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Sample records for antimalarial drugs molecular

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

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    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

  2. 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

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

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    Mubjer, Reem A; Adeel, Ahmed A; Chance, Michael L; Hassan, Amir A

    2011-08-21

    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). 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. 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. 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 parasites from Yemen. Mutant pfcrtT76 is highly prevalent but it

  4. Molecular characterization of Plasmodium falciparum uracil-DNA glycosylase and its potential as a new anti-malarial drug target

    OpenAIRE

    Suksangpleng, Thidarat; Leartsakulpanich, Ubolsree; Moonsom, Saengduen; Siribal, Saranya; Boonyuen, Usa; Wright, George E; Chavalitshewinkoon-Petmitr, Porntip

    2014-01-01

    Background Based on resistance of currently used anti-malarials, a new anti-malarial drug target against Plasmodium falciparum is urgently needed. Damaged DNA cannot be transcribed without prior DNA repair; therefore, uracil-DNA glycosylase, playing an important role in base excision repair, may act as a candidate for a new anti-malarial drug target. Methods Initially, the native PfUDG from parasite crude extract was partially purified using two columns, and the glycosylase activity was monit...

  5. Antimalarial drug induced decrease in creatinine clearance

    NARCIS (Netherlands)

    Landewé, R. B.; Vergouwen, M. S.; Goeei The, S. G.; van Rijthoven, A. W.; Breedveld, F. C.; Dijkmans, B. A.

    1995-01-01

    To confirm the antimalarial drug induced increase of creatinine to determine the factors contributing to this effect. Patients with rheumatoid arthritis (RA) (n = 118) who have used or still use antimalarials (chloroquine or hydroxychloroquine). Serum creatinines prior to antimalarials and serum

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

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    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.

  7. 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.

  8. Counterfeit and substandard antimalarial drugs in Cambodia.

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    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.

  9. Antimalarial Drugs for Pediatrics - Prescribing and Dispensing ...

    African Journals Online (AJOL)

    Purpose: To assess dispensing and prescribing practices with regard to antimalarial drugs for pediatrics in private pharmacies and public hospitals in Dar es Salaam, Tanzania. Methods: This was a cross-sectional, descriptive study that assessed the knowledge and practice of 200 drug dispensers in the private community ...

  10. Prevalence of Plasmodium falciparum Molecular Markers of Antimalarial Drug Resistance in a Residual Malaria Focus Area in Sabah, Malaysia.

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    Norahmad, Nor Azrina; Mohd Abd Razak, Mohd Ridzuan; Abdullah, Noor Rain; Sastu, Umi Rubiah; Imwong, Mallika; Muniandy, Prem Kumar; Saat, Muhammad Nor Farhan; Muhammad, Amirrudin; Jelip, Jenarun; Tikuson, Moizin; Yusof, Norsalleh; Rundi, Christina; Mudin, Rose Nani; Syed Mohamed, Ami Fazlin

    2016-01-01

    Chloroquine (CQ) and fansidar (sulphadoxine-pyrimethamine, SP) were widely used for treatment of Plasmodium falciparum for several decades in Malaysia prior to the introduction of Artemisinin-based Combination Therapy (ACT) in 2008. Our previous study in Kalabakan, located in south-east coast of Sabah showed a high prevalence of resistance to CQ and SP, suggesting the use of the treatment may no longer be effective in the area. This study aimed to provide a baseline data of antimalarial drug resistant markers on P. falciparum isolates in Kota Marudu located in the north-east coast of Sabah. Mutations on genes associated with CQ (pfcrt and pfmdr1) and SP (pfdhps and pfdhfr) were assessed by PCR amplification and restriction fragment length polymorphism. Mutations on the kelch13 marker (K13) associated with artemisinin resistance were determined by DNA sequencing technique. The assessment of pfmdr1 copy number variation associated with mefloquine resistant was done by real-time PCR technique. A low prevalence (6.9%) was indicated for both pfcrt K76T and pfmdr1 N86Y mutations. All P. falciparum isolates harboured the pfdhps A437G mutation. Prevalence of pfdhfr gene mutations, S108N and I164L, were 100% and 10.3%, respectively. Combining the different resistant markers, only two isolates were conferred to have CQ and SP treatment failure markers as they contained mutant alleles of pfcrt and pfmdr1 together with quintuple pfdhps/pfdhfr mutation (combination of pfdhps A437G+A581G and pfdhfr C59R+S108N+I164L). All P. falciparum isolates carried single copy number of pfmdr1 and wild type K13 marker. This study has demonstrated a low prevalence of CQ and SP resistance alleles in the study area. Continuous monitoring of antimalarial drug efficacy is warranted and the findings provide information for policy makers in ensuring a proper malaria control.

  11. Prevalence of Plasmodium falciparum Molecular Markers of Antimalarial Drug Resistance in a Residual Malaria Focus Area in Sabah, Malaysia.

    Directory of Open Access Journals (Sweden)

    Nor Azrina Norahmad

    Full Text Available Chloroquine (CQ and fansidar (sulphadoxine-pyrimethamine, SP were widely used for treatment of Plasmodium falciparum for several decades in Malaysia prior to the introduction of Artemisinin-based Combination Therapy (ACT in 2008. Our previous study in Kalabakan, located in south-east coast of Sabah showed a high prevalence of resistance to CQ and SP, suggesting the use of the treatment may no longer be effective in the area. This study aimed to provide a baseline data of antimalarial drug resistant markers on P. falciparum isolates in Kota Marudu located in the north-east coast of Sabah. Mutations on genes associated with CQ (pfcrt and pfmdr1 and SP (pfdhps and pfdhfr were assessed by PCR amplification and restriction fragment length polymorphism. Mutations on the kelch13 marker (K13 associated with artemisinin resistance were determined by DNA sequencing technique. The assessment of pfmdr1 copy number variation associated with mefloquine resistant was done by real-time PCR technique. A low prevalence (6.9% was indicated for both pfcrt K76T and pfmdr1 N86Y mutations. All P. falciparum isolates harboured the pfdhps A437G mutation. Prevalence of pfdhfr gene mutations, S108N and I164L, were 100% and 10.3%, respectively. Combining the different resistant markers, only two isolates were conferred to have CQ and SP treatment failure markers as they contained mutant alleles of pfcrt and pfmdr1 together with quintuple pfdhps/pfdhfr mutation (combination of pfdhps A437G+A581G and pfdhfr C59R+S108N+I164L. All P. falciparum isolates carried single copy number of pfmdr1 and wild type K13 marker. This study has demonstrated a low prevalence of CQ and SP resistance alleles in the study area. Continuous monitoring of antimalarial drug efficacy is warranted and the findings provide information for policy makers in ensuring a proper malaria control.

  12. THE TRAGEDY CAUSED BY FAKE ANTIMALARIAL DRUGS

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    Pierre Ambroise-Thomas

    2012-01-01

    Full Text Available

    Counterfeit antimalarials (mainly artemisinin derivatives is a crucial health problem in developing countries, particularly in Africa. The illegal production, sale and distribution of fake drugs is a huge market evaluated to several billion of dollars and represents more than 50% of the pharmaceutical market in several African countries. Fake drugs have led to a very great number of deaths from untreated malaria or fatality provoked by toxic ingredients. These fake medicines increase the risk of artemisinin resistance developed by the use of sub therapeutic dosages of antimalarials. Tackling this criminal traffic is the objective of an international  programme created by WHO  and involves the international police and custom organizations like INTERPOL. Several very important and encouraging results have been obtained, but the problem will be completely solved if genuine antimalarials, free-of-charge, are handed-over to populations in sub Sahara African countries.

     

     

  13. THE TRAGEDY CAUSED BY FAKE ANTIMALARIAL DRUGS

    Directory of Open Access Journals (Sweden)

    Pierre Ambroise-Thomas

    2012-05-01

    Full Text Available Counterfeit antimalarials (mainly artemisinin derivatives is a crucial health problem in developing countries, particularly in Africa. The illegal production, sale and distribution of fake drugs is a huge market evaluated to several billion of dollars and represents more than 50% of the pharmaceutical market in several African countries. Fake drugs have led to a very great number of deaths from untreated malaria or fatality provoked by toxic ingredients. These fake medicines increase the risk of artemisinin resistance developed by the use of sub therapeutic dosages of antimalarials. Tackling this criminal traffic is the objective of an international  programme created by WHO  and involves the international police and custom organizations like INTERPOL. Several very important and encouraging results have been obtained, but the problem will be completely solved if genuine antimalarials, free-of-charge, are handed-over to populations in sub Sahara African countries.

  14. The tragedy caused by fake antimalarial drugs.

    Science.gov (United States)

    Ambroise-Thomas, Pierre

    2012-01-01

    Counterfeit antimalarials (mainly artemisinin derivatives) is a crucial health problem in developing countries, particularly in Africa. The illegal production, sale and distribution of fake drugs is a huge market evaluated to several billion of dollars and represents more than 50% of the pharmaceutical market in several African countries. Fake drugs have led to a very great number of deaths from untreated malaria or fatality provoked by toxic ingredients. These fake medicines increase the risk of artemisinin resistance developed by the use of sub therapeutic dosages of antimalarials. Tackling this criminal traffic is the objective of an international program created by WHO and involves the international police and custom organizations like INTERPOL. Several very important and encouraging results have been obtained, but the problem will be completely solved if genuine antimalarials, free-of-charge, are handed-over to populations in sub Sahara African countries.

  15. Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs.

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    Piscianz, Elisa; Cuzzoni, Eva; Sharma, Rajan; Tesser, Alessandra; Sapra, Pooja; Tommasini, Alberto

    2017-09-11

    The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Pricing, distribution, and use of antimalarial drugs.

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    Foster, S. D.

    1991-01-01

    Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much as half of antimalarials distributed in many developing countries. Use of antimalarials through the health services is often poor; drug shortages are common and overprescription and overuse of injections are significant problems. Anxiety over drug costs may prevent patients from getting the necessary treatment for malaria, especially because of the seasonal appearance of this disease when people's cash reserves are very low. The high costs may lead them to unofficial sources, which will sell a single tablet instead of a complete course of treatment, and subsequently to increased, often irrational demand for more drugs and more injections. Increasingly people are resorting to self-medication for malaria, which may cause delays in seeking proper treatment in cases of failure, especially in areas where chloroquine resistance has increased rapidly. Self-medication is now widespread, and measures to restrict the illicit sale of drugs have been unsuccessful. The "unofficial" channels thus represent an unacknowledged extension of the health services in many countries; suggestions are advanced to encourage better self-medication by increasing the knowledge base among the population at large (mothers, schoolchildren, market sellers, and shopkeepers), with an emphasis on correct dosing and on the importance of seeking further treatment without delay, if necessary. PMID:1893512

  17. Country-wide surveillance of molecular markers of antimalarial drug resistance in Senegal by use of positive Malaria Rapid Diagnostic Tests

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Sow, Doudou; Nag, Sidsel

    2017-01-01

    In Senegal, antimalarial drugs used in treatment and prevention of malaria are one of the main reasons for the current success in controlling malaria. However, the successful control of malaria is highly dependent on continued effectiveness of these drugs which may be compromised by the spread...

  18. Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities.

    Science.gov (United States)

    Gorka, Alexander P; de Dios, Angel; Roepe, Paul D

    2013-07-11

    Historically, the most successful molecular target for antimalarial drugs has been heme biomineralization within the malarial parasite digestive vacuole. Heme released from catabolized host red blood cell hemoglobin is toxic, so malarial parasites crystallize heme to nontoxic hemozoin. For years it has been accepted that a number of effective quinoline antimalarial drugs (e.g., chloroquine, quinine, amodiaquine) function by preventing hemozoin crystallization. However, recent studies over the past decade have revealed a surprising molecular diversity in quinoline-heme molecular interactions. This diversity shows that even closely related quinoline drugs may have quite different molecular pharmacology. This paper reviews the molecular diversity and highlights important implications for understanding quinoline antimalarial drug resistance and for future drug design.

  19. Terahertz absorption spectra of commonly used antimalarial drugs

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    Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

    2018-03-01

    Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

  20. Molecular modeling of the voltammetric oxidation at a glassy carbon electrode of the antimalarial drug primaquine and its prodrugs succinylprimaquine and maleylprimaquine

    Energy Technology Data Exchange (ETDEWEB)

    La-Scalea, Mauro A. [Lapen, Laboratorio de Planejamento e Sintese de Quimioterapicos Potencialmente Ativos Contra Endemias Tropicais, Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580 Bl. 13 sup., 05508-900 Sao Paulo (Brazil)]. E-mail: scalea@usp.br; Menezes, Carla M.S. [Lapen, Laboratorio de Planejamento e Sintese de Quimioterapicos Potencialmente Ativos Contra Endemias Tropicais, Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580 Bl. 13 sup., 05508-900 Sao Paulo (Brazil)]. E-mail: casmenezes@yahoo.com; Matsutami, Guilherme C. [Lapen, Laboratorio de Planejamento e Sintese de Quimioterapicos Potencialmente Ativos Contra Endemias Tropicais, Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580 Bl. 13 sup., 05508-900 Sao Paulo (Brazil); Polli, Michelle C. [Lapen, Laboratorio de Planejamento e Sintese de Quimioterapicos Potencialmente Ativos Contra Endemias Tropicais, Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580 Bl. 13 sup., 05508-900 Sao Paulo (Brazil); Serrano, Silvia H.P. [Departamento de Quimica Fundamental, Instituto de Quimica, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 748 Bl. 2 sup., 05508-90 Sao Paulo (Brazil); Ferreira, Elizabeth I. [Lapen, Laboratorio de Planejamento e Sintese de Quimioterapicos Potencialmente Ativos Contra Endemias Tropicais, Departamento de Farmacia, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580 Bl. 13 sup., 05508-900 Sao Paulo (Brazil)

    2006-07-15

    The 8-aminoquinoline primaquine (PQ) is the only antimalarial drug used as tissue schizonticide and relapsing malaria. Antichagasic activity was also reported. Nevertheless, as it also shows serious side effects, prodrugs such as succinyl and maleyl derivatives have been proposed to decrease its toxicity. Although PQ mechanism of action has not been completely elucidated, the promotion of oxidative stress is an advanced hypothesis that could explain its activity in both plasmodia and trypanosome parasites. The oxidation of PQ and its prodrugs, maleylprimaquine (MPQ) and succinylprimaquine (SPQ), was studied by cyclic voltammetry using glassy carbon electrode. All compounds were oxidized in aqueous medium, with the charge transfer process being pH-dependent in acidic medium and pH-independent in a weak basic medium, being the neutral form more easily oxidized. This indicated that the protonation of the nitrogen atoms displays a determinant role in the voltammetric oxidation, being both prodrugs more easily oxidized than PQ protonated forms, in the order: SPQ < MPQ < PQ. For a better understanding of this behavior, a molecular modeling study was performed using the AM1 semi-empirical method from Spartan 04 for Linux (v.119, Wavefunction Inc.). The medium pH showed to be fundamental not only to the electronic density of the quinoline ring but also to the rearrangement of the nitrogen side chain. The electronic density of primaquine non-protonated quinoline ring is higher than that in its protonated and diprotonated species. Also, the use of prodrugs and the degree of saturation of the carriers (maleic or succinic acid) interfere with this feature. SPQ and MPQ have a slight increase in the quinoline electronic density in comparison to PQ. Nevertheless, the carrier in the side chain of SPQ is closer to the quinoline ring than it is in MPQ, which accounts for the higher electronic density in the former. The most significant effect occurs in the correspondent protonated

  1. 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

  2. Antimalarial drug policy in India: Past, present & future

    Science.gov (United States)

    Anvikar, Anupkumar R.; Arora, Usha; Sonal, G.S.; Mishra, Neelima; Shahi, Bharatendu; Savargaonkar, Deepali; Kumar, Navin; Shah, Naman K.; Valecha, Neena

    2014-01-01

    The use of antimalarial drugs in India has evolved since the introduction of quinine in the 17th century. Since the formal establishment of a malaria control programme in 1953, shortly after independence, treatments provided by the public sector ranged from chloroquine, the mainstay drug for many decades, to the newer, recently introduced artemisinin based combination therapy. The complexity of considerations in antimalarial treatment led to the formulation of a National Antimalarial Drug Policy to guide procurement as well as communicate best practices to both public and private healthcare providers. Challenges addressed in the policy include the use of presumptive treatment, the introduction of alternate treatments for drug-resistant malaria, the duration of primaquine therapy to prevent relapses of vivax malaria, the treatment of malaria in pregnancy, and the choice of drugs for chemoprophylaxis. While data on antimalarial drug resistance and both public and private sector treatment practices have been recently reviewed, the policy process of setting national standards has not. In this perspective on antimalarial drug policy, this review highlights its relevant history, analyzes the current policy, and examines future directions. PMID:24718394

  3. The antimalarial drug artemisinin alkylates heme in infected mice

    Science.gov (United States)

    Robert, Anne; Benoit-Vical, Françoise; Claparols, Catherine; Meunier, Bernard

    2005-01-01

    Heme alkylation by the antimalarial drug artemisinin is reported in vivo, within infected mice that have been treated at pharmacologically relevant doses. Adducts resulting from the alkylation of heme by the drug were characterized in the spleen of treated mice, and their glucuroconjugated derivatives were present in the urine. Because these heme-artemisinin adducts were not observed in noninfected mice, this report confirms that the alkylating activity of this antimalarial drug is related to the presence of the parasite in infected animals. The identification of heme-artemisinin adducts in mice should be considered as the signature of the alkylation capacity of artemisinin in vivo. PMID:16155128

  4. The current status of antimalarial drug research with special reference to application of QSAR models.

    Science.gov (United States)

    Ojha, Probir Kumar; Roy, Kunal

    2015-01-01

    Malaria, the most virulent parasitic disease, has become a devastating health problem in tropical and subtropical regions, especially in Africa, due to favorable temperature and rainfall conditions for the development of the causative vector. Due to the spread of multidrug resistance to the marketed antimalarial drugs including the "magic bullet" artemisinin, discovery and development of new antimalarial drugs is one of the utmost challenges. Different government and non-government chemical regulatory authorities have recommended the application of non-animal, alternative techniques and in particular, in silico, methods in order to provide information about the basic physicochemical properties as well as the ecological and human health effects of chemicals before they reach into the market for public use. In this aspect, application of chemometric methods along with structure-based approaches may be useful for the design and discovery of new antimalarial compounds. The quantitative structureactivity relationship (QSAR) along with molecular docking and pharmacophore modeling techniques play a crucial role in the field of drug design. QSAR focuses on the chemical attributes influencing the activity and thereby allows synthesis of selective potential candidate molecules. In this communication, we have reviewed the QSAR reports along with some pharmacophore modeling and docking studies of antimalarial agents published during the year 2011 to 2014 and attempted to focus on the importance of physicochemical properties and structural features required for antimalarial activity of different chemical classes of compounds. Note that this is not an exhaustive review and all the given examples should be considered as the representative ones. The reader will gain an insight of the current status of QSAR and related in silico models developed for different classes of antimalarial compounds. This review suggests that combination of both ligand and structure-based drug designing

  5. 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 ...

