug [Chapter 25 in Manual of Industrial Microbiology and Biotechnology, 3rd edition

    Energy Technology Data Exchange (ETDEWEB)

    Petzold, Christopher; Keasling, Jay

    2011-07-18

    This document is Chapter 25 in the Manual of Industrial Microbiology and Biotechnology, 3rd edition. Topics covered include: Incorporation of Amorpha-4,11-Diene Biosynthetic Pathway into E. coli; Amorpha-4,11-Diene Pathway Optimization; "-Omics" Analyses for Increased Amorpha-4,11-Diene Production; Biosynthetic Oxidation of Amorpha-4,11-Diene.

  20. Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads

    DEFF Research Database (Denmark)

    Jensen, Kasper; Plichta, Damian Rafal; Panagiotou, Gianni;

    2012-01-01

    The parasite Plasmodium falciparum is the main agent responsible for malaria. In this study, we exploited a recently published chemical library from GlaxoSmithKline (GSK) that had previously been confirmed to inhibit parasite growth of the wild type (3D7) and the multi-drug resistance (D2d) strains......, in order to uncover the weak links in the proteome of the parasite. We predicted 293 proteins of P. falciparum, including the six out of the seven verified targets for P. falciparum malaria treatment, as targets of 4645 GSK active compounds. Furthermore, we prioritized druggable targets, based on a number...... on integration of available chemical-protein and protein-protein interaction data. Our work suggests that a large number of the P. falciparum proteome is potentially druggable and could therefore serve as novel drug targets in the fight against malaria. At the same time, prioritized compounds from the GSK...

  1. The impact of text message reminders on adherence to antimalarial treatment in northern Ghana: a randomized trial.

    Science.gov (United States)

    Raifman, Julia R G; Lanthorn, Heather E; Rokicki, Slawa; Fink, Günther

    2014-01-01

    Low rates of adherence to artemisinin-based combination therapy (ACT) regimens increase the risk of treatment failure and may lead to drug resistance, threatening the sustainability of current anti-malarial efforts. We assessed the impact of text message reminders on adherence to ACT regimens. Health workers at hospitals, clinics, pharmacies, and other stationary ACT distributors in Tamale, Ghana provided flyers advertising free mobile health information to individuals receiving malaria treatment. The messaging system automatically randomized self-enrolled individuals to the control group or the treatment group with equal probability; those in the treatment group were further randomly assigned to receive a simple text message reminder or the simple reminder plus an additional statement about adherence in 12-hour intervals. The main outcome was self-reported adherence based on follow-up interviews occurring three days after treatment initiation. We estimated the impact of the messages on treatment completion using logistic regression. 1140 individuals enrolled in both the study and the text reminder system. Among individuals in the control group, 61.5% took the full course of treatment. The simple text message reminders increased the odds of adherence (adjusted OR 1.45, 95% CI [1.03 to 2.04], p-value 0.028). Receiving an additional message did not result in a significant change in adherence (adjusted OR 0.77, 95% CI [0.50 to 1.20], p-value 0.252). The results of this study suggest that a simple text message reminder can increase adherence to antimalarial treatment and that additional information included in messages does not have a significant impact on completion of ACT treatment. Further research is needed to develop the most effective text message content and frequency. ClinicalTrials.gov NCT01722734.

  2. The impact of text message reminders on adherence to antimalarial treatment in northern Ghana: a randomized trial.

    Directory of Open Access Journals (Sweden)

    Julia R G Raifman

    Full Text Available BACKGROUND: Low rates of adherence to artemisinin-based combination therapy (ACT regimens increase the risk of treatment failure and may lead to drug resistance, threatening the sustainability of current anti-malarial efforts. We assessed the impact of text message reminders on adherence to ACT regimens. METHODS: Health workers at hospitals, clinics, pharmacies, and other stationary ACT distributors in Tamale, Ghana provided flyers advertising free mobile health information to individuals receiving malaria treatment. The messaging system automatically randomized self-enrolled individuals to the control group or the treatment group with equal probability; those in the treatment group were further randomly assigned to receive a simple text message reminder or the simple reminder plus an additional statement about adherence in 12-hour intervals. The main outcome was self-reported adherence based on follow-up interviews occurring three days after treatment initiation. We estimated the impact of the messages on treatment completion using logistic regression. RESULTS: 1140 individuals enrolled in both the study and the text reminder system. Among individuals in the control group, 61.5% took the full course of treatment. The simple text message reminders increased the odds of adherence (adjusted OR 1.45, 95% CI [1.03 to 2.04], p-value 0.028. Receiving an additional message did not result in a significant change in adherence (adjusted OR 0.77, 95% CI [0.50 to 1.20], p-value 0.252. CONCLUSION: The results of this study suggest that a simple text message reminder can increase adherence to antimalarial treatment and that additional information included in messages does not have a significant impact on completion of ACT treatment. Further research is needed to develop the most effective text message content and frequency. TRIAL REGISTRATION: ClinicalTrials.gov NCT01722734.