  6. 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...

  7. Antimalarial drug use among caregivers in Ghana | Abuaku | African ...

    African Journals Online (AJOL)

    Methodology: Household surveys, using multi-stage sampling, were conducted in 2 sentinel districts, Wassa West and Kassena Nankana, established to monitor chloroquine resistance in the country. Five hundred caregivers were interviewed in each district to determine patterns of antimalarial drug use among caregivers of ...

  8. Quality of Antimalarial Drugs Analysed in the National Quality ...

    African Journals Online (AJOL)

    During the period 2002–2005, the National Quality Control Laboratory analysed 229 samples of antimalarial drugs. In 2002, 42% of these products failed to comply with compendial specifications, with the sulfadoxine/ sulfamethoxypyrazine and pyrimethamine combination products forming 39% of the total failures.

  9. Artemisinin anti-malarial drugs in China

    Directory of Open Access Journals (Sweden)

    Zongru Guo

    2016-03-01

    Full Text Available Discovered by Youyou Tu, one of the 2015 Nobel Prize winners in Physiology or Medicine, together with many other Chinese scientists, artemisinin, artemether and artesunate, as well as other artemisinins, have brought the global anti-malarial treatment to a new era, saving millions of lives all around the world for the past 40 years. The discoveries of artemisinins were carried out beginning from the 1970s, a special period in China, by hundreds of scientists all together under the “whole nation” system. This article focusing on medicinal chemistry research, briefly introduced the discovery and invention course of the scientists according to the published papers, and highlighted their academic contribution and achievements.

  10. From crystal to compound: structure-based antimalarial drug discovery.

    Science.gov (United States)

    Drinkwater, Nyssa; McGowan, Sheena

    2014-08-01

    Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

  11. Quality Testing of Artemisinin-Based Antimalarial Drugs in Myanmar.

    Science.gov (United States)

    Guo, Suqin; Kyaw, Myat Phone; He, Lishan; Min, Myo; Ning, Xiangxue; Zhang, Wei; Wang, Baomin; Cui, Liwang

    2017-10-01

    Artemisinin-based combination therapies are the frontline treatment of Plasmodium falciparum malaria. The circulation of falsified and substandard artemisinin-based antimalarials in Southeast Asia has been a major predicament for the malaria elimination campaign. To provide an update of this situation, we purchased 153 artemisinin-containing antimalarials, as convenience samples, in private drug stores from different regions of Myanmar. The quality of these drugs in terms of their artemisinin derivative content was tested using specific dipsticks for these artemisinin derivatives, as point-of-care devices. A subset of these samples was further tested by high-performance liquid chromatography (HPLC). This survey identified that > 35% of the collected drugs were oral artesunate and artemether monotherapies. When tested with the dipsticks, all but one sample passed the assays, indicating that the detected artemisinin derivative content corresponded approximately to the labeled contents. However, one artesunate injection sample was found to contain no active ingredient at all by the dipstick assay and subsequent HPLC analysis. The continued circulation of oral monotherapies and the description, for the first time, of falsified parenteral artesunate provides a worrisome picture of the antimalarial drug quality in Myanmar during the malaria elimination phase, a situation that deserves more oversight from regulatory authorities.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Quinolone-3-diarylethers: a new class of antimalarial drug.

    OpenAIRE

    Nilsen Aaron; LaCrue Alexis N; White Karen L; Forquer Isaac P; Cross R Matthew; Marfurt Jutta; Mather Michael W; Delves Michael J; Shackleford David M; Saenz Fabian E; Morrisey Joanne M; Steuten Jessica; Mutka Tina; Li Yuexin; Wirjanata Grennady

    2013-01-01

    The goal for developing new antimalarial drugs is to find a molecule that can target multiple stages of the parasite's life cycle thus impacting prevention treatment and transmission of the disease. The 4(1H) quinolone 3 diarylethers are selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. These compounds are highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite a...

  14. Phase I Clinical Testing Antimalarial Drugs.

    Science.gov (United States)

    1977-10-01

    The 52-week, safety and tolerance test administration of 500 mg mefloquine weekly continues. Four of the 5 groups (10 each) have compelted the drug...in 2 subjects receiving drug. Three additional acute studies involving oral mefloquine administration were completed and reports submitted. These...formulation B-512, transient nausea and diarrhea occurred in some subjects receiving 1000 mg and all subjects receiving 1500 mg mefloquine . No other

  15. Quality of Antimalarials at the Epicenter of Antimalarial Drug Resistance: Results from an Overt and Mystery Client Survey in Cambodia

    Science.gov (United States)

    Yeung, Shunmay; Lawford, Harriet L. S.; Tabernero, Patricia; Nguon, Chea; van Wyk, Albert; Malik, Naiela; DeSousa, Mikhael; Rada, Ouk; Boravann, Mam; Dwivedi, Prabha; Hostetler, Dana M.; Swamidoss, Isabel; Green, Michael D.; Fernandez, Facundo M.; Kaur, Harparkash

    2015-01-01

    Widespread availability of monotherapies and falsified antimalarials is thought to have contributed to the historical development of multidrug-resistant malaria in Cambodia. This study aimed to document the quality of artemisinin-containing antimalarials (ACAs) and to compare two methods of collecting antimalarials from drug outlets: through open surveyors and mystery clients (MCs). Few oral artemisinin-based monotherapies and no suspected falsified medicines were found. All 291 samples contained the stated active pharmaceutical ingredient (API) of which 69% were considered good quality by chemical analysis. Overall, medicine quality did not differ by collection method, although open surveyors were less likely to obtain oral artemisinin-based monotherapies than MCs. The results are an encouraging indication of the positive impact of the country's efforts to tackle falsified antimalarials and artemisinin-based monotherapies. However, poor-quality medicines remain an ongoing challenge that demands sustained political will and investment of human and financial resources. PMID:25897063

  16. Antimalarial drug use in general populations of tropical Africa

    Directory of Open Access Journals (Sweden)

    Gardella Florence

    2008-07-01

    Full Text Available Abstract Background The burden of Plasmodium falciparum malaria has worsened because of the emergence of chloroquine resistance. Antimalarial drug use and drug pressure are critical factors contributing to the selection and spread of resistance. The present study explores the geographical, socio-economic and behavioural factors associated with the use of antimalarial drugs in Africa. Methods The presence of chloroquine (CQ, pyrimethamine (PYR and other antimalarial drugs has been evaluated by immuno-capture and high-performance liquid chromatography in the urine samples of 3,052 children (2–9 y, randomly drawn in 2003 from the general populations at 30 sites in Senegal (10, Burkina-Faso (10 and Cameroon (10. Questionnaires have been administered to the parents of sampled children and to a random sample of households in each site. The presence of CQ in urine was analysed as dependent variable according to individual and site characteristics using a random – effect logistic regression model to take into account the interdependency of observations made within the same site. Results According to the sites, the prevalence rates of CQ and PYR ranged from 9% to 91% and from 0% to 21%, respectively. In multivariate analysis, the presence of CQ in urine was significantly associated with a history of fever during the three days preceding urine sampling (OR = 1.22, p = 0.043, socio-economic level of the population of the sites (OR = 2.74, p = 0.029, age (2–5 y = reference level; 6–9 y OR = 0.76, p = 0.002, prevalence of anti-circumsporozoite protein (CSP antibodies (low prevalence: reference level; intermediate level OR = 2.47, p = 0.023, proportion of inhabitants who lived in another site one year before (OR = 2.53, p = 0.003, and duration to reach the nearest tarmacked road (duration less than one hour = reference level, duration equal to or more than one hour OR = 0.49, p = 0.019. Conclusion Antimalarial drug pressure varied considerably from

  17. Dihydroorotate dehydrogenase: A drug target for the development of antimalarials.

    Science.gov (United States)

    Singh, Anju; Maqbool, Mudasir; Mobashir, Mohammad; Hoda, Nasimul

    2017-01-05

    Malaria is a critical human disease with extensive exploration yet unestablished due to occurrence of frequent drug resistance. This aspect of malaria pharmacology calls for the introduction of new antimalarial. The drugs reported till date targeted different stages of the parasites in order to stop their growth and proliferation. Beside this, various drugs that could inhibit the imperative enzymes of the parasite have also been reported. Amid them, dihydroorotate dehydrogenase (DHODH) has a key worth. DHODH is involved in the de novo pyrimidine biosynthesis of the malarial parasite which acts as a primary source of energy for its survival. Since life of the parasite utterly depends on pyrimidine biosynthesis, so it can be used as an apt drug target for malaria eradication. In addition to this, DHODH is also present in human and their active sites have significant structural dissimilarities, so the development of selective inhibitors may prove to be a milestone in search of new antimalarials. Inhibitors of human DHODH have been used to treat autoimmune diseases such as, rheumatoid arthritis or multiple sclerosis and have been investigated in the treatment of cancer, viral diseases, as well as in plant pathology. Here, we have reviewed the important role of DHODH as a viable drug target against malaria, its importance for the survival of the parasite, and DHODH inhibitors reported so far. The rate of success of the reported DHODH inhibitors and further required improvements have also been accounted. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Substandard anti-malarial drugs in Burkina Faso

    Directory of Open Access Journals (Sweden)

    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

  19. Towards histone deacetylase inhibitors as new antimalarial drugs.

    Science.gov (United States)

    Andrews, Katherine T; Tran, Thanh N; Fairlie, David P

    2012-01-01

    Histone deacetylases (HDACs) are important enzymes that effect post-translational modifications of proteins by altering the acetylation state of lysine residues. HDACs control epigenetic changes that trigger cell transformation and proliferation of transformed cells associated with many diseases. These enzymes are validated drug targets for some types of cancer and are promising therapeutic targets for a range of other diseases, including malaria. Annually, there are ~500 million clinical cases of malaria and ~0.8-1.2 million deaths. There is no licensed vaccine for preventing malaria, and parasites that cause malaria are becoming resistant to current drugs, necessitating the search for new therapies. HDAC inhibitors are emerging as a promising new class of antimalarial drugs with potent and selective action against Plasmodium parasites in vitro. Recent studies on the effects of HDAC inhibitors on the growth and development of P. falciparum have provided important new information on transcriptional regulation in malaria parasites and have validated the potential of this class of inhibitors for malaria therapy. To realise effective HDAC inhibitors for clinical trials, next generation inhibitors must not inhibit other human HDACs or proteins required for normal human physiology, be highly selective in killing parasites in vivo without killing normal host cells, and have improved bioavailability and pharmacokinetic profiles. This review summarizes current knowledge about malaria parasite HDACs and HDAC inhibitors with antimalarial properties, and provides insights for their development into new drugs for treatment of malaria.

  20. malaria and anti-malarial drugs utilisation among adults in a rural

    African Journals Online (AJOL)

    Vihar

    Magreth Komanya (Bsc Nursing). AMREF. ABSTRACT. Objective: To study malaria and examine determinants of anti-malarial drugs utilization among ..... anti-malarials for prophylaxis and chemotherapy or may be provided with prescription forms to buy drugs. Moreover the general understanding that pregnant women are ...

  1. Selection of a trioxaquine as an antimalarial drug candidate

    Science.gov (United States)

    Coslédan, Frédéric; Fraisse, Laurent; Pellet, Alain; Guillou, François; Mordmüller, Benjamin; Kremsner, Peter G.; Moreno, Alicia; Mazier, Dominique; Maffrand, Jean-Pierre; Meunier, Bernard

    2008-01-01

    Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC50 value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26–32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules. PMID:18987321

  2. 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 . Eradication efforts are hampered by two major drawbacks-the absence of an effective vaccine coupled with the widespread occurrence of drug-resistant strains to frontline antimalarials and, of late, the emergence of resistance to current antimalarials of choice...

  3. Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors

    Science.gov (United States)

    Urbán, Patricia; Estelrich, Joan; Adeva, Alberto; Cortés, Alfred; Fernàndez-Busquets, Xavier

    2011-12-01

    Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with

  4. The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.

    Science.gov (United States)

    Carvalho, Luis; Martínez-García, Marta; Pérez-Victoria, Ignacio; Manzano, José Ignacio; Yardley, Vanessa; Gamarro, Francisco; Pérez-Victoria, José M

    2015-10-01

    The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  5. 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

    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...... on a few P. falciparum samples, the molecular level of CQ resistance in P. falciparum was high since nearly all parasites had the Pfcrt mutant haplotypes CVIET (55%) or SVMNT (42%), though frequency of Pfmdr1 wild type haplotype was relatively low (35%). Molecular levels of SP resistance in P. falciparum...

  6. Quality of antimalarials at the epicenter of antimalarial drug resistance: results from an overt and mystery client survey in Cambodia.

    Science.gov (United States)

    Yeung, Shunmay; Lawford, Harriet L S; Tabernero, Patricia; Nguon, Chea; van Wyk, Albert; Malik, Naiela; DeSousa, Mikhael; Rada, Ouk; Boravann, Mam; Dwivedi, Prabha; Hostetler, Dana M; Swamidoss, Isabel; Green, Michael D; Fernandez, Facundo M; Kaur, Harparkash

    2015-06-01

    Widespread availability of monotherapies and falsified antimalarials is thought to have contributed to the historical development of multidrug-resistant malaria in Cambodia. This study aimed to document the quality of artemisinin-containing antimalarials (ACAs) and to compare two methods of collecting antimalarials from drug outlets: through open surveyors and mystery clients (MCs). Few oral artemisinin-based monotherapies and no suspected falsified medicines were found. All 291 samples contained the stated active pharmaceutical ingredient (API) of which 69% were considered good quality by chemical analysis. Overall, medicine quality did not differ by collection method, although open surveyors were less likely to obtain oral artemisinin-based monotherapies than MCs. The results are an encouraging indication of the positive impact of the country's efforts to tackle falsified antimalarials and artemisinin-based monotherapies. However, poor-quality medicines remain an ongoing challenge that demands sustained political will and investment of human and financial resources. © The American Society of Tropical Medicine and Hygiene.

  7. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

    Science.gov (United States)

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K; Rosenthal, Philip J

    2015-09-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. © The American Society of Tropical Medicine and Hygiene.

  8. 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...... 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...

  9. Next-Generation Antimalarial Drugs: Hybrid Molecules as a New Strategy in Drug Design.

    Science.gov (United States)

    Muregi, Francis W; Ishih, Akira

    2010-02-01

    Malaria is a disease that affects nearly 40% of the global population, and chemotherapy remains the mainstay of its control strategy. The global malaria situation is increasingly being exacerbated by the emergence of drug resistance to most of the available antimalarials, necessitating search for novel drugs. A recent rational approach of antimalarial drug design characterized as "covalent bitherapy" involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual-activity into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs. If the selective toxicity of hybrid prodrugs can be demonstrated in vivo with good bioavailability at the target site in the parasite, it would offer various advantages including dosage compliance, minimized toxicity, ability to design better drug combinations, and cheaper preclinical evaluation while achieving the ultimate object of delaying or circumventing the development of resistance. This review is focused on several hybrid molecules that have been developed, with particular emphasis on those deemed to have high potential for development for clinical use. Drug Dev Res 71: 20-32, 2010. © 2009 Wiley-Liss, Inc.

  10. A qualitative assessment of the challenges of WHO prequalification for anti-malarial drugs in China.

    Science.gov (United States)

    Huang, Yangmu; Pan, Ke; Peng, Danlu; Stergachis, Andy

    2018-04-03

    While China is a major manufacturer of artemisinin and its derivatives, it lags as a global leader in terms of the total export value of anti-malarial drugs as finished pharmaceutical products ready for marketing and use by patients. This may be due to the limited number of World Health Organization (WHO) prequalified anti-malarial drugs from China. Understanding the reasons for the slow progress of WHO prequalification (PQ) in China can help improve the current situation and may lead to greater efforts in malaria eradication by Chinese manufacturers. In-depth interviews were conducted in China between November 2014 and December 2016. A total of 26 key informants from central government agencies, pharmaceutical companies, universities, and research institutes were interviewed, all of which had current or previous experience overseeing or implementing anti-malarial research and development in China. Chinese anti-malarial drugs that lack WHO PQ are mainly exported for use in the African private market. High upfront costs with unpredictable benefits, as well as limited information and limited technical support on WHO PQ, were reported as the main barriers to obtain WHO PQ for anti-malarial drugs by respondents from Chinese pharmaceutical companies. Potential incentives identified by respondents included tax relief, human resource training and consultation, as well as other incentives related to drug approval, such as China's Fast Track Channel. Government support, as well as innovative incentives and collaboration mechanisms are needed for further adoption of WHO PQ for anti-malarial drugs in China.

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

    Science.gov (United States)

    Bissinger, Rosi; Barking, Susanne; Alzoubi, Kousi; Liu, Guilai; Liu, Guoxing; Lang, Florian

    2015-01-01

    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. 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. 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. 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. © 2015 S. Karger AG, Basel.

  12. Antimalarial Drug Resistance Associated Molecular Markers in ...

    African Journals Online (AJOL)

    Nigerian Journal of Parasitology. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 34, No 2 (2013) >. Log in or Register to get access to full text downloads.

  13. Modulating effects of plasma containing anti-malarial antibodies on in vitro anti-malarial drug susceptibility in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Udomsangpetch Rachanee

    2010-11-01

    Full Text Available Abstract Background The efficacy of anti-malarial drugs is determined by the level of parasite susceptibility, anti-malarial drug bioavailability and pharmacokinetics, and host factors including immunity. Host immunity improves the in vivo therapeutic efficacy of anti-malarial drugs, but the mechanism and magnitude of this effect has not been characterized. This study characterized the effects of 'immune' plasma to Plasmodium falciparumon the in vitro susceptibility of P. falciparum to anti-malarial drugs. Methods Titres of antibodies against blood stage antigens (mainly the ring-infected erythrocyte surface antigen [RESA] were measured in plasma samples obtained from Thai patients with acute falciparum malaria. 'Immune' plasma was selected and its effects on in vitro parasite growth and multiplication of the Thai P. falciparum laboratory strain TM267 were assessed by light microscopy. The in vitro susceptibility to quinine and artesunate was then determined in the presence and absence of 'immune' plasma using the 3H-hypoxanthine uptake inhibition method. Drug susceptibility was expressed as the concentrations causing 50% and 90% inhibition (IC50 and IC90, of 3H-hypoxanthine uptake. Results Incubation with 'immune' plasma reduced parasite maturation and decreased parasite multiplication in a dose dependent manner. 3H-hypoxanthine incorporation after incubation with 'immune' plasma was decreased significantly compared to controls (median [range]; 181.5 [0 to 3,269] cpm versus 1,222.5 [388 to 5,932] cpm (p= 0.001. As a result 'immune' plasma reduced apparent susceptibility to quinine substantially; median (range IC50 6.4 (0.5 to 23.8 ng/ml versus 221.5 (174.4 to 250.4 ng/ml (p = 0.02, and also had a borderline effect on artesunate susceptibility; IC50 0.2 (0.02 to 0.3 ng/ml versus 0.8 (0.2 to 2.3 ng/ml (p = 0.08. Effects were greatest at low concentrations, changing the shape of the concentration-effect relationship. IC90 values were not

  14. 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

  15. Assessing anti-malarial drug effects ex vivo using the haemozoin detection assay

    NARCIS (Netherlands)

    Rebelo, Maria; Tempera, Carolina; Fernandes, José F.; Grobusch, Martin P.; Hänscheid, Thomas

    2015-01-01

    In vitro sensitivity assays are crucial to detect and monitor drug resistance. Plasmodium falciparum has developed resistance to almost all anti-malarial drugs. Although different in vitro drug assays are available, some of their inherent characteristics limit their application, especially in the

  16. Comparison of antimalarial activity of Artemisia turanica extract with current drugs in vivo.

    Science.gov (United States)

    Taherkhani, Mahboubeh; Rustaiyan, Abdolhossein; Nahrevanian, Hossein; Naeimi, Sabah; Taherkhani, Tofigh

    2013-03-01

    The purpose of this study was to compare antimalarial activity of Artemisia turanica Krasch as Iranian flora with current antimalarial drugs against Plasmodium berghei in vivo in mice. Air-dried aerial parts of Iranian flora A. turanica were collected from Khorasan, northeastern Iran, extracted with Et2O/MeOH/Petrol and defatted. Toxicity of herbal extracts was assessed on male NMRI mice, and their antimalarial efficacy was compared with antimalarial drugs [artemether, chloroquine and sulfadoxinepyrimethamine (Fansidar)] on infected P. berghei animals. All the groups were investigated for parasitaemia, body weight, hepatomegaly, splenomegaly and anemia. The significance of differences was determined by Analysis of Variances (ANOVA) and Student's t-test using Graph Pad Prism software. The inhibitory effects of A. turanica extract on early decline of P. berghei parasitaemia highlights its antimalarial activity, however, this effect no longer can be observed in the late infection. This may be due to the metabolic process of A. turanica crude extract by mice and reduction of its concentration in the body. Crude extract of A. turanica represented its antisymptomatic effects by stabilization of body, liver and spleen weights. This study confirmed antimalarial effects of A. turanica extracts against murine malaria in vivo during early infection, however, there are more benefits on pathophysiological symptoms by this medication.

  17. Factors contributing to antimalarial drug resistance in Rachuonyo ...

    African Journals Online (AJOL)

    Qualitative and quantitative data were collected among 380 respondents including health care providers, people seeking malaria treatment and Community Own Resource (CORPs), from 47 registered health facilities. The study revealed that all health facilities were using general-purpose trucks to transport antimalarial ...

  18. Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa.

    Science.gov (United States)

    Nayyar, Gaurvika M L; Breman, Joel G; Newton, Paul N; Herrington, James

    2012-06-01

    Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin resistance or tolerance in Plasmodium falciparum on the Thailand-Cambodia border makes protection of the effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and 450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is more important than ever. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Strengthening of national capacity in implementation of antimalarial drug quality assurance in Thailand.

    Science.gov (United States)

    Vijaykadga, Saowanit; Cholpol, Sawat; Sitthimongkol, Saipin; Pawaphutanan, Anusorn; Pinyoratanachot, Arunya; Rojanawatsirivet, Chaiporn; Kovithvattanapong, Rojana; Thimasarn, Krongthong

    2006-01-01

    Substandard and counterfeit pharmaceutical products, including antimalarial drugs, appear to be widespread internationally and affect both the developing and developed countries. The aim of the study was to investigate the quality of antimalarial drugs, ie, artesunate (ART), chloroquine (CHL), mefloquine (MEF), quinine (QUI), sulfadoxine/pyrimethamine (S/P) and tetracycline (TT) obtained from the government sector and private pharmacies in 4 Thai provinces: Mae Hong Son, Kanchanaburi, Ranong, and Chanthaburi. Three hundred sixty-nine samples of 6 antimalarial drugs from 27 government hospitals, 27 malaria clinics, and 53 drugstores, were collected. Drug quality was assessed by simple disintegration test and semi-quantitative thin-layer chromatography in each province; 10% passed, 100% failed and doubtful samples were sent to be verified by high performance liquid chromatography (HPLC) at the Thai National Drug Analysis Laboratory, (NL). Fifteen point four percent of ART, 11.1% of CHL and 29.4% of QUI were substandard. Based on the finding, drug regulatory authorities in the country took appropriate action against violators to ensure that antimalarial drugs consumed by malaria patients are of good quality.

  20. Peptide deformylase: a new target in antibacterial, antimalarial and anticancer drug discovery.

    Science.gov (United States)

    Sangshetti, Jaiprakash N; Khan, Firoz A Kalam; Shinde, Devanand B

    2015-01-01

    Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum) and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322 (Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors and future perspectives of different PDF inhibitors.

  1. POTENCY OF THE INDONESIAN MEDICINAL PLANTS AS ANTIMALARIAL DRUGS

    Directory of Open Access Journals (Sweden)

    Subeki Subeki

    2012-12-01

    Full Text Available The Indonesian traditional herbal medicine has been practiced for many centuries in Indonesia to treat malaria diseases. Although modern medicine is becoming increasingly important, herbal medicine is still very popular. In order to select raw material for preparation of safety herbal medicines, forty five medicinal plants have been tested for acute toxicity in mouse at a dose 715 mg/kg body weight. The extracts of Asclepias curassavica leave, Alstonia scholaris leave, Decospermum fruticosum leave, Elaocarpus petiolatus bark, Elaocarpus parvifolius bark, Eurycoma longifolia root, Garcinia rigida bark, Nephelium lappaceum bark, Pentaspodan motleyi leave, Picrasma javanica leave, Phyllanthus niruri whole, Quassia indica leave, Syzygium pycnanthum bark, Tetrasera scandens leave, Cratoxylum glaucum bark, Sandoricum emarginatum bark, Mallotus paniculatus leave, Microcos ovatolanceolata bark, Poikilospermum suaveolens leave, Fibraurea chloroleuea leave, Tetrasera scandens root, and Timonius billitonensis bark showed toxicity with mortality level of 20-100%. The remaining 32 plant extracts were not toxic at dose tested. The toxic plant species should be considered in the preparation of herbal medicines. Of the safety extracts were tested for their antimalarial activity against Plasmodium berghei in vivo at a dose 715 mg/kg body weight. Extract of Carica papaya leave was most active than other plant extracts with parasitemia 1.13%, while control showed 17.21%. More research is needed to scientifically prove efficacy and to identity antimalarial constituents in the plant extracts. Key words: Indonesian medicinal plant, jamu, toxicity, antimalarial activity, Plasmodium berghei.

  2. Amazonian Plant Natural Products: Perspectives for Discovery of New Antimalarial Drug Leads

    Directory of Open Access Journals (Sweden)

    Lucio H. Freitas-Junior

    2013-08-01

    Full Text Available Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria.

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

    Directory of Open Access Journals (Sweden)

    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

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

    OpenAIRE

    Tatyana Andreyevna Lisitsyna; N M Kosheleva

    2010-01-01

    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

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

    Directory of Open Access Journals (Sweden)

    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

  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

    Reduced sensitivity of Plasmodium falciparum to formerly recommended cheap and well-known antimalarial drugs places an increasing burden on malaria control programs and national health systems in endemic countries. The high costs of the new artemisinin-based combination treatments underline the use...... 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. Correlation of in vitro sensitivity of chloroquine and other antimalarials with the partner drug resistance to Plasmodium falciparum malaria in selected sites of India

    Directory of Open Access Journals (Sweden)

    Supriya Sharma

    2017-01-01

    Full Text Available Background: Antimalarial drug resistance is a potential threat for control and elimination of malaria. To ascertain the status of antimalarial drug resistance at the study sites, correlation between in vitro drug sensitivity pattern and drug resistance molecular markers in Plasmodium falciparum malaria was undertaken. Materials and Methods: Polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt K76T and pfmdr1 N86Y were studied in relation to the in vitro susceptibility of P. falciparum in culture (n = 10 and field isolates (n = 40 to chloroquine (CQ, amodiaquine (AQ, quinine (QN, mefloquine (MQ and artemisinin (ART. The prevalence of drug resistance molecular markers, pfdhfr (codon S108N, C59R, N51I, I164 L and A16V, pfdhps (codon S436F and A437G, pfATPase6 (codon D639G and E431K and mutation in the propeller domain of pfK13 gene were also analysed. Chi-square test and parametric Pearson correlation test were performed using SPSS version 17. Results: In vitro assay showed 18% resistance to CQ, 8% to AQ and 4% to QN. However, no resistance was observed towards MQ and ART. The mutations in pfcrt and pfmdr1 were statistically not significantly associated with susceptibility responses for antimalarials; however, increased IC50values of drugs were reflected as mutant and/or mixed isolates for both gene polymorphisms. CQ was found as independent predictor for other antimalarials, i.e., AQ, QN and ART, with r2 score 0.241, 0.241 and 0.091, respectively. Mutation in the pfATPase6 gene at codon E431K was observed in only one sample from Tripura which also had increased IC50value of 6.28 nM. However, moderate numbers of mutations at codon S108N, C59R and I164 L for pfdhfr gene and S436F and A437G for pfdhps gene were also observed. None of the samples showed mutation in propeller domain of pfK13 gene. Conclusion: The correlation between IC50and molecular markers for antimalarial drug resistance is reported for the first time through

  8. Insights into cytochrome bc 1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

    Science.gov (United States)

    Sodero, Ana Carolina Rennó; Abrahim-Vieira, Bárbara; Torres, Pedro Henrique Monteiro; Pascutti, Pedro Geraldo; Garcia, Célia RS; Ferreira, Vitor Francisco; da Rocha, David Rodrigues; Ferreira, Sabrina Baptista; Silva, Floriano Paes

    2017-01-01

    BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc 1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite. PMID:28327793

  9. Five-year surveillance of molecular markers of Plasmodium falciparum antimalarial drug resistance in Korogwe District, Tanzania: accumulation of the 581G mutation in the P. falciparum dihydropteroate synthase gene

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Lusingu, John P; Mmbando, Bruno

    2009-01-01

    In January 2007, Tanzania replaced sulfadoxine-pyrimethamine (SP) with artemether-lumefantrine for treatment of uncomplicated malaria. This study examined the impact of widespread SP use on molecular markers of Plasmodium falciparum drug resistance in blood samples from persons living in two...

  10. Development in Assay Methods for in Vitro Antimalarial Drug Efficacy Testing: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Shweta Sinha

    2017-10-01

    Full Text Available The emergence and spread of drug resistance are the major challenges in malaria eradication mission. Besides various strategies laid down by World Health Organization, such as vector management, source reduction, early case detection, prompt treatment, and development of new diagnostics and vaccines, nevertheless the need for new and efficacious drugs against malaria has become a critical priority on the global malaria research agenda. At several screening stages, millions of compounds are screened (1,000–2,000,000 compounds per screening campaign, before pre-clinical trials to select optimum lead. Carrying out in vitro screening of antimalarials is very difficult as different assay methods are subject to numerous sources of variability across different laboratories around the globe. Despite this, in vitro screening is an essential part of antimalarial drug development as it enables to resource various confounding factors such as host immune response and drug–drug interaction. Therefore, in this article, we try to illustrate the basic necessity behind in vitro study and how new methods are developed and subsequently adopted for high-throughput antimalarial drug screening and its application in achieving the next level of in vitro screening based on the current approaches (such as stem cells.

  11. 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.

  12. Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development

    Science.gov (United States)

    McCarthy, James S.; Marquart, Louise; Sekuloski, Silvana; Trenholme, Katharine; Elliott, Suzanne; Griffin, Paul; Rockett, Rebecca; O'Rourke, Peter; Sloots, Theo; Angulo-Barturen, Iñigo; Ferrer, Santiago; Jiménez-Díaz, María Belén; Martínez, María-Santos; Duparc, Stephan; Leroy, Didier; Wells, Timothy N. C.; Baker, Mark

    2016-01-01

    Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ−/− (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.) PMID:27044554

  13. Targetting the hemozoin synthesis pathway for antimalarial drug and detected by TEM (Transmission electron microscope)

    Science.gov (United States)

    Abbas, Jamilah; Artanti, Nina; Sundowo, Andini; Dewijanti, Indah Dwiatmi; Hanafi, Muhammad; Lisa, Syafrudin, Din

    2017-11-01

    Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasite species, the alarming spread of drug resistance and limited number of effective drug available now. Therefore it is important to discover new antimalarial drug. Malaria is caused by a singlecelled parasite from the genus Plasmodium. Plasmodium falciparum parasite infect red blood cells, ingesting and degradation hemoglobin in the acidic food vacuola trough a sequential metabolic process involving multiple proteases. During these process, hemoglobin is utilized as the predominant source of nutrition. Proteolysis of hemoglobin yields amino acid for protein synthesis as well as toxic heme. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria parasite has evolved a distinct mechanism for detoxification of heme through conversion into insoluble crystalline pigment, known as hemozoin (β hematoin). Hemozoin synthesis is an indispensable process for the parasite and is the target for action of several known antimalarial drug. TEM (Transmission Electron Microscope) technology for hemozoin formation in vitro assay was done in this research. Calophyllum aerophyllum Lauterb as medicinal plants was used as a source of antimalarial drug. Acetone extracts of C. lowii showed growth inhibition against parasite P. falciparum with IC50 = 5.2 µg/mL. Whereas from hexane, acetone and methanol fraction of C. aerophyllum showed growth inhibition with IC50 = 0.054, 0.055 and 0.0054 µg/mL respectively. New drug from Calophyllum might have potential compounds that have unique structures and mechanism of action which required to develop new drug for treatment of sensitive and drug resistant strain of malaria.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

    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. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. interventional studies of anti-malarial drugs utilization in public

    African Journals Online (AJOL)

    DR. AMINU

    ABSTRACT. The best way to analyze drug utilization and evaluate impact of an intervention in health care institutions is to study the universal indicators, which are not dependent either on investigator or time of measurement. The aim of this study was to characterize the prescription pattern of public health institutions in ...

  17. Effect of Antimalarial Drugs and Malaria Infection on Oxidative ...

    African Journals Online (AJOL)

    The increase in lipid peroxidation and decrease in GSH and ascorbic acid levels in women who were malaria positive and in those who had taken drugs is indicative of oxidative stress. (Afr. J. Reprod. Health 2010; 14[3]: 209-212). Key words: Pregnant women, malaria, lipid peroxidation, reduced glutathione, Ascorbic acid ...

  18. Interventional studies of anti-malarial drugs utilization in public ...

    African Journals Online (AJOL)

    The best way to analyze drug utilization and evaluate impact of an intervention in health care institutions is to study the universal indicators, which are not dependent either on investigator or time of measurement. The aim of this study was to characterize the prescription pattern of public health institutions in Kano, Nigeria ...

  19. Photoreactivity of biologically active compounds. VII. Interaction of antimalarial drugs with melanin in vitro as part of phototoxicity screening.

    Science.gov (United States)

    Kristensen, S; Orsteen, A L; Sande, S A; Tønnesen, H H

    1994-10-01

    The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds accumulate in melanin-rich tissues and cause toxic reactions which may be light induced. As part of the screening of the photochemical properties and phototoxic capabilities of antimalarials, the in vitro interaction of eight antimalarials with melanin was studied. The dissociation constant for the drug-melanin complex and the relative number of binding sites on melanin were estimated for six of the drugs using a curve-fitting program. The reaction rate for the formation of the melanin-drug complex was determined, and the complexes were further characterized by zeta potential measurements.

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

    Directory of Open Access Journals (Sweden)

    Abong'o Benard

    2010-10-01

    Full Text Available Abstract Background 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. Methods 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 Results Stratification of the type of anti-malarial drugs taken revealed that 37.0% used sulphadoxine/pyrimethamine (SP, 32.0% artemisinin-based combined therapy (ACT, 11.1% anti-pyretics, 7.3% chloroquine (CQ, 7.1% quinine, 2.5% amodiaquine (AQ, while 3.0% used others which were perceived as anti-malarials (cough syrups and antibiotics. In a regression model, it was demonstrated that age (P = 0.050, household size (P = 0.047, household head (P = 0.049, household source of income (P = 0.015, monthly income (P = 0.020, duration of use (P = 0.029, dosage of drugs taken (P = 0.036, and source of drugs (P = 0.005 significantly influenced anti-malarial drug use. Overall, 38.8% of respondents used drugs as recommended by the Ministry of Health. Conclusion This study demonstrates that consumers require access to correct and comprehensible information associated with use of drugs, including self-prescription. There is potential need by the Kenyan government to improve malaria care and decrease malaria-related morbidity and

  1. Photoreactivity of biologically active compounds. VIII. Photosensitized polymerization of lens proteins by antimalarial drugs in vitro.