  3. Preparation, characterization and in vitro release kinetics of polyaspartamide-based conjugates containing antimalarial and anticancer agents for combination therapy

    CSIR Research Space (South Africa)

    Aderibigbe, BA

    2016-09-01

    Full Text Available Malaria is treated by combination of two drugs in order to overcome drug resistance. Antimalarials have been found to be more effective by combining them with low doses of anticancer drugs. Polymer-drug conjugates containing aminoquinoline...

  4. ARTEMISININ: THE JOURNEY FROM NATURAL PRODUCT TO ...

    African Journals Online (AJOL)

    services, many parents lose their children to complications ... ARTEMISININ: THE JOURNEY FROM NATURAL PRODUCT TO NOBEL PRIZE. SUMMARY ... Medicine, where she has remained for over 55 years. After joining ... An advantage of.

  5. Severe Embryotoxicity of Artemisinin Derivatives in Experimental Animals, but Possibly Safe in Pregnant Women

    Directory of Open Access Journals (Sweden)

    Qigui Li

    2009-12-01

    Full Text Available Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesison the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration–course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women.

  6. Severe embryotoxicity of artemisinin derivatives in experimental animals, but possibly safe in pregnant women.

    Science.gov (United States)

    Li, Qigui; Weina, Peter J

    2009-12-25

    Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesis on the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT) from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration-course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women.

  7. Continued Sensitivity of Plasmodium falciparum to Artemisinin in Guyana, With Absence of Kelch Propeller Domain Mutant Alleles

    Science.gov (United States)

    Rahman, Reyaud; Martin, Maria Jesus Sanchez; Persaud, Shamdeo; Ceron, Nicolas; Kellman, Dwayne; Musset, Lise; Carter, Keith H.; Ringwald, Pascal

    2016-01-01

    Because of concerns about possible emergence of artemisinin resistance strains of Plasmodium falciparum in mining areas of the interior of Guyana, a 7-day artesunate trial was conducted from March to December 2014. The day-3 parasite clearance rate, the efficacy of artesunate at day 28, and polymorphism of Kelch 13 (PfK13)—the marker of artemisinin resistance—were assessed. The study confirmed the continued sensitivity of P falciparum to artemisinin. A 7-day course of artesunate was 100% efficacious with only 2% (95% confidence interval, .1%–10.9%) of enrolled subjects positive at day 3. All day-0 parasite samples were wild type. Continued resistance monitoring is nevertheless recommended, given the widespread availability and uncontrolled use of artemisinin drugs in mining areas of Guyana.

  8. World Antimalarial Resistance Network (WARN IV: Clinical pharmacology

    Directory of Open Access Journals (Sweden)

    Gbotosho Grace O

    2007-09-01

    Full Text Available Abstract A World Antimalarial Resistance Network (WARN database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics. By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component

  9. Exploring the Contribution of Candidate Genes to Artemisinin Resistance in Plasmodium falciparum▿

    Science.gov (United States)

    Imwong, Mallika; Dondorp, Arjen M.; Nosten, Francois; Yi, Poravuth; Mungthin, Mathirut; Hanchana, Sarun; Das, Debashish; Phyo, Aung Phae; Lwin, Khin Maung; Pukrittayakamee, Sasithon; Lee, Sue J.; Saisung, Suwannee; Koecharoen, Kitti; Nguon, Chea; Day, Nicholas P. J.; Socheat, Duong; White, Nicholas J.

    2010-01-01

    The reduced in vivo sensitivity of Plasmodium falciparum has recently been confirmed in western Cambodia. Identifying molecular markers for artemisinin resistance is essential for monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Four candidate genes, including the P. falciparum mdr1 (pfmdr1) gene, the P. falciparum ATPase6 (pfATPase6) gene, the 6-kb mitochondrial genome, and ubp-1, encoding a deubiquitinating enzyme, of artemisinin-resistant P. falciparum strains from western Cambodia were examined and compared to those of sensitive strains from northwestern Thailand, where the artemisinins are still very effective. The artemisinin-resistant phenotype did not correlate with pfmdr1 amplification or mutations (full-length sequencing), mutations in pfATPase6 (full-length sequencing) or the 6-kb mitochondrial genome (full-length sequencing), or ubp-1 mutations at positions 739 and 770. The P. falciparum CRT K76T mutation was present in all isolates from both study sites. The pfmdr1 copy numbers in western Cambodia were significantly lower in parasite samples obtained in 2007 than in those obtained in 2005, coinciding with a local change in drug policy replacing artesunate-mefloquine with dihydroartemisinin-piperaquine. Artemisinin resistance in western Cambodia is not linked to candidate genes, as was suggested by earlier studies. PMID:20421395