    Science.gov (United States)

    Kristensen, S; Wang, R H; Tønnesen, H H; Dillon, J; Roberts, J E

    1995-02-01

    The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds cause dermal and ocular toxic reactions that may be light induced. The in vitro photopolymerization of calf lens proteins in the presence of antimalarial drugs was studied as part of a screening of the photochemical properties and phototoxic capabilities of these compounds. The pseudo-first-order rate constant for the reaction was calculated, and related to the amount of light absorbed by the compounds in order to determine the relative photosensitizing effect of each drug. The reaction mechanisms were evaluated by adding a variety of quenchers to the reaction medium during irradiation. Based on the results obtained in this study and previous knowledge about the pharmacokinetic behavior of these compounds, several of the drugs investigated have to be considered as potential photosensitizers in the human lens, the retina and the skin.

  2. Exploration of Scaffolds from Natural Products with Antiplasmodial Activities, Currently Registered Antimalarial Drugs and Public Malarial Screen Data

    Directory of Open Access Journals (Sweden)

    Samuel Egieyeh

    2016-01-01

    Full Text Available In light of current resistance to antimalarial drugs, there is a need to discover new classes of antimalarial agents with unique mechanisms of action. Identification of unique scaffolds from natural products with in vitro antiplasmodial activities may be the starting point for such new classes of antimalarial agents. We therefore conducted scaffold diversity and comparison analysis of natural products with in vitro antiplasmodial activities (NAA, currently registered antimalarial drugs (CRAD and malaria screen data from Medicine for Malaria Ventures (MMV. The scaffold diversity analyses on the three datasets were performed using scaffold counts and cumulative scaffold frequency plots. Scaffolds from the NAA were compared to those from CRAD and MMV. A Scaffold Tree was also generated for each of the datasets and the scaffold diversity of NAA was found to be higher than that of MMV. Among the NAA compounds, we identified unique scaffolds that were not contained in any of the other compound datasets. These scaffolds from NAA also possess desirable drug-like properties making them ideal starting points for antimalarial drug design considerations. The Scaffold Tree showed the preponderance of ring systems in NAA and identified virtual scaffolds, which may be potential bioactive compounds.

  3. In Vitro and In Vivo Potentiation of Artemisinin and Synthetic Endoperoxide Antimalarial Drugs by Metalloporphyrins

    Science.gov (United States)

    Benoit-Vical, Françoise; Robert, Anne; Meunier, Bernard

    2000-01-01

    The in vitro potentiation of artemisinin by synthetic manganese porphyrin complexes has been recently reported (F. Benoit-Vical, A. Robert, and B. Meunier, Antimicrob. Agents Chemother. 43:2555–2558, 1999). Since the activity of artemisinin and synthetic antimalarial endoperoxides is related to their interaction with heme (S. R. Meshnick, A. Thomas, A. Ranz, C. M. Xu, and H. Z. Pan, Mol. Biochem. Parasitol. 49:181–190, 1991), an improvement of their efficiency may be expected in the presence of a synthetic metalloporphyrin having the same activating role as endogenous heme. With the aim to boost the activity of antimalarial endoperoxide drugs, we were thus led to evaluate the in vitro and in vivo potentiation of natural and synthetic drugs of this family by a nontoxic and cheap metalloporphyrin. The potentiation of artemisinin, β-artemether, and arteflene (Ro 42-1611) by synthetic heme models is reported. In vitro studies on the chloroquine-resistant Plasmodium falciparum FcB1-Columbia strain indicate a synergistic effect of the manganese complex of meso-tetrakis(4-sulfonatophenylporphyrin) (Mn-TPPS) on the activity of artemisinin or β-artemether, whereas this heme model has no influence on the activity of arteflene. A significant synergistic effect on rodent malaria was also observed in vivo between artemisinin and Mn-TPPS using Plasmodium vinckei petteri strain. PMID:10991867

  4. 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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. 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...

  6. Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity

    Directory of Open Access Journals (Sweden)

    Jufrizal Syahri

    2017-01-01

    Full Text Available Objective: To synthesize chalcone derivatives and investigate their antimalarial activity toward chloroquine-sensitive Plasmodium falciparum 3D7 (Pf3D7 strain; to develop quantitative structureactivity relationships (QSAR model to estimate IC50 values for biological activity of antimalarial and compared to experimental measurement; and to determine the binding interactions of the most active compounds with targeting P. falciparum dihydrofolate reductase-thymidylate synthase using molecular docking simulation. Methods: Seven chalcone derivatives have been synthesized from substituted acetophenone and substituted benzaldehyde in ethanol with the presence of bases catalysis at reflux condition. The QSAR analysis was conducted by using Gaussian 09 software to predict IC50 value for antimalarial activity. The in vitro test was evaluated against the chloroquine-sensitive Pf3D7 strain. Finally, the docking studies were performed with the CDOCKER protocol under the receptor-ligand interaction section in Discovery Studio® 3.1 (Accelrys, Inc., San Diego, USA. Results: Among the synthesized chalcone, a prenylated chalcone 5c and an allylated chalcones 10a showed the best IC 50 values of 1.08 and 1.73 μg/mL respectively against Pf3D7 strain (1.37 and 2.33 μg/mL based on QSAR analysis. Comparison between the prediction of IC50 value generated from the QSAR and the outcome from an in vitro assay showed a similar result as seen from the r2 value (r2 = 0.99. The most active compound 5c was employed in the docking simulation to determine the potential binding interactions with active sites of P. falciparum dihydrofolate reductase-thymidylate synthase (protein data bank ID: 1J3I. The docking simulation study showed 5c bind well with Ala16, Ser108, Ile164, Trp48, and Phe58 which are the crucial interactions that could possibly interrupt the sequential catalysis reactions in the thymidylate cycle and subsequently prevent deoxythymidine monophosphate production

  7. 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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  8. 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.

  9. Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

    Directory of Open Access Journals (Sweden)

    Kotaki Hajime

    2010-11-01

    Full Text Available Abstract Background Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. Methods The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM, quinine (0.3 - 2.4 μM, halofantrine (0.1 - 2.0 μM and mefloquine (0.1 - 2.0 μM. The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. Results Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine Conclusions In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.

  10. 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.

  11. A simple and inexpensive haemozoin-based colorimetric method to evaluate anti-malarial drug activity.

    Science.gov (United States)

    Men, Tran Thanh; Huy, Nguyen Tien; Trang, Dai Thi Xuan; Shuaibu, Mohammed Nasir; Hirayama, Kenji; Kamei, Kaeko

    2012-08-09

    The spread of drug resistance in malaria parasites and the limited number of effective drugs for treatment indicates the need for new anti-malarial compounds. Current assays evaluating drugs against Plasmodium falciparum require expensive materials and equipment, thus limiting the search for new drugs, particularly in developing countries. This study describes an inexpensive procedure that is based on the advantage of a positive correlation between the haemozoin level of infected erythrocytes and parasite load. The relationship between parasitaemia and the haemozoin level of infected erythrocytes was investigated after converting haemozoin into monomeric haem. The 50% inhibitory concentration (IC50) values of chloroquine, quinine, artemisinin, quinidine and clotrimazole against P. falciparum K1 and 9A strains were determined using the novel assay method. The haemozoin of parasites was extracted and converted into monomeric haem, allowing the use of a colorimeter to efficiently and rapidly measure the growth of the parasites. There was a strong and direct linear relationship between the absorbance of haem converted from haemozoin and the percentage of the parasite (R2 = 0.9929). Furthermore, the IC50 values of drugs were within the range of the values previously reported. The haemozoin-based colorimetric assay can be considered as an alternative, simple, robust, inexpensive and convenient method, making it applicable in developing countries.

  12. 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. Published 2012. This article is a US Government work and is in the public domain in the USA.

  13. Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors.

    Science.gov (United States)

    Golden, Encouse B; Cho, Hee-Yeon; Hofman, Florence M; Louie, Stan G; Schönthal, Axel H; Chen, Thomas C

    2015-03-01

    Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells. Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress-induced cell death, autophagy, and cell death. All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis. Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas.

  14. Malaria overdiagnosis and subsequent overconsumption of antimalarial drugs in Angola: Consequences and effects on human health.

    Science.gov (United States)

    Manguin, Sylvie; Foumane, Vincent; Besnard, Patrick; Fortes, Filomeno; Carnevale, Pierre

    2017-07-01

    Microscopic blood smear examinations done in health centers of Angola demonstrated a large overdiagnosis of malaria cases with an average rate of errors as high as 85%. Overall 83% of patients who received Coartem ® had an inappropriate treatment. Overestimated malaria diagnosis was noticed even when specific symptoms were part of the clinical observation, antimalarial treatments being subsequently given. Then, malaria overdiagnosis has three main consequences, (i) the lack of data reliability is of great concern, impeding epidemiological records and evaluation of the actual influence of operations as scheduled by the National Malaria Control Programme; (ii) the large misuse of antimalarial drug can increase the selective pressure for resistant strain and can make a false consideration of drug resistant P. falciparum crisis; and (iii) the need of strengthening national health centers in term of human, with training in microscopy, and equipment resources to improve malaria diagnosis with a large scale use of rapid diagnostic tests associated with thick blood smears, backed up by a "quality control" developed by the national health authorities. Monitoring of malaria cases was done in three Angolan health centers of Alto Liro (Lobito town) and neighbor villages of Cambambi and Asseque (Benguéla Province) to evaluate the real burden of malaria. Carriers of Plasmodium among patients of newly-borne to 14 years old, with or without fever, were analyzed and compared to presumptive malaria cases diagnosed in these health centers. Presumptive malaria cases were diagnosed six times more than the positive thick blood smears done on the same children. In Alto Liro health center, the percentage of diagnosis error reached 98%, while in Cambambi and Asseque it was of 79% and 78% respectively. The percentage of confirmed malaria cases was significantly higher during the dry (20.2%) than the rainy (13.2%) season. These observations in three peripheral health centers confirmed what

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Antimalarial drug utilization by women in Ethiopia: a knowledge-attitudes-practice study.

    Science.gov (United States)

    Yeneneh, H; Gyorkos, T W; Joseph, L; Pickering, J; Tedla, S

    1993-01-01

    A survey was undertaken between December 1991 and February 1992 to assess the knowledge, attitudes, and practices with respect to malaria of 300 women from six randomly selected rural communities in central Ethiopia. A total of 85% were able to recognize one or more of the common symptoms of the disease; however, the modes of transmission were generally misunderstood and only 23% believed that transmission could be prevented. More women preferred to obtain antimalarials from government clinics rather than from private drug shops, mission clinics, unofficial suppliers of injections, open markets, or from leftover sources. Under-5-year-olds were identified as the most malaria-vulnerable group and given priority for treatment; severity of illness was the principal determinant in seeking treatment. Decisions about treatment were generally made jointly by both parents. Knowledge about the transmissibility of malaria decreased with increasing distance from a health unit (odds ratio: 0.48; 95% confidence interval: 0.27, 0.86). A logistic regression analysis indicated that literacy and village were the most important variables associated with knowledge about preventing malaria.

  17. 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. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Bibliometric Analysis of Worldwide Publications on Antimalarial Drug Resistance (2006–2015

    Directory of Open Access Journals (Sweden)

    Waleed M. Sweileh

    2017-01-01

    Full Text Available Background. In response to international efforts to control and eradicate malaria, we designed this study to give a bibliometric overview of research productivity in antimalarial drug resistance (AMDR. Methods. Keywords related to AMDR were used to retrieve relevant literature using Scopus database. Results. A total of 976 publications with an h-index of 63 were retrieved. The number of publications showed a noticeable increase starting in the early 1990s. The USA was the most productive country with 337 publications equivalent to one-third of worldwide publications in this field. More than two-thirds of publications by the USA (236, 70.03% were made by international collaboration. Of the top ten productive countries, two countries were from Mekong subregion, particularly Thailand and Cambodia. The Malaria Journal was the most productive journal (136, 13.93% in this field. Mahidol University (80, 8.20% in Thailand was the most productive institution. Seven articles in the top-ten list were about artemisinin resistance in Plasmodium falciparum, one was about chloroquine resistance, one was about sulfadoxine-pyrimethamine resistance, and the remaining one was about general multidrug resistance. Conclusion. Eradication and control of AMDR require continuing research activity to help international health organizations identify spots that require an immediate action to implement appropriate measures.

  19. Structural mapping of the ClpB ATPases of Plasmodium falciparum: Targeting protein folding and secretion for antimalarial drug design.

    Science.gov (United States)

    AhYoung, Andrew P; Koehl, Antoine; Cascio, Duilio; Egea, Pascal F

    2015-09-01

    Caseinolytic chaperones and proteases (Clp) belong to the AAA+ protein superfamily and are part of the protein quality control machinery in cells. The eukaryotic parasite Plasmodium falciparum, the causative agent of malaria, has evolved an elaborate network of Clp proteins including two distinct ClpB ATPases. ClpB1 and ClpB2 are involved in different aspects of parasitic proteostasis. ClpB1 is present in the apicoplast, a parasite-specific and plastid-like organelle hosting various metabolic pathways necessary for parasite growth. ClpB2 localizes to the parasitophorous vacuole membrane where it drives protein export as core subunit of a parasite-derived protein secretion complex, the Plasmodium Translocon of Exported proteins (PTEX); this process is central to parasite virulence and survival in the human host. The functional associations of these two chaperones with parasite-specific metabolism and protein secretion make them prime drug targets. ClpB proteins function as unfoldases and disaggregases and share a common architecture consisting of four domains-a variable N-terminal domain that binds different protein substrates, followed by two highly conserved catalytic ATPase domains, and a C-terminal domain. Here, we report and compare the first crystal structures of the N terminal domains of ClpB1 and ClpB2 from Plasmodium and analyze their molecular surfaces. Solution scattering analysis of the N domain of ClpB2 shows that the average solution conformation is similar to the crystalline structure. These structures represent the first step towards the characterization of these two malarial chaperones and the reconstitution of the entire PTEX to aid structure-based design of novel anti-malarial drugs. © 2015 The Protein Society.

  20. Alternatives to currently used antimalarial drugs: in search of a magic bullet.

    Science.gov (United States)

    Bhagavathula, Akshaya Srikanth; Elnour, Asim Ahmed; Shehab, Abdulla

    2016-11-04

    Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners' collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic

  1. Characterizing the binding interaction between antimalarial artemether (AMT) and bovine serum albumin (BSA): Spectroscopic and molecular docking methods.

    Science.gov (United States)

    Shi, Jie-Hua; Pan, Dong-Qi; Wang, Xiou-Xiou; Liu, Ting-Ting; Jiang, Min; Wang, Qi

    2016-09-01

    Artemether (AMT), a peroxide sesquiterpenoides, has been widely used as an antimalarial for the treatment of multiple drug-resistant strains of plasmodium falciparum malaria. In this work, the binding interaction of AMT with bovine serum albumin (BSA) under the imitated physiological conditions (pH7.4) was investigated by UV spectroscopy, fluorescence emission spectroscopy, synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), three-dimensional fluorescence spectroscopy and molecular docking methods. The experimental results indicated that there was a change in UV absorption of BSA along with a slight red shift of absorption wavelength, indicating that the interaction of AMT with BSA occurred. The intrinsic fluorescence of BSA was quenched by AMT due to the formation of AMT-BSA complex. The number of binding sites (n) and binding constant of AMT-BSA complex were about 1 and 2.63×10(3)M(-1) at 298K, respectively, suggesting that there was stronger binding interaction of AMT with BSA. Based on the analysis of the signs and magnitudes of the free energy change (ΔG(0)), enthalpic change (ΔH(0)) and entropic change (ΔS(0)) in the binding process, it can be concluded that the binding of AMT with BSA was enthalpy-driven process due to |ΔH°|>|TΔS°|. The results of experiment and molecular docking confirmed the main interaction forces between AMT and BSA were van der Waals force. And, there was a slight change in the BSA conformation after binding AMT but BSA still retains its secondary structure α-helicity. However, it had been confirmed that AMT binds on the interface between sub-domain IIA and IIB of BSA. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

    Science.gov (United States)

    Maurya, Shiv Shyam; Khan, Shabana I; Bahuguna, Aparna; Kumar, Deepak; Rawat, Diwan S

    2017-03-31

    A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Making the most of clinical data: reviewing the role of pharmacokinetic-pharmacodynamic models of anti-malarial drugs.

    Science.gov (United States)

    Simpson, Julie A; Zaloumis, Sophie; DeLivera, Alysha M; Price, Ric N; McCaw, James M

    2014-09-01

    Mechanistic within-host models integrating blood anti-malarial drug concentrations with the parasite-time profile provide a valuable decision tool for determining dosing regimens for anti-malarial treatments, as well as a formative component of population-level drug resistance models. We reviewed published anti-malarial pharmacokinetic-pharmacodynamic models to identify the challenges for these complex models where parameter estimation from clinical field data is limited. The inclusion of key pharmacodynamic processes in the mechanistic structure adopted varies considerably. These include the life cycle of the parasite within the red blood cell, the action of the anti-malarial on a specific stage of the life cycle, and the reduction in parasite growth associated with immunity. With regard to estimation of the pharmacodynamic parameters, the majority of studies simply compared descriptive summaries of the simulated outputs to published observations of host and parasite responses from clinical studies. Few studies formally estimated the pharmacodynamic parameters within a rigorous statistical framework using observed individual patient data. We recommend three steps in the development and evaluation of these models. Firstly, exploration through simulation to assess how the different parameters influence the parasite dynamics. Secondly, application of a simulation-estimation approach to determine whether the model parameters can be estimated with reasonable precision based on sampling designs that mimic clinical efficacy studies. Thirdly, fitting the mechanistic model to the clinical data within a Bayesian framework. We propose that authors present the model both schematically and in equation form and give a detailed description of each parameter, including a biological interpretation of the parameter estimates.

  4. CPP-ZFN: A potential DNA-targeting anti-malarial drug

    Directory of Open Access Journals (Sweden)

    Nain Vikrant

    2010-09-01

    . Implications of the hypothesis Targeting of the Plasmodium genome using ZFN has great potential for the development of anti-malarial drugs. It allows the development of a single drug against all malarial infections, including multidrug-resistant strains. Availability of multiple ZFN target sites in a single gene will provide alternative drug target sites to combat the development of resistance in the future.

  5. 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

  6. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

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

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    López-Antuñano Francisco Javier

    1999-01-01

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria.

    Science.gov (United States)

    Achan, Jane; Talisuna, Ambrose O; Erhart, Annette; Yeka, Adoke; Tibenderana, James K; Baliraine, Frederick N; Rosenthal, Philip J; D'Alessandro, Umberto

    2011-05-24

    Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    International Nuclear Information System (INIS)

    Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N.

    2002-01-01

    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- 3 H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl- 3 H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [ 3 H] ethyl iodide

  12. 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.

  13. SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology

    Science.gov (United States)

    2010-01-01

    restricted availability of anti-malarial drugs or other medicines in rural or under-resourced areas. PMID:20979633

  14. Peculiarities in cases of spina bifida cystica managed recently in south-east Nigeria: could antimalarial drugs be a major but unrecognized etiologic factor?

    Science.gov (United States)

    Emejulu, Jude-Kennedy C; Okwaraoha, Blaise Ogedi

    2011-01-01

    Spina bifida is a long-known disease arising from the incomplete fusion of the caudal neuropore in the first month of intrauterine life. It is thought to have a multifactorial etiology, the most important of which is folic acid deficiency. In evaluating its etiology, the role of antifolate agents like antimalarial drugs is rarely given a strong mention. This is a 44-month prospective study of consecutive cases of spina bifida cystica presenting to the Neurosurgery Unit of Nnamdi Azikiwe University Teaching Hospital, Nnewi, South-East Nigeria. Data collection was with a structured proforma from presentation, and collation done with Microsoft Excel broadsheet and data analysis with SPSS and χ2 test. A total of 41 cases of spina bifida were attended to within the period, with 92.7% cases of spina bifida cystica. Most presented by >12-24 months, with a consistent history of maternal ingestion of antimalarial drugs during the first trimester of pregnancy. Spina bifida cystica was diagnosed mostly in children whose mothers ingested antimalarial drugs during the first trimester of gestation. There may be a need to critically evaluate the contribution of antimalarial drugs to the etiopathogenesis of this malformation and develop safer antimalarial treatment in pregnancy. Copyright © 2012 S. Karger AG, Basel.

  15. 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.

  16. Analysis of the electrochemical reactivity of natural hemozoin and β-hemozoin in the presence of antimalarial drugs

    International Nuclear Information System (INIS)

    Esteban Reyes-Cruz, Victor; Urbano Reyes, Gustavo; Veloz Rodriguez, Maria Aurora; Imbert Palafox, Jose Luis

    2011-01-01

    We report an evaluation of the reactivity of hemozoin (HZ) and β-hemozoin (β-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 β-HZ from Triatoma, which suggests that cellular molecules are embedded in an oxidising environment due to the presence of β-HZ and indicates that like HZ, β-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 β-HZ with quinine and amodiaquine, a more oxidative stress was generated between the second one and the β-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.

  17. 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

  18. Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment

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    Shaukat Ayesha M

    2012-06-01

    Full Text Available Abstract Background Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. Methods Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998–2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. Results Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. Conclusions The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision

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

    Directory of Open Access Journals (Sweden)

    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

  20. The effect of intermittent preventive treatment on anti-malarial drug resistance spread in areas with population movement.

    Science.gov (United States)

    Teboh-Ewungkem, Miranda I; Mohammed-Awel, Jemal; Baliraine, Frederick N; Duke-Sylvester, Scott M

    2014-11-15

    The use of intermittent preventive treatment in pregnant women (IPTp), children (IPTc) and infant (IPTi) is an increasingly popular preventive strategy aimed at reducing malaria risk in these vulnerable groups. Studies to understand how this preventive intervention can affect the spread of anti-malarial drug resistance are important especially when there is human movement between neighbouring low and high transmission areas. Because the same drug is sometimes utilized for IPTi and for symptomatic malaria treatment, distinguishing their individual roles on accelerating the spread of drug resistant malaria, with or without human movement, may be difficult to isolate experimentally or by analysing data. A theoretical framework, as presented here, is thus relevant as the role of IPTi on accelerating the spread of drug resistance can be isolated in individual populations and when the populations are interconnected and interact. A previously published model is expanded to include human movement between neighbouring high and low transmission areas, with focus placed on the malaria parasites. Parasite fitness functions, determined by how many humans the parasites can infect, are used to investigate how fast resistance can spread within the neighbouring communities linked by movement, when the populations are at endemic equilibrium. Model simulations indicate that population movement results in resistance spreading fastest in high transmission areas, and the more complete the anti-malarial resistance the faster the resistant parasite will tend to spread through a population. Moreover, the demography of infection in low transmission areas tends to change to reflect the demography of high transmission areas. Additionally, when regions are strongly connected the rate of spread of partially resistant parasites (R1) relative to drug sensitive parasites (RS), and fully resistant parasites (R2) relative to partially resistant parasites (R1) tend to behave the same in both

  1. Substandard antimalarials available in Afghanistan: a case for assessing the quality of drugs in resource poor settings.

    Science.gov (United States)

    Lalani, Mirza; Kaur, Harparkash; Mohammed, Nader; Mailk, Naiela; Wyk, Albert van; Jan, Sakhi; Kakar, Rishtya Meena; Mojadidi, Mohammed Khalid; Leslie, Toby

    2015-06-01

    Good-quality antimalarials are crucial for the effective treatment and control of malaria. A total of 7,740 individual and packaged tablets, ampoules, and syrups were obtained from 60 randomly selected public (N = 35) and private outlets (N = 25) in Afghanistan. Of these, 134 samples were screened using the Global Pharma Health Fund (GPHF) MiniLab® in Kabul with 33/126 (26%) samples failing the MiniLab® disintegration test. The quality of a subsample (N = 37) of cholorquine, quinine, and sulfadoxine/pyrimethamine tablets was assessed by in vitro dissolution testing following U.S. Pharmacopeia (USP) monographs at a bioanalytical laboratory in London, United Kingdom. Overall, 12/32 (32%) samples of sulfadoxine/pyrimethamine and quinine were found not to comply with the USP tolerance limits. Substandard antimalarials were available in Afghanistan demonstrating that continuous monitoring of drug quality is warranted. However, in Afghanistan as in many low-income countries, capacity to determine and monitor drug quality using methods such as dissolution testing needs to be established to empower national authorities to take appropriate action in setting up legislation and regulation. © The American Society of Tropical Medicine and Hygiene.

  2. 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...... levels suppressed the lymphocytes' proliferation, but not their IL-2 production. All three quinolines suppressed the proliferation of lymphocytes, but not equally, with mefloquine having the strongest effect. Quinine suppressed the growth at therapeutic concentrations. The IL-2 production was suppressed...... at concentrations twice as high as those required to suppress lymphocyte proliferation. Addition of exogenous IL-2 only partially reversed the suppressive effect on lymphocyte proliferation. Delayed addition of the quinolines decreased their suppressive effect, but not completely. The mechanisms of action on human...

  3. Antimalarial drug utilization by women in Ethiopia: a knowledge-attitudes-practice study.

    OpenAIRE

    Yeneneh, H.; Gyorkos, T. W.; Joseph, L.; Pickering, J.; Tedla, S.

    1993-01-01

    A survey was undertaken between December 1991 and February 1992 to assess the knowledge, attitudes, and practices with respect to malaria of 300 women from six randomly selected rural communities in central Ethiopia. A total of 85% were able to recognize one or more of the common symptoms of the disease; however, the modes of transmission were generally misunderstood and only 23% believed that transmission could be prevented. More women preferred to obtain antimalarials from government clinic...

  4. Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

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    Reagan M Mogire

    Full Text Available Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

  5. Malavefes: A computational voice-enabled malaria fuzzy informatics software for correct dosage prescription of anti-malarial drugs

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    Olugbenga O. Oluwagbemi

    2018-04-01

    Full Text Available Malaria is one of the infectious diseases consistently inherent in many Sub-Sahara African countries. Among the issues of concern are the consequences of wrong diagnosis and dosage administration of anti-malarial drugs on sick patients; these have resulted into various degrees of complications ranging from severe headaches, stomach and body discomfort, blurred vision, dizziness, hallucinations, and in extreme cases, death. Many expert systems have been developed to support different infectious disease diagnoses, but not sure of any yet, that have been specifically designed as a voice-based application to diagnose and translate malaria patients’ symptomatic data for pre-laboratory screening and correct prescription of proper dosage of the appropriate medication. We developed Malavefes, (a malaria voice-enabled computational fuzzy expert system for correct dosage prescription of anti-malarial drugs using Visual Basic.NET., and Java programming languages. Data collation for this research was conducted by survey from existing literature and interview from public health experts. The database for this malaria drug informatics system was implemented using Microsoft Access. The Root Sum Square (RSS was implemented as the inference engine of Malavefes to make inferences from rules, while Centre of Gravity (CoG was implemented as the defuzzification engine. The drug recommendation module was voice-enabled. Additional anti-malaria drug expiration validation software was developed using Java programming language. We conducted a user-evaluation of the performance and user-experience of the Malavefes software. Keywords: Informatics, Bioinformatics, Fuzzy, Anti-malaria, Voice computing, Dosage prescription

  6. 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.

  7. G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets.

    Science.gov (United States)

    Harris, Lynne M; Monsell, Katelyn R; Noulin, Florian; Famodimu, M Toyin; Smargiasso, Nicolas; Damblon, Christian; Horrocks, Paul; Merrick, Catherine J

    2018-03-01

    G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum , which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences, P. falciparum parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in P. falciparum but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in P. falciparum may present a target for development of other new antimalarial drugs. Copyright © 2018 American Society for Microbiology.

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

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    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

  9. Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: A retrospective cohort study.

    Science.gov (United States)

    Mittal, Lavanya; Zhang, Lingqiao; Feng, Rui; Werth, Victoria P

    2018-01-01

    Although existing evidence demonstrates the efficacy of antimalarials for rheumatic skin disease, the safety of these medications, and particularly quinacrine, remains debated. We investigated the toxicity risk associated with antimalarials in patients with cutaneous lupus erythematosus and dermatomyositis. A total of 532 patients (mean age, 52.29 years; sample composition by sex, 85.15% female vs 14.85% male) were selected from 2 databases on cutaneous lupus erythematosus (69.92%) and dermatomyositis (30.08%). Details regarding treatment and toxicities were extracted and 5 treatment courses were defined (ie, hydroxychloroquine [HCQ], chloroquine [CQ], quinacrine [Q], HCQ-Q combination therapy [HCQ-Q], and CQ-Q combination therapy [CQ-Q]). The hazard ratio for each major toxicity was estimated by using the Cox proportional hazard model to compare the different treatments with HCQ. The most common toxicities included cutaneous eruption, gastrointestinal upset, mucocutaneous dyspigmentation, neurologic toxicity, and retinopathy. The hazards of cutaneous eruption, gastrointestinal upset, and neurologic toxicities were lower with HCQ-Q than with HCQ; however, this may represent selection bias. Although there was increased retinopathy risk with CQ and CQ-Q versus with HCQ, retinopathy was not seen with Q. Retrospective analysis. With the exception of retinopathy, which was not seen with Q, the risks for other toxicities associated with Q monotherapy or combination treatment were not significantly different from those with HCQ. Published by Elsevier Inc.

  10. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests.

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    Sylla Thiam

    Full Text Available BACKGROUND: While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. METHODS AND FINDINGS: Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases. An estimated 516,576 courses of inappropriate ACT prescription were averted. CONCLUSIONS: The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were

  11. Major Reduction in Anti-Malarial Drug Consumption in Senegal after Nation-Wide Introduction of Malaria Rapid Diagnostic Tests

    Science.gov (United States)

    Thiam, Sylla; Thior, Moussa; Faye, Babacar; Ndiop, Médoune; Diouf, Mamadou Lamine; Diouf, Mame Birame; Diallo, Ibrahima; Fall, Fatou Ba; Ndiaye, Jean Louis; Albertini, Audrey; Lee, Evan; Jorgensen, Pernille; Gaye, Oumar; Bell, David

    2011-01-01

    Background While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. Methods and Findings Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT) and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584873 suspect fever cases). An estimated 516576 courses of inappropriate ACT prescription were averted. Conclusions The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were achieved in ACT

  12. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests.

    Science.gov (United States)

    Thiam, Sylla; Thior, Moussa; Faye, Babacar; Ndiop, Médoune; Diouf, Mamadou Lamine; Diouf, Mame Birame; Diallo, Ibrahima; Fall, Fatou Ba; Ndiaye, Jean Louis; Albertini, Audrey; Lee, Evan; Jorgensen, Pernille; Gaye, Oumar; Bell, David

    2011-04-06

    While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT) and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases). An estimated 516,576 courses of inappropriate ACT prescription were averted. The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were achieved in ACT procurement. Programmes need to be allowed

  13. 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

  14. Community perceptions of targeted anti-malarial mass drug administrations in two provinces in Vietnam: a quantitative survey.

    Science.gov (United States)

    Nguyen, Thuy-Nhien; Thu, Pham N Huong; Hung, Ngo Trong; Son, Do Hung; Tien, Nguyen Thanh; Van Dung, Nguyen; Quang, Huynh Hong; Seidlein, Lorenz von; Cheah, Phaik Yeong; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J; Hien, Tran Tinh

    2017-01-06

    As part of a targeted malaria elimination project, mass drug administrations (MDAs) were conducted in Vietnam. The impact of MDAs on malaria transmission depends largely on the efficacy of the anti-malarial drug regimen, the malaria epidemiology in the site and the population coverage. To explore why some people participate in MDAs and others do not, a quantitative survey of the villagers' perceptions was undertaken in Vietnam. In 2013/2014 MDAs were conducted in a village in Binh Phuoc province and a village in Ninh Thuan province. Within three months of the drug administration, 59 respondents in a village in Binh Phuoc and 79 respondents in a village in Ninh Thuan were randomly selected and interviewed. Comprehension of the purpose of the intervention was of paramount importance for participation in the intervention. Respondents aware that the intervention aims to protect against malaria were significantly more likely to participate than respondents who were unaware of the MDA's purpose. Secondly, how and by whom villagers were informed was critical for participation. There was a strong association between sensitization by an informant such as a member of the local health team with participation in the intervention. The study suggests several approaches to increase participation in mass drug administration campaigns. Training trustworthy informants to sensitize the study population is critical to maximize village participation in this setting. To achieve high coverage the entire community must understand and agree with the intervention.

  15. 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 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.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.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 regulatory mechanisms. Measures to stop the

  16. Quality of Antimalarial Drugs and Antibiotics in Papua New Guinea: A Survey of the Health Facility Supply Chain

    Science.gov (United States)

    Hetzel, Manuel W.; Page-Sharp, Madhu; Bala, Nancy; Pulford, Justin; Betuela, Inoni; Davis, Timothy M. E.; Lavu, Evelyn K.

    2014-01-01

    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 regulatory

  17. 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.

    Science.gov (United States)

    Mishra, Neelima; Gupta, Ruchi; Singh, Sagya; Rana, Roma; Shahi, Bhartendu; Das, Manoj Kumar; Anvikar, Anupkumar R; Valecha, Neena

    2013-12-01

    Widespread resistance to chloroquine was the mainstay to implement artemisinin-based 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. 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. 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 non-antimalarial treatment (NM) in both malaria positive (0.3%) and malaria negative (2.1%) cases. 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 ≤ 15 yr was the main hindrance in the implementation of the recommended

  18. Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms.

    Science.gov (United States)

    Okorji, Uchechukwu P; Velagapudi, Ravikanth; El-Bakoush, Abdelmeneim; Fiebich, Bernd L; Olajide, Olumayokun A

    2016-11-01

    Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40 μM) for 24 h. ELISAs and western blotting were used to detect pro-inflammatory cytokines, nitric oxide, prostaglandin E 2 (PGE 2 ), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity and Aβ levels were measured with ELISA kits. Protein levels of targets in nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signalling, as well as heme oxygenase-1 (HO-1), NQO1 and nuclear factor-erythroid 2-related factor 2 (Nrf2) were also measured with western blot. NF-κB binding to the DNA was investigated using electrophoretic mobility shift assays (EMSA). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), DNA fragmentation and reactive oxygen species (ROS) assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE 2 /COX-2/mPGES-1, tumour necrosis factor-alpha (TNFα) and interleukin (IL)-6); Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-κB and p38 MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug

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

    Science.gov (United States)

    Agomo, Chimere Obiora; Oyibo, Wellington Aghoghovwia; Sutherland, Colin; Hallet, Rachael; Oguike, Mary

    2016-01-01

    Background 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). Methods 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. Results 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, Pfmdr186Yand184F 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

  20. Resistance of Plamodium falciparum to Antimalarial Drugs in Zaragoza (Antioquia, Colombia, 1998

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    Silvia Blair-Trujillo

    2002-04-01

    Full Text Available Plasmodium falciparum sensitivity to chloroquine (CHL, amodiaquine (AMO and sulfadoxine/pyrimethamine (SDX/PYR was assessed in vivo and in vitro in a representative sample from the population of Zaragoza in El Bajo Cauca region (Antioquia-Colombia. There were 94 patients with P. falciparum evaluated. For the in vivo test the patients were followed by clinical examination and microscopy, during 7 days. The in vitro test was performed following the recommendations of the World Health Organization. The in vivo prevalence of resistance to CHL was 67%, to AMO 3% and to SDX/PYR 9%. The in vitro test showed sensitivity to all antimalarials evaluated. Concordance for CHL between the in vivo and in vitro tests was 33%. For AMO and SDX/PYR, the concordance was 100%. We conclude that a high percentage of patients are resistant to CHL (in vivo. A high rate of intestinal parasitism might explain in part, the differences observed between the in vivo and the in vitro results. Therefore, new policies and treatment regimens should be proposed for the treatment of the infection in the region. Nationwide studies assessing the degree of resistance are needed.

  1. Spatial distribution and cluster analysis of retail drug shop characteristics and antimalarial behaviors as reported by private medicine retailers in western Kenya: informing future interventions.