  10. Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro

    Directory of Open Access Journals (Sweden)

    Lilik Maslachah

    2015-03-01

    Full Text Available The presence of the P. falciparum resistance and decreased of efficacy against artemisinin and its derivatives result in increasingly complex malaria issues. Malaria has become one of the currently unresolved world’s health problems due to the lack of new artemisinin replacement drugs. This study aimed to provide evidence that the repeated exposure of in vitro artemisinin may cause a change in P. falciparum Papua 2300 strain phenotypic. This study was conducted during the period of February to November 2013 in Biomedics Brawijaya University and the Faculty of Veterinary Medicine, Airlangga University. A post-test control only experimental design was used. In vitro cultures of P. falciparum Papua 2300 strain were treated by repeated artemisin in IC50 concentration and were observed for their viability and IC50 using probit analysis. The control group did not show any changes after IC50value and PO1 treatment. An increase in IC50 value was occurred after PO2. Repeated exposures of artemisinin in PO2, PO3 and PO4 had shorter viability periods than PO1. The viability of was stable after PO3 in this group. In conclusion, repeated exposures of artemisinin influence changes in IC50 value and viability period of P. falciparum Papua 2300 strain.

  11. Antimalarial properties of imipramine and amitriptyline

    Energy Technology Data Exchange (ETDEWEB)

    Dutta, P.; Siegel, L.; Pinto, J.; Meshnick, S.

    1986-03-01

    This laboratory has previously demonstrated that imipramine (IM) and amitriptyline (AM), inhibit the conversion of riboflavin to its coenzymic derivatives. Several other laboratories have shown that dietary riboflavin deficiency is protective against malarial infection. In the present investigation, the authors determined whether IM and AM exert antimalarial effects similar to that of riboflavin deficiency, as they have hypothesized. In addition, they evaluated whether these drugs, like other antimalarial agents, increase the hemolytic response to ferriprotoporphyrin IX (FP). The growth of P. falciparum (FCR3) in the absence or presence of these drugs (80 ..mu..M) was measured by incubating parasitized erythrocytes for 48 h in RPMI 1640 medium. Parasitemia was determined by counting erythrocyte smears and monitoring (/sup 3/H)hypoxanthine uptake. With no drug, parasitemia was 20.3 +/- 5.3%, whereas in the presence of IM and AM, parasitemia was reduced to 7.3 +/- 0.8% and 13.6 +/- 2.8%, respectively. The uptake of (/sup 3/H)hypoxanthine was reduced to 47 +/- 3.6% and 54 +/- 2.9% of control by IM and AM, respectively. Assays of hemolysis were conducted by incubating 0.5% RBC suspension in NaCl-Tris buffer for 3 h at 37/sup 0/C with variable concentrations of drugs and/or FP (1-7 ..mu..M). Both drugs at 10 to 100 ..mu..M significantly enhanced hemolysis induced by FP. No hemolysis by these drugs was detected in the absence of FP. It is concluded that the tricyclic antidepressants, IM and AM, possess substantial antimalarial properties, thereby supporting the hypothesis that drugs which interfere with riboflavin metabolism should also provide protection against malaria.

  12. [Historical overview of antimalarials used in Venezuela].

    Science.gov (United States)

    Zerpa de Artiles, N

    1993-06-01

    A historical review of antimalarials used in Venezuela is presented from the time when the bark of quina was used until the massive distribution of quinine and metoquine by the Dirección de Malariología y Saneamiento Ambiental. The utility of chloroquine and primaquine against sensible parasite isolates and of sulfadoxine-pyrimethamine and quinine, currently used against P. falciparum resistant strains, is thoroughly discussed. The author suggests use of artemisimine and its derivatives as a very promising antimalarial drug. She also stresses the possibility of the application of new antimalaria vaccine against P. falciparum blood states, presently assayed in the country as an additional tool in malaria control programs.

  13. Antimalarial pharmacology and therapeutics of atovaquone.

    Science.gov (United States)

    Nixon, Gemma L; Moss, Darren M; Shone, Alison E; Lalloo, David G; Fisher, Nicholas; O'Neill, Paul M; Ward, Stephen A; Biagini, Giancarlo A

    2013-05-01

    Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.

  14. Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon

    Directory of Open Access Journals (Sweden)

    Thalabard Jean-Christophe

    2010-02-01

    Full Text Available Abstract Background The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT, is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging. Methods Studies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28 were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis. Findings The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ is as effective as other