    Science.gov (United States)

    Rusk, Andria; Highfield, Linda; Wilkerson, J Michael; Harrell, Melissa; Obala, Andrew; Amick, Benjamin

    2016-02-19

    Efforts to improve malaria case management in sub-Saharan Africa have shifted focus to private antimalarial retailers to increase access to appropriate treatment. Demands to decrease intervention cost while increasing efficacy requires interventions tailored to geographic regions with demonstrated need. Cluster analysis presents an opportunity to meet this demand, but has not been applied to the retail sector or antimalarial retailer behaviors. This research conducted cluster analysis on medicine retailer behaviors in Kenya, to improve malaria case management and inform future interventions. Ninety-seven surveys were collected from medicine retailers working in the Webuye Health and Demographic Surveillance Site. Survey items included retailer training, education, antimalarial drug knowledge, recommending behavior, sales, and shop characteristics, and were analyzed using Kulldorff's spatial scan statistic. The Bernoulli purely spatial model for binomial data was used, comparing cases to controls. Statistical significance of found clusters was tested with a likelihood ratio test, using the null hypothesis of no clustering, and a p value based on 999 Monte Carlo simulations. The null hypothesis was rejected with p values of 0.05 or less. A statistically significant cluster of fewer than expected pharmacy-trained retailers was found (RR = .09, p = .001) when compared to the expected random distribution. Drug recommending behavior also yielded a statistically significant cluster, with fewer than expected retailers recommending the correct antimalarial medication to adults (RR = .018, p = .01), and fewer than expected shops selling that medication more often than outdated antimalarials when compared to random distribution (RR = 0.23, p = .007). All three of these clusters were co-located, overlapping in the northwest of the study area. Spatial clustering was found in the data. A concerning amount of correlation was found in one specific region in the study area where

  2. A single LC-tandem mass spectrometry method for the simultaneous determination of 14 antimalarial drugs and their metabolites in human plasma.

    Science.gov (United States)

    Hodel, E M; Zanolari, B; Mercier, T; Biollaz, J; Keiser, J; Olliaro, P; Genton, B; Decosterd, L A

    2009-04-01

    Among the various determinants of treatment response, the achievement of sufficient blood levels is essential for curing malaria. For helping us at improving our current understanding of antimalarial drugs pharmacokinetics, efficacy and toxicity, we have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 200mul of plasma for the simultaneous determination of 14 antimalarial drugs and their metabolites which are the components of the current first-line combination treatments for malaria (artemether, artesunate, dihydroartemisinin, amodiaquine, N-desethyl-amodiaquine, lumefantrine, desbutyl-lumefantrine, piperaquine, pyronaridine, mefloquine, chloroquine, quinine, pyrimethamine and sulfadoxine). Plasma is purified by a combination of protein precipitation, evaporation and reconstitution in methanol/ammonium formate 20mM (pH 4.0) 1:1. Reverse-phase chromatographic separation of antimalarial drugs is obtained using a gradient elution of 20mM ammonium formate and acetonitrile both containing 0.5% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 21min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effect variability, overall process efficiency, standard addition experiments as well as antimalarials short- and long-term stability in plasma. The reactivity of endoperoxide-containing antimalarials in the presence of hemolysis was tested both in vitro and on malaria patients samples. With this method, signal intensity of artemisinin decreased by about 20% in the presence of 0.2% hemolysed red-blood cells in plasma, whereas its derivatives were essentially not affected. The method is precise (inter-day CV%: 3.1-12.6%) and sensitive

  3. 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.

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

    Science.gov (United States)

    Malisa, Allen Lewis; Kiriba, Deodatus

    2012-03-28

    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. 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. 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$). 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.

  5. Structural analysis of the antimalarial drug halofantrine by means of Raman spectroscopy and density functional theory calculations.

    Science.gov (United States)

    Frosch, Torsten; Popp, Jürgen

    2010-01-01

    The structure of the antimalarial drug halofantrine is analyzed by means of density functional theory (DFT) calculations, IR, and Raman spectroscopy. Strong, selective enhancements of the Raman bands of halofantrine at 1621 and 1590 cm(-1) are discovered by means of UV resonance Raman spectroscopy with excitation wavelength lambda(exc)=244 nm. These signal enhancements can be exploited for a localization of small concentrations of halofantrine in a biological environment. The Raman spectrum of halofantrine is calculated by means of DFT calculations [B3LYP/6-311+G(d,p)]. The calculation is very useful for a thorough mode assignment of the Raman bands of halofantrine. The strong bands at 1621 and 1590 cm(-1) in the UV Raman spectrum are assigned to combined C[Double Bond]C stretching vibrations in the phenanthrene ring of halofantrine. These bands are considered as putative marker bands for pipi interactions with the biological target molecules. The calculation of the electron density demonstrates a strong distribution across the phenanthrene ring of halofantrine, besides the electron withdrawing effect of the Cl and CF(3) substituents. This strong and even electron density distribution supports the hypothesis of pipi stacking as a possible mode of action of halofantrine. Complementary IR spectroscopy is performed for an investigation of vibrations of polar functional groups of the halofantrine molecule.

  6. 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

    2012-02-01

    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. 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. 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.

  7. Latest advances in molecular topology applications for drug discovery.

    Science.gov (United States)

    Zanni, Riccardo; Galvez-Llompart, Maria; García-Domenech, Ramón; Galvez, Jorge

    2015-01-01

    Molecular topology (MT) has emerged in recent years as a powerful approach for the in silico generation of new drugs. In the last decade, its application has become more and more popular among the leading research groups in the field of quantitative structure-activity relationships (QSAR) and drug design. This has, in turn, contributed to the rapid development of new techniques and applications of MT in QSAR studies, as well as the introduction of new topological indices. This review collates the main innovative techniques in the field of MT and provides a description of the novel topological indices recently introduced, through an exhaustive recompilation of the most significant works carried out by the leading research groups in the field of drug design and discovery. The objective is to show the importance of MT methods combined with the effectiveness of the descriptors. Recent years have witnessed a remarkable rise in QSAR methods based on MT and its application to drug design. New methodologies have been introduced in the area such as QSAR multi-target, Markov networks or perturbation methods. Moreover, novel topological indices, such as Bourgas' descriptors and other new concepts as the derivative of a graph or cliques capable to distinguish between conformers, have also been introduced. New drugs have also been discovered, including anticonvulsants, anineoplastics, antimalarials or antiallergics, just to name a few. In the authors' opinion, MT and QSAR have moved from an attractive possibility to representing a foundation stone in the process of drug discovery.

  8. 1,2,4-Triazole and 1,3,4-oxadiazole analogues: Synthesis, MO studies, in silico molecular docking studies, antimalarial as DHFR inhibitor and antimicrobial activities.

    Science.gov (United States)

    Thakkar, Sampark S; Thakor, Parth; Doshi, Hiren; Ray, Arabinda

    2017-08-01

    1,2,4-Triazole and 1,3,4-oxadiazole analogues are of interest due to their potential activity against microbial and malarial infections. In search of suitable antimicrobial and antimalarial compounds, we report here the synthesis, characterization and biological activities of 1,2,4-triazole and 1,3,4-oxadiazole analogues (SS 1-SS 10). The molecules were characterized by IR, mass, 1 H NMR, 13 C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains, the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR computationally as well as in vitro to prove their candidature as lead dihydrofolate reductase inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. 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.

  10. 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.

  11. Generation of an affinity matrix useful in the purification of natural inhibitors of plasmepsin II, an antimalarial-drug target.

    Science.gov (United States)

    Ramírez, Angel R; Guerra, Yasel; Otero, Anabel; García, Beatriz; Berry, Colin; Mendiola, Judith; Hernández-Zanui, Aida; Chávez, María de Los A

    2009-02-01

    An affinity matrix containing the antimalarial drug target Plm II (plasmepsin II) as ligand was generated. This enzyme belongs to the family of Plasmodium (malarial parasite) aspartic proteinases, known as Plms (plasmepsins). The procedure established to obtain the support has two steps: the immobilization of the recombinant proenzyme of Plm II to NHS (N-hydroxysuccinimide)-activated Sepharose and the activation of the immobilized enzyme by incubation at pH 4.4 and 37 degrees C. The coupling reaction resulted in a high percentage immobilization (95.5%), and the matrices obtained had an average of 4.3 mg of protein/ml of gel. The activated matrices, but not the inactive ones, were able to hydrolyse two different chromogenic peptide substrates and haemoglobin. This ability was completely blocked by the addition of the general aspartic-proteinase inhibitor, pepstatin A, to the reaction mixture. The matrices were useful in the affinity purification of the Plm II inhibitory activity detected in marine invertebrates, such as Xestospongia muta (giant barrel sponge) and the gorgonian (sea-fan coral) Plexaura homomalla (black sea rod), with increases of 10.2- and 5.9-fold in the specific inhibitory activity respectively. The preliminary K(i) values obtained, 46.4 nM (X. muta) and 1.9 nM (P. homomalla), and the concave shapes of the inhibition curves reveal that molecules are reversible tight-binding inhibitors of Plm II. These results validated the use of the affinity matrix for the purification of Plm II inhibitors from complex mixtures and established the presence of Plm II inhibitors in some marine invertebrates.

  12. 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

  13. 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

  14. Formulation of Dihydroartemisinin-Piperaquine (DHP Generic Tablet as Antimalarials Drug

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    Nanang Yunarto

    2016-09-01

    Full Text Available The incidence of malaria in Indonesia is about two million cases annually. Dihydroartemisinin-piperaquine (DHP is the first line therapy recommended for uncomplicated malaria treatment, whereas  DHP is still fully imported. The generic DHP tablet formulation has the potential to become the first of DHP drug which is locally produced. This study is aimed to formulate generic DHP film coated tablets for antimalaria drug. Tablets were compressed with the combination of wet granulation for piperaquine phosphate (PQP and direct compression method for DHA and coated with a moisture barier coating material. The parameters to evaluate the quality of DHP tablets are physical properties, assay, and dissolution test. DHA and PQP assay were performed by HPLC method. The dissolution testing was conducted by in house method using HCl 0.1 N medium. The result shows physical properties of film-coated tablets meet the requirement, i.e. uniform weight, 7.0-8.5 kp hardness, 0.02% friability and 3 minute 22 seconds disintegration. The assay to determine  DHA in tablet was 95.17% and PQP was 97.05%. The result of dissolution testing shows the content of DHA and PQP in the tablet were 113.51% and 96.55%, respesctively. The formulation which is developed meets the general requirement of API in tablet 90–110% and dissolution requirement >75%.

  15. 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

    the available sample preparation strategies combined with liquid chromatographic (LC) analysis to determine antimalarials in whole blood, plasma and urine published over the last decade. Sample preparation can be done by protein precipitation, solid-phase extraction, liquid-liquid extraction or dilution. After...... LC separation, the preferred detection tool is tandem mass spectrometry (MS/MS) but other detection methods have been used e.g. UV, fluorescence and electrochemical detection. Major trends for sample preparation of the different groups of antimalarials for each matrix and its detection have been...

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

    Science.gov (United States)

    Maaswinkel, Hans; Zhu, Liqun; Weng, Wei

    2015-04-02

    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. In a preliminary experiment, the overall toxic effects in terms of motor and respiratory impairments were determined during a 3-hour exposure to the drugs at relatively high doses (21.5 and 43 mgL). In the second experiment, behavioral testing was performed 24 h after a 3.5-h drug exposure to a low dose (14.25 mgL) of either drug. For the two high doses, erythro-mefloquine resulted in severe motor problems and respiratory problems occurred. In goldfish treated with threo-mefloquine, at 43 mgL the motor/respiratory impairments were less severe and at 21.5 mgL no such problems were observed. For the lower dose (14.25 mgL), erythro-mefloquine reduced locomotion. There was also a tendency for increased freezing, and the preference for quadrant two of the observation container was increased. No behavioral effects of threo-mefloquine were found. The results demonstrate that in goldfish exposed to the drugs dissolved in the water, threo-mefloquine has less severe toxic effects as compared to erythro-mefloquine. These findings are consistent with other studies and support the usefulness of the small-fish model for predicting adverse effects of new antimalarial drugs during the initial phases of drug development.

  17. Accessibility of Antimalarials in Secondary Health Care Facilities ...

    African Journals Online (AJOL)

    Accessibility of Antimalarials in Secondary Health Care Facilities and Community Pharmacies in Lagos State – A Comparative Study. ... Private partnership pharmacies do not stock antimalarials as a matter of policy, since the drugs are supposed to be obtained free from the hospital. This first line antimalarial cost about six ...

  18. The molecular evolution of four anti-malarial immune genes in the Anopheles gambiae species complex

    Directory of Open Access Journals (Sweden)

    Simard Frederic

    2008-03-01

    Full Text Available Abstract Background If the insect innate immune system is to be used as a potential blocking step in transmission of malaria, then it will require targeting one or a few genes with highest relevance and ease of manipulation. The problem is to identify and manipulate those of most importance to malaria infection without the risk of decreasing the mosquito's ability to stave off infections by microbes in general. Molecular evolution methodologies and concepts can help identify such genes. Within the setting of a comparative molecular population genetic and phylogenetic framework, involving six species of the Anopheles gambiae complex, we investigated whether a set of four pre-selected immunity genes (gambicin, NOS, Rel2 and FBN9 might have evolved under selection pressure imposed by the malaria parasite. Results We document varying levels of polymorphism within and divergence between the species, in all four genes. Introgression and the sharing of ancestral polymorphisms, two processes that have been documented in the past, were verified in this study in all four studied genes. These processes appear to affect each gene in different ways and to different degrees. However, there is no evidence of positive selection acting on these genes. Conclusion Considering the results presented here in concert with previous studies, genes that interact directly with the Plasmodium parasite, and play little or no role in defense against other microbes, are probably the most likely candidates for a specific adaptive response against P. falciparum. Furthermore, since it is hard to establish direct evidence linking the adaptation of any candidate gene to P. falciparum infection, a comparative framework allowing at least an indirect link should be provided. Such a framework could be achieved, if a similar approach like the one involved here, was applied to all other anopheline complexes that transmit P. falciparum malaria.

  19. The Antimalarial Drug Quinine Disrupts Tat2p-mediated Tryptophan Transport and Causes Tryptophan Starvation*

    Science.gov (United States)

    Khozoie, Combiz; Pleass, Richard J.; Avery, Simon V.

    2009-01-01

    Quinine is a major drug of choice for the treatment of malaria. However, the primary mode of quinine action is unclear, and its efficacy is marred by adverse reactions among patients. To help address these issues, a genome-wide screen for quinine sensitivity was carried out using the yeast deletion strain collection. Quinine-sensitive mutants identified in the screen included several that were defective for tryptophan biosynthesis (trp strains). This sensitivity was confirmed in independent assays and was suppressible with exogenous Trp, suggesting that quinine caused Trp starvation. Accordingly, quinine was found to inhibit [3H]Trp uptake by cells, and the quinine sensitivity of a trp1Δ mutant could be rescued by overexpression of Trp permeases, encoded by TAT1 and TAT2. The site of quinine action was identified specifically as the high affinity Trp/Tyr permease, Tat2p, with which quinine associated in a Trp-suppressible manner. A resultant action also on Tyr levels was reflected by the Tyr-suppressible quinine hypersensitivity of an aro7Δ deletion strain, which is auxotrophic for Tyr (and Phe). The present genome-wide dataset provides an important resource for discovering modes of quinine toxicity. That potential was validated with our demonstration that Trp and Tyr uptake via Tat2p is a major target of cellular quinine toxicity. The results also suggest that dietary tryptophan supplements could help to avert the toxic effects of quinine. PMID:19416971

  20. 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...

  1. Drug Development of the Antimalarial Agent Artemisinin: Total Synthesis, Analog Synthesis, and Structure-Activity Relationship Studies

    Science.gov (United States)

    1990-08-15

    jHoluenesulfonyl hydrazide in tetrahydrofuran (THF), solvolysis of the ketal group and subsequent hydrazone formation was observed. Under base...ARTEMISININ: TOTAL SYNTHESIS , ANALOG SYNTHESIS , AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES mc Mitchell A. Avery, Ph.D. SRI International...Antimalarial Agent Artemisinin: Total Synthesis , Analog Synthesis and Structure-Activity Relationship Studies 12 PERSONAL AUTHOR(S) Mitchell A

  2. The antimalarial drug, Ro 42-1611 (arteflene), does not affect cytoadherence and cytokine-inducing properties of Plasmodium falciparum malaria parasites

    DEFF Research Database (Denmark)

    Jakobsen, P H; Staalsø, T; Bendtzen, K

    1995-01-01

    The purpose of this study was to investigate the ability of the antimalarial drug, Ro 42-1611 to block parasite mediated cytokine induction in vitro as well as cytoadherence of infected erythrocytes to melanoma cells in vitro. The biological activity of Ro 42-1611 was confirmed as it blocked...... Plasmodium falciparum growth in cultures. Ro 42-1611, had no major effect on TNF, IL-alpha or IL-6 cytokine release from mononuclear cells stimulated with malaria antigens or lipopolysaccharide and it did not affect cell viability. Ro 42-1611 only slightly suppressed cytoadherence of infected erythrocytes...

  3. The prevalence and degree of resistance of Plasmodium falciparum to first-line antimalarial drugs: an in vitro study from a malaria endemic region in Yemen

    International Nuclear Information System (INIS)

    Al-Shamahy, H.; Al-Harazy, Abdulilah Hussein; Harmal, Nabil S.; Al-Kabsi, Abdulgudos N.

    2007-01-01

    Unpublished studies on antimalarial drug efficacy have found low levels of chloroquine resistance in Yemen. This study was carried out to determine the current prevalence of drug resistance in Plasmodium falciparum in Yemen to the main anti-malarial drugs and to determine the effective concentration (EC) values. The WHO standard protocol was used for the selection of subjects, collection of blood samples, culture techniques, examination of post-culture blood slides and interpretation of results. The in vitro micro-test Mark III was used for assessing susceptibility of P. falciparum isolates. The criteria for blood parasite density was met by 219 P. falciparum malaria patients. Chloroquine resistance was found in 47% of isolated P. falciparum schizonts. Mefloquine resistance was found in 5.2%. In addition, the EC50 and EC95 values in blood that inhibited schizont maturation in resistant isolates were higher than the normal therapeutic level for mefloquine. No resistance occurred against quinine or artemisinin, with no growth at the cut off level for quinine and inhibition at low concentrations of artemisinin. Our study confirmed the occurrence of chloroquine-resistant P. falciparum and a slow increase in the rate of this resistance will increase further and spread over all the foci of malaria in Yemen. The low rate of chloroquine-resistant P. falciparum was lower than that reported in Africa or Southeast Asia, but is the first report of the mefloquine resistance in Yemen. Finally, the isolates were sensitive to low concentrations of quinine and artemisinin. (author)

  4. A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

    Science.gov (United States)

    Reuling, Isaie J; van de Schans, Lisanne A; Coffeng, Luc E; Lanke, Kjerstin; Meerstein-Kessel, Lisette; Graumans, Wouter; van Gemert, Geert-Jan; Teelen, Karina; Siebelink-Stoter, Rianne; van de Vegte-Bolmer, Marga; de Mast, Quirijn; van der Ven, André J; Ivinson, Karen; Hermsen, Cornelus C; de Vlas, Sake; Bradley, John; Collins, Katharine A; Ockenhouse, Christian F; McCarthy, James

    2018-01-01

    Background Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes (ClinicalTrials.gov, NCT02836002). Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Findings Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the

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

    Directory of Open Access Journals (Sweden)

    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

  6. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand

    Directory of Open Access Journals (Sweden)

    Gil José

    2002-10-01

    Full Text Available Abstract Background The increasing levels of Plasmodium falciparum resistance to chloroquine (CQ in Thailand have led to the use of alternative antimalarials, which are at present also becoming ineffective. In this context, any strategies that help improve the surveillance of drug resistance, become crucial in overcoming the problem. Methods In the present study, we have established the in vitro sensitivity to CQ, mefloquine (MF, quinine (QUIN and amodiaquine (AMQ of 52 P. falciparum isolates collected in Thailand, and assessed the prevalence of four putative genetic polymorphisms of drug resistance, pfcrt K76T, pfmdr1 N86Y, pfmdr1 D1042N and pfmdr1 Y1246D, by PCR-RFLP. Results The percentage of isolates resistant to CQ, MF, and AMQ was 96% (50/52, 62% (32/52, and 58% (18/31, respectively, while all parasites were found to be sensitive to QUIN. In addition, 41 (79% of the isolates assayed were resistant simultaneously to more than one drug; 25 to CQ and MF, 9 to CQ and AMQ, and 7 to all three drugs, CQ, MF and AMQ. There were two significant associations between drug sensitivity and presence of particular molecular markers, i CQ resistance / pfcrt 76T (P = 0.001, and ii MF resistance / pfmdr1 86N (P Conclusions i In Thailand, the high levels of CQ pressure have led to strong selection of the pfcrt 76T polymorphism and ii pfmdr1 86N appears to be a good predictor of in vitro MF resistance.

  9. A new double-antibody sandwich ELISA targeting Plasmodium falciparum aldolase to evaluate anti-malarial drug sensitivity

    Directory of Open Access Journals (Sweden)

    Brun Reto

    2009-10-01

    Full Text Available Abstract Background The standard in vitro test to assess anti-malarial activity of chemical compounds is the [3H]hypoxanthine incorporation assay. It is a radioactivity-based method to measure DNA replication of Plasmodium in red blood cells. The method is highly reproducible, however, the handling of radioactive material is costly, hazardous and requires the availability of appropriate technology and trained staff. Several other ways to evaluate in vitro anti-malarial activity do exist, all with their own assets and limitations. Methods The newly developed double-antibody sandwich ELISA described here is based on the properties of a non-overlapping pair of monoclonal antibodies directed against Plasmodium falciparum aldolase. This glycolytic enzyme possesses some unique nucleotide sequences compared to the human isoenzymes and has been highly conserved through evolution. Out of twenty possibilities, the most sensitive antibody pair was selected and used to quantitatively detect parasite aldolase in infected blood lysates. Results A total of 34 compounds with anti-malarial activity were tested side-by-side by ELISA and the [3H]hypoxanthine incorporation assay. The novel ELISA provided IC50s closely paralleling those from the radioactivity-based assay (R = 0.99, p Conclusion The newly developed ELISA presents several advantages over the comparative method, the [3H]hypoxanthine incorporation assay. The assay is highly reproducible, less hazardous (involves no radioactivity and requires little and cheap technical equipment. Relatively unskilled personnel can conduct this user-friendly assay. All this makes it attractive to be employed in resource-poor laboratories.

  10. El citocromo P-450 y la respuesta terapéutica a los antimaláricos Cytochrome P-450 and the response to antimalarial drugs

    Directory of Open Access Journals (Sweden)

    Valentina Guzmán

    2006-01-01

    permitan responder a las interrogantes que aún subsisten, entre ellas cuál es la ruta metabólica de otros medicamentos antimaláricos, la distribución en la población de los alelos de las enzimas que participan en su metabolismo, y la contribución de tales mutaciones al fracaso terapéutico, y predecir la respuesta a los tratamientos antimaláricos. CONCLUSIONES: La respuesta terapéutica a los medicamentos antimaláricos es un proceso multifactorial y poco comprendido, por lo que no es posible asignar a un fenotipo o a un genotipo una determinada responsabilidad en la respuesta terapéutica antimalárica. Se debe contemplar la influencia de factores biológicos y sociales, tales como la alimentación, el estado nutricional y cualquier proceso inflamatorio e infeccioso concomitante, que puedan ser frecuentes en las zonas con malaria endémica.OBJECTIVES: To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. METHODS: We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina", "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina", "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina", "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that

  11. Targeting molecular networks for drug research

    Directory of Open Access Journals (Sweden)

    José Pedro Pinto

    2014-06-01

    Full Text Available The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks. Of the possible interventions for altering networks, the use of drugs is presently the most feasible. In this mini-review, we present and discuss some exemplary approaches of how analysis of molecular interaction networks can contribute to pharmacology (e.g., by identifying new drug targets or prediction of drug side effects, as well as listing pointers to relevant resources and software to guide future research. We also outline recent progress in the use of drugs for in vitro reprogramming of cells, which constitutes an example par excellence for altering molecular interaction networks with drugs.

  12. 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

  13. 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.

  14. 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

    Directory of Open Access Journals (Sweden)

    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

  15. Molecular Modeling: A Powerful Tool for Drug Design and Molecular ...

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 9; Issue 5. Molecular Modeling: A Powerful Tool for Drug Design and Molecular Docking. Rama Rao Nadendla. General Article Volume 9 Issue 5 May 2004 pp 51-60. Fulltext. Click here to view fulltext PDF. Permanent link:

  16. Molecular Modeling: A Powerful Tool for Drug Design and Molecular ...

    Indian Academy of Sciences (India)

    Molecular modeling has become a valuable and essential tool to medicinal chemists in the drug design process. Molecular modeling describes the generation, manipula- tion or representation of three-dimensional structures of molecules and associated physico-chemical properties. It involves a range of computerized ...

  17. Dissolution enhancement of a poorly water-soluble antimalarial drug by means of a modified multi-fluid nozzle pilot spray drier

    International Nuclear Information System (INIS)

    Sahoo, Nanda Gopal; Kakran, Mitali; Li Lin; Judeh, Zaher; Mueller, Rainer H.

    2011-01-01

    A spray drier with a modified multi-fluid nozzle was used to prepare microparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of improving its dissolution in water. ART was co-spray dried with a hydrophilic polymer, polyethylene glycol (PEG). The differential scanning calorimetry and X-ray diffraction studies showed that the crystallinity of ART decreased after spray drying. Compared to the physical mixture of ART and PEG, the amorphous phase of ART in the spray dried ART-PEG composites increased, which depended on the weight ratio of drug to polymer. The phase-solubility studies revealed that the aqueous solubility of ART was improved by the presence of PEG. The dissolution of ART from the spray dried ART-PEG composites was more rapid than that from their respective physical mixture and the original ART powder. For example, the dissolution of ART from the spray dried ART-PEG composite (1:6) was 6.5 times higher than that from the original ART powder in the first 30 min. In the mathematical modeling, the Weibull and Korsemeyer-Peppas models were found to best fit to the in vitro dissolution data and then the drug release mechanism was considered as the Fickian diffusion.

  18. Dissolution enhancement of a poorly water-soluble antimalarial drug by means of a modified multi-fluid nozzle pilot spray drier

    Energy Technology Data Exchange (ETDEWEB)

    Sahoo, Nanda Gopal; Kakran, Mitali [School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798 (Singapore); Li Lin, E-mail: mlli@ntu.edu.sg [School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798 (Singapore); Judeh, Zaher [School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, Singapore 637459 (Singapore); Mueller, Rainer H. [Free University of Berlin, Department of Pharmacy, Biopharmaceutics and Nutricosmetics, Kelchstrass 31, Berlin (Germany)

    2011-03-12

    A spray drier with a modified multi-fluid nozzle was used to prepare microparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of improving its dissolution in water. ART was co-spray dried with a hydrophilic polymer, polyethylene glycol (PEG). The differential scanning calorimetry and X-ray diffraction studies showed that the crystallinity of ART decreased after spray drying. Compared to the physical mixture of ART and PEG, the amorphous phase of ART in the spray dried ART-PEG composites increased, which depended on the weight ratio of drug to polymer. The phase-solubility studies revealed that the aqueous solubility of ART was improved by the presence of PEG. The dissolution of ART from the spray dried ART-PEG composites was more rapid than that from their respective physical mixture and the original ART powder. For example, the dissolution of ART from the spray dried ART-PEG composite (1:6) was 6.5 times higher than that from the original ART powder in the first 30 min. In the mathematical modeling, the Weibull and Korsemeyer-Peppas models were found to best fit to the in vitro dissolution data and then the drug release mechanism was considered as the Fickian diffusion.

  19. Quinoline-based antimalarial hybrid compounds.

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    Vandekerckhove, Stéphanie; D'hooghe, Matthias

    2015-08-15

    Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia.

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    Dwivedi, Ankit; Khim, Nimol; Reynes, Christelle; Ravel, Patrice; Ma, Laurence; Tichit, Magali; Bourchier, Christiane; Kim, Saorin; Dourng, Dany; Khean, Chanra; Chim, Pheaktra; Siv, Sovannaroth; Frutos, Roger; Lek, Dysoley; Mercereau-Puijalon, Odile; Ariey, Frédéric; Menard, Didier; Cornillot, Emmanuel

    2016-06-14

    Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008-2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential. To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010-2011 from 16 health centres in malaria endemics areas in Cambodia. Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance. The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia.

  1. Structural requirements of 3-carboxyl-4(1H)-quinolones as potential antimalarials from 2D and 3D QSAR analysis.

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    Li, Jiazhong; Li, Shuyan; Bai, Chongliang; Liu, Huanxiang; Gramatica, Paola

    2013-07-01

    Malaria is a fatal tropical and subtropical disease caused by the protozoal species Plasmodium. Many commonly available antimalarial drugs and therapies are becoming ineffective because of the emergence of multidrug resistant Plasmodium falciparum, which drives the need for the development of new antimalarial drugs. Recently, a series of 3-carboxyl-4(1H)-quinolone analogs, derived from the famous compound endochin, were reported as promising candidates for orally efficacious antimalarials. In this study, to analyze the structure-activity relationships (SAR) of these quinolones and investigate the structural requirements for antimalarial activity, the 2D multiple linear regressions (MLR) method and 3D comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods are employed to evolve different QSAR models. All these models give satisfactory results with highly accurate fitting and strong external predictive abilities for chemicals not used in model development. Furthermore, the contour maps from 3D models can provide an intuitive understanding of the key structure features responsible for the antimalarial activities. In conclusion, we summarize the detailed position-specific structural requirements of these derivatives accordingly. All these results are helpful for the rational design of new compounds with higher antimalarial bioactivities. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Time Course of the Changes in Novel Trioxane Antimalarial 99/411 Pharmacokinetics upon Antiepileptic Drugs Co-Administration in SD Rats

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    Yeshwant Singh

    2014-01-01

    Full Text Available Objective. The study aimed to evaluate the influences of coadministration of antiepileptic drugs (AEDs on an antimalarial candidate 99/411 pharmacokinetic (PK profile. Method. For this, single oral dose PK drug interaction studies were conducted between 99/411 and FDA approved AEDs, namely, Phenytoin (PHT, Carbamazepine (CBZ, and Gabapentin (GB in both male and female SD rats, to assess the coadministered and intersexual influences on 99/411 PK profile. Results. Studies revealed that there were no significant alterations in the PK profile of 99/411 upon PHT and CBZ coadministration in both male and female rats, while systemic exposure of 99/411 was significantly increased by about 80% in female rats upon GB coadministration. In terms of AUC, there was an increase from 2471 ± 586 to 4560 ± 1396 ng·h/mL. Overall, it was concluded that simultaneous administration of AEDs with 99/411 excludes the requirements for dose adjustment, additional therapeutic monitoring, contraindication to concomitant use, and/or other measures to mitigate risk, except for GB coadministration in females. These findings are further helpful to predict such interactions in humans, when potentially applied through proper allometric scaling to extrapolate the data.

  3. 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

  4. Has molecular imaging delivered to drug development?

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    Murphy, Philip S.; Patel, Neel; McCarthy, Timothy J.

    2017-10-01

    Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

  5. Anti-malarial prescribing practices in Sudan eight years after introduction of artemisinin-based combination therapies and implications for development of drug resistance.

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    Elmannan, Abeer Abuzeid Atta; Elmardi, Khalid Abdelmutalab; Idris, Yassir Ali; Spector, Jonathan M; Ali, Nahid Abdelgadir; Malik, Elfatih Mohamed

    2015-03-26

    The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) as first-line treatment for uncomplicated malaria. Sudan revised its malaria treatment policy accordingly in 2004. However, eight years after ACTs were introduced in Sudan the patterns of ACT prescribing practices among health care providers remain unclear. We systematically analyzed use of ACTs in a large number of primary health facilities and we discuss the public health implications of our findings. This cross-sectional study was based on WHO's guidance for investigating drug use in health facilities. Data were collected from 40 randomly selected primary health centers in five localities in Gezira State, Sudan. The primary outcome of the study was the proportion of patients who were adequately managed according to Sudan's recommended malaria treatment guidelines. Twelve drug-use indicators were used to assess key ACT prescribing practices. One thousand and two hundred patients diagnosed with uncomplicated malaria were recruited into the study. ACT was prescribed for 88.6%patients and artemether injections were (incorrectly) prescribed in 9.5% of cases. Only 40.9% of patients in the study were correctly diagnosed and 26.9% were adequately managed according to the nationally recommended treatment guidelines. Incorrect prescribing activities included failure to use generic medicine names (88.2%), incorrect dosage (27.7%), and unexplained antibiotic co-prescription (24.2%). Dispensing practices were also poor, with labeling practices inadequate (97.1%) and insufficient information given to patients about their prescribed treatment (50.5%). Irrational malaria treatment practices are common in Sudan. This has important public health implications since failure to adhere to nationally recommended guidelines could play a role in the future development of drug resistance. As such, identifying ways to improve the anti-malarial prescribing practices of heath workers in Sudan may

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

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    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

  7. 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.

  8. 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.

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    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.

  9. Systems Pharmacology in Small Molecular Drug Discovery.

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    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-02-18

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  10. Systems Pharmacology in Small Molecular Drug Discovery

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    Wei Zhou

    2016-02-01

    Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  11. 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.

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    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.

  12. Molecularly targeted drugs for metastatic colorectal cancer

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    Cheng YD

    2013-11-01

    Full Text Available Ying-dong Cheng, Hua Yang, Guo-qing Chen, Zhi-cao Zhang Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China Abstract: The survival rate of patients with metastatic colorectal cancer (mCRC has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin–fluorouracil–irinotecan (FOLFIRI chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin–fluorouracil–oxaliplatin (FOLFOX or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs. Keywords: metastatic colorectal cancer (mCRC, antiangiogenic drug, bevacizumab, aflibercept, regorafenib, cetuximab, panitumumab, clinical trial, molecularly targeted therapy

  13. 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.

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

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    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

  15. The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether.

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    Conyers, Ryan C; Mazzone, Jennifer R; Siegler, Maxime A; Tripathi, Abhai K; Sullivan, David J; Mott, Bryan T; Posner, Gary H

    2014-03-01

    Sixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25-27 days) of malaria-infected mice. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Nonlinear mixed-effects modelling of in vitro drug susceptibility and molecular correlates of multidrug resistant Plasmodium falciparum.

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    Julie A Simpson

    molecular markers of anti-malarial drug susceptibility.

  17. Prevalence of molecular markers of Plasmodium falciparum drug resistance in Dakar, Senegal

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    Wurtz Nathalie

    2012-06-01

    Full Text Available Abstract Background As a result of the widespread resistance to chloroquine and sulphadoxine-pyrimethamine, artemisinin-based combination therapy (ACT (including artemether-lumefantrine and artesunate-amodiaquine has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Intermittent preventive treatments with anti-malarial drugs based on sulphadoxine-pyrimethamine are also given to children or pregnant women once per month during the transmission season. Since 2006, there have been very few reports on the susceptibility of Plasmodium falciparum to anti-malarial drugs. To estimate the prevalence of resistance to several anti-malarial drugs since the introduction of the widespread use of ACT, the presence of molecular markers associated with resistance to chloroquine and sulphadoxine-pyrimethamine was assessed in local isolates at the military hospital of Dakar. Methods The prevalence of genetic polymorphisms in genes associated with anti-malarial drug resistance, i.e., Pfcrt, Pfdhfr, Pfdhps and Pfmdr1, and the copy number of Pfmdr1 were evaluated for a panel of 174 isolates collected from patients recruited at the military hospital of Dakar from 14 October 2009 to 19 January 2010. Results The Pfcrt 76T mutation was identified in 37.2% of the samples. The Pfmdr1 86Y and 184F mutations were found in 16.6% and 67.6% of the tested samples, respectively. Twenty-eight of the 29 isolates with the 86Y mutation were also mutated at codon 184. Only one isolate (0.6% had two copies of Pfmdr1. The Pfdhfr 108N/T, 51I and 59R mutations were identified in 82.4%, 83.5% and 74.1% of the samples, respectively. The double mutant (108N and 51I was detected in 83.5% of the isolates, and the triple mutant (108N, 51I and 59R was detected in 75.3%. The Pfdhps 437G, 436F/A and 613S mutations were found in 40.2%, 35.1% and 1.8% of the samples, respectively. There was no double mutant (437G and 540E or no quintuple mutant (Pfdhfr 108N, 51I and 59R

  18. 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

  19. Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin.

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    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. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  20. Cytogenetic and oxidative status of human lymphocytes after exposure to clinically relevant concentrations of antimalarial drugs atovaquone and proguanil hydrochloride in vitro.

    Science.gov (United States)

    Dinter, Domagoj; Gajski, Goran; Domijan, Ana-Marija; Garaj-Vrhovac, Vera

    2015-12-01

    Atovaquone (ATO) and proguanil hydrochloride (PROG) is the fixed combination for the prevention and treatment of Plasmodium falciparum malaria. As safe and effective antimalarial drugs are needed in both the treatment and the prophylaxis of malaria, this study was performed to investigate their possible cyto/genotoxic potential towards human lymphocytes and the possible mechanism responsible for it. Two different concentrations of ATO and PROG were used with and without S9 metabolic activation. The concentrations used were those found in human plasma when a fixed-dose combination of ATO and PROG was used: 2950/130 ng/mL after prophylactic treatment and 11 800/520 ng/mL after treatment of malaria, respectively. Possible cellular and DNA-damaging effects were evaluated by cell viability and alkaline comet assays, while oxidative stress potential was evaluated by formamidopyrimidine-DNA glycosylase (Fpg)-modified comet assay, in addition to measuring malondialdehyde and glutathione levels. According to our results, the ATO/PROG combination displayed only weak cyto/genotoxic potential towards human lymphocytes with no impact on oxidative stress parameters, suggesting that oxidative stress is not implicated in their mechanism of action towards human lymphocytes. Given that the key portion of the damaging effects was induced after S9 metabolic activation, it is to presume that the principal metabolite of PROG, cycloguanil, had the greatest impact. The obtained results indicate that the ATO/PROG combination is relatively safe for the consumption from the aspect of cyto/genotoxicity, especially if used for prophylactic treatment. Nevertheless, further cytogenetic research and regular patient monitoring are needed to minimize the risk of adverse events especially among frequent travellers. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  1. Factors related to compliance to anti-malarial drug combination: example of amodiaquine/sulphadoxine-pyrimethamine among children in rural Senegal

    Directory of Open Access Journals (Sweden)

    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.

  2. 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 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...

  3. 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

    Full Text Available Abstract Background In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1 therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma. Methods A monoclonal antibody (MAb that reacts with the N-side chain of the CQ molecule was prepared by use of a CQ analogue. A specific and reliable ELISA for detection of CQ was developed. The developed assay was validated by measuring CQ in tablets sold in Denmark, India and Sudan. Furthermore, kinetics of CQ concentrations in plasma of four volunteers, who ingested two tablets of Malarex® containing, 250 mg CQ base, were measured before drug intake, three hours later and thereafter at days 1, 3, 7, 14, 21 and 28. The same plasma samples were simultaneously measured by high performance liquid chromatography (HPLC. Results The ELISA proved an easy-to-handle and very sensitive tool for the detection of CQ with a lower limit of detection at 3.9 ng/ml. ELISA levels of CQ in plasma showed high agreement with the levels obtained by HPLC (r = 0.98. The specificity in the negative control group was 100%. Conclusion The developed ELISA can be used for quality screening of CQ in pharmaceutical formulations and for drug monitoring in malaria and in other infectious diseases, such as HIV, where CQ proved to be an effective therapeutic agent. The methodology has been exploited to develop monoclonal

  4. QSAR modeling and chemical space analysis of antimalarial compounds

    Science.gov (United States)

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-05-01

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including 3000 molecules tested in one or several of 17 anti- Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  5. QSAR modeling and chemical space analysis of antimalarial compounds.

    Science.gov (United States)

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-05-01

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  6. Thiazole Containing Heterocycles With Antimalarial Activity.

    Science.gov (United States)

    Kumawat, Mukesh Kumar

    2017-07-25

    Heterocyclic compounds are the main class of medicinally important compounds. Many heterocyclic compounds bearing a five member ring in their structure have a good spectrum of biological activities. Thiazole is an important class of five membered heterocyclic compounds. Thiazole and its derivatives exhibited a broad range of biological activities due to the presence of various reaction posses. Thiazole, heterocyclic nucleus is present in several potent pharmacologically active molecules such as Sulfathiazole (antimicrobial drug), Ritonavir (antiretroviral drug), Tiazofurin (antineoplastic drug) and Abafungin (antifungal drug) etc. The search for some novel biologically active thiazoles is to be continued in the field of medicinal chemistry for investigators. An aim of this review is to identify and try making a SAR (Structure Activity Relationship) of substituted thiazole nucleus as possible new antimalarials. Author undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyse the interventions and findings of included studies using a conceptual framework. Fifteen papers were included in the review; the majority were described about many biological activity of thiazole nucleus. Seven papers were find that had impacted upon the thaizoles as antimalarials. Some papers focused on the design, synthesis and antimalarial activity evaluation of thiazole derivatives. This review identified and made a SAR (Structure Activity Relationship) of substituted thiazole nucleus as possible new antimalarials. This review describes ongoing research in the search for novel thiazoles as targets and new antimalarial drug molecules. Copyright© Bentham Science Publishers; For any queries

  7. Molecular dynamics simulations and novel drug discovery.

    Science.gov (United States)

    Liu, Xuewei; Shi, Danfeng; Zhou, Shuangyan; Liu, Hongli; Liu, Huanxiang; Yao, Xiaojun

    2018-01-01

    Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein-ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery. Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets. Expert opinion: MD simulations have been used widely in investigating the pathogenic mechanisms of diseases caused by protein misfolding, in virtual screening, and in investigating drug resistance mechanisms caused by mutations of the target. These issues are very difficult to solve by experimental methods alone. Thus, in the future, MD simulations will have wider application with the further improvement of computational capacity and the development of better sampling methods and more accurate force fields together with more efficient analysis methods.

  8. 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. Copyright © 2013 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  9. Effect of selected anti-malarial drugs on the blood chemistry and brain serotonin levels in male rabbits.

    Science.gov (United States)

    Eigbibhalu, Ukpo Grace; Albert Taiwo, Ebuehi Osaretin; Douglass, Idiakheua Akhabue; Abimbola, Efunogbon Aderonke

    2013-01-01

    The effects of oral administration of sulfadoxine - pyrimethamine (SP), artesunate (A) and sulfadoxine - pyrimethamine - artesunate (SPA) on blood chemistry and brain serotonin in rabbits were investigated. Forty rabbits were divided into four groups of ten animals each. The group that served as the control received 2ml of distilled water while the other groups were received 1.25/25mg base/kg body weight of SP, 3.3mg/kg body weight of A and 1.25/25mg base/kg body weight of SP plus 3.3mg/kg body weight of A respectively by oral route daily for 3 days in a week for four weeks. At the end of each week of drug administration, three rabbits from each group were anaesthetized, blood was taken from the jugular veins using sterile needle and serum was extracted. The rabbits were sacrificed by decapitation; the liver and brain tissues were excised and homogenized. Total blood protein, cholesterol, triglyceride, albumin, creatinine and urea concentrations, creatine kinase, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, ALP activities were assayed using CX5 synchron autoanalyzer. The brain and liver serotonin levels were determined using high performance liquid chromatography (HPLC). There were no significant differences (P levels of rabbits administered SP, A and SPA were significantly higher as compared to the control throughout the duration of the study Data of the study indicate that oral administration of SP, A or SPA in rabbits do not affect blood chemistry, but affected brain serotonin levels and could alter some neural functions.

  10. Molecular Rift: Virtual Reality for Drug Designers.

    Science.gov (United States)

    Norrby, Magnus; Grebner, Christoph; Eriksson, Joakim; Boström, Jonas

    2015-11-23

    Recent advances in interaction design have created new ways to use computers. One example is the ability to create enhanced 3D environments that simulate physical presence in the real world--a virtual reality. This is relevant to drug discovery since molecular models are frequently used to obtain deeper understandings of, say, ligand-protein complexes. We have developed a tool (Molecular Rift), which creates a virtual reality environment steered with hand movements. Oculus Rift, a head-mounted display, is used to create the virtual settings. The program is controlled by gesture-recognition, using the gaming sensor MS Kinect v2, eliminating the need for standard input devices. The Open Babel toolkit was integrated to provide access to powerful cheminformatics functions. Molecular Rift was developed with a focus on usability, including iterative test-group evaluations. We conclude with reflections on virtual reality's future capabilities in chemistry and education. Molecular Rift is open source and can be downloaded from GitHub.

  11. Innovative high-performance liquid chromatography method development for the screening of 19 antimalarial drugs based on a generic approach, using design of experiments, independent component analysis and design space.

    Science.gov (United States)

    Debrus, B; Lebrun, P; Kindenge, J Mbinze; Lecomte, F; Ceccato, A; Caliaro, G; Mbay, J Mavar Tayey; Boulanger, B; Marini, R D; Rozet, E; Hubert, Ph

    2011-08-05

    An innovative methodology based on design of experiments (DoE), independent component analysis (ICA) and design space (DS) was developed in previous works and was tested out with a mixture of 19 antimalarial drugs. This global LC method development methodology (i.e. DoE-ICA-DS) was used to optimize the separation of 19 antimalarial drugs to obtain a screening method. DoE-ICA-DS methodology is fully compliant with the current trend of quality by design. DoE was used to define the set of experiments to model the retention times at the beginning, the apex and the end of each peak. Furthermore, ICA was used to numerically separate coeluting peaks and estimate their unbiased retention times. Gradient time, temperature and pH were selected as the factors of a full factorial design. These retention times were modelled by stepwise multiple linear regressions. A recently introduced critical quality attribute, namely the separation criterion (S), was also used to assess the quality of separations rather than using the resolution. Furthermore, the resulting mathematical models were also studied from a chromatographic point of view to understand and investigate the chromatographic behaviour of each compound. Good adequacies were found between the mathematical models and the expected chromatographic behaviours predicted by chromatographic theory. Finally, focusing at quality risk management, the DS was computed as the multidimensional subspace where the probability for the separation criterion to lie in acceptance limits was higher than a defined quality level. The DS was computed propagating the prediction error from the modelled responses to the quality criterion using Monte Carlo simulations. DoE-ICA-DS allowed encountering optimal operating conditions to obtain a robust screening method for the 19 considered antimalarial drugs in the framework of the fight against counterfeit medicines. Moreover and only on the basis of the same data set, a dedicated method for the

  12. Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request.

    Science.gov (United States)

    Hogan, William R; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

    2017-03-03

    The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication. In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action. A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

  13. "Every drug goes to treat its own disease…" - a qualitative study of perceptions and experiences of taking anti-retrovirals concomitantly with anti-malarials among those affected by HIV and malaria in Tanzania

    DEFF Research Database (Denmark)

    Mangesho, Peter E; Reynolds, Joanna; Lemnge, Martha

    2014-01-01

    and supporting the clinical management and treatment for co-infected individuals. METHODS: A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and malaria co-infection. Focus group discussions were held with people receiving treatment for HIV and/or malaria...... to their compromised immune status but saw the disease as unavoidable. For those enrolled in the clinical controlled study, taking anti-malarials together with ARVs was largely seen as unproblematic, with health workers' advice and endorsement of concomitant drug taking influential in reported adherence. However......, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. CONCLUSIONS: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes...

  14. Molecular dynamics of a proguanil derivative

    African Journals Online (AJOL)

    pc

    ABSTRACT. Proguanil is a prophylactic antimalarial drug t stopping the malaria parasites from reprod molecular dynamics of a derivative of Progua benzene ring of the molecule of Proguanil derivative. The molecular geometries of chemical calculations at the Restricted Hatre. 31G(d,p) and 6-31++G. Also, Density Func.

  15. The Use of Antimalarial Drugs

    African Journals Online (AJOL)

    new cycle of exo-erythrocytic division called secondary exo-erythrocytic schizogony_ This stage is responsible for the late relapses associated with these species of parasite. It does not occur in P. falciparum infections. In fue red blood cells the parasites become trophozoites, take 2-3 days to develop, divide and form mature.

  16. Pyrimidines in antimalarial drug design

    CSIR Research Space (South Africa)

    Moleele, SS

    2008-09-01

    Full Text Available Malaria causes the death of 2-3 million people annually, most of these children under 5 years of age. Approximately 300 million cases of acute malaria are reported each year, 90% of these in Africa. Until recently, folate metabolism has been...

  17. Ultrasound Molecular Imaging and Drug Delivery.

    Science.gov (United States)

    Caskey, Charles F

    2017-06-01

    Ultrasound is a rapidly advancing field with many emerging diagnostic and therapeutic applications. For diagnostics, new vascular targets are routinely identified and mature technologies are being translated to humans, while other recent innovations may bring about the creation of acoustic reporter genes and micron-scale resolution with ultrasound. As a cancer therapy, ultrasound is being explored as an adjuvant to immune therapies and to deliver acoustically or thermally active drugs to tumor regions. Ultrasound-enhanced delivery across the blood brain barrier (BBB) could potentially be very impactful for brain cancers and neurodegenerative diseases where the BBB often impedes the delivery of therapeutic molecules. In this minireview, we provide an overview of these topics in the field of ultrasound that are especially relevant to the interests of World Molecular Imaging Society.

  18. 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.

  19. Human serum albumin binding of certain antimalarials

    Science.gov (United States)

    Marković, Olivera S.; Cvijetić, Ilija N.; Zlatović, Mario V.; Opsenica, Igor M.; Konstantinović, Jelena M.; Terzić Jovanović, Nataša V.; Šolaja, Bogdan A.; Verbić, Tatjana Ž.

    2018-03-01

    Interactions between eight in-house synthesized aminoquinolines, along with well-known chloroquine, and human serum albumin (HSA) have been studied by fluorescence spectroscopy. The synthesized aminoquinolines, despite being structurally diverse, were found to be very potent antimalarials. Fluorescence measurements indicate that three compounds having additional thiophene or benzothiophene substructure bind more strongly to HSA than other studied compounds. Competitive binding experiments indicate that these three compounds bind significantly stronger to warfarin compared to diazepam binding site. Fluorescence quenching at three temperatures (20, 25, and 37 °C) was analyzed using classical Stern-Volmer equation, and a static quenching mechanism was proposed. The enthalpy and entropy changes upon sulphur-containing compound-HSA interactions were calculated using Van't Hoff equation. Positive values of enthalpy and entropy changes indicate that non-specific, hydrophobic interactions are the main contributors to HSA-compound interaction. Molecular docking and calculated lipophilicity descriptors indicate the same, pointing out that the increased lipophilicity of sulphur-containing compounds might be a reason for their better binding to HSA. Obtained results might contribute to design of novel derivatives with improved pharmacokinetic properties and drug efficacy.

  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

    essential proteins and the effect of their perturbations on the metabolic network of P. falciparum, as well as indication of drug resistance emergence. Finally, we predict potential off-target effects on the human host with associations to cancer, neurological and dermatological disorders, based......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...... 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. In Vivo Antimalarial Activity of Solvent Fractions of the Leaves of ...

    African Journals Online (AJOL)

    Increasing resistance of Plasmodium falciparum to almost all the available antimalarial drugs urges a search for newer antimalarial drugs. Justicia schimperiana Hochst. Ex Nees is traditionally used for the treatment of malaria and a study conducted previously on the crude leaf extract confirmed that the plant is endowed ...

  2. Quinoline-Based Hybrid Compounds with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Xhamla Nqoro

    2017-12-01

    Full Text Available The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies.

  3. The antimalarial ferroquine: from bench to clinic

    Directory of Open Access Journals (Sweden)

    Biot C.

    2011-08-01

    Full Text Available Ferroquine (FQ, SSR97193 is currently the most advanced organometallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocenecontaining compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

  4. 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...

  5. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.

    Directory of Open Access Journals (Sweden)

    Julia Penna-Coutinho

    Full Text Available The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2. The IC(50 values for each drug in both tests were similar, were lowest for posaconazole (<5 µM and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.

  6. 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

  7. Antimalarial properties of imipramine and amitriptyline

    International Nuclear Information System (INIS)

    Dutta, P.; Siegel, L.; Pinto, J.; Meshnick, S.

    1986-01-01

    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 μM) was measured by incubating parasitized erythrocytes for 48 h in RPMI 1640 medium. Parasitemia was determined by counting erythrocyte smears and monitoring ( 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 ( 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 0 C with variable concentrations of drugs and/or FP (1-7 μM). Both drugs at 10 to 100 μM 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

  8. [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.

  9. Mechanochemical Synthesis, In vivo Anti-malarial and Safety Evaluation of Amodiaquine-zinc Complex

    Directory of Open Access Journals (Sweden)

    Arise Rotimi Olusanya

    2017-09-01

    Full Text Available So far, some prospective metal-based anti-malarial drugs have been developed. The mechanochemical synthesis and characterization of Zn (II complex with amodiaquine and its anti-malarial efficacy on Plasmodium berghei-infected mice and safety evaluation were described in this study.

  10. Plasmodium falciparum neutral aminopeptidases: new targets for anti-malarials.

    Science.gov (United States)

    Skinner-Adams, Tina S; Stack, Colin M; Trenholme, Katharine R; Brown, Chris L; Grembecka, Jolanta; Lowther, Jonathan; Mucha, Artur; Drag, Marcin; Kafarski, Pawel; McGowan, Sheena; Whisstock, James C; Gardiner, Donald L; Dalton, John P

    2010-01-01

    The neutral aminopeptidases M1 alanyl aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) of the human malaria parasite Plasmodium falciparum are targets for the development of novel anti-malarial drugs. Although the functions of these enzymes remain unknown, they are believed to act in the terminal stages of haemoglobin degradation, generating amino acids essential for parasite growth and development. Inhibitors of both enzymes are lethal to P. falciparum in culture and kill the murine malaria P. chabaudi in vivo. Recent biochemical, structural and functional studies provide the substrate specificity and mechanistic binding data needed to guide the development of more potent anti-malarial drugs. Together with biological studies, these data form the rationale for choosing PfM1AAP and PfM17LAP as targets for anti-malarial development. Copyright 2009 Elsevier Ltd. All rights reserved.

  11. Dried whole plant Artemisia annua as an antimalarial therapy.

    Directory of Open Access Journals (Sweden)

    Mostafa A Elfawal

    2012-12-01

    Full Text Available Drugs are primary weapons for reducing malaria in human populations. However emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed. Currently the most effective anti-malarial is artemisinin, which is extracted from the leaves of Artemisia annua. Due to poor pharmacokinetic properties and prudent efforts to curtail resistance to monotherapies, artemisinin is prescribed only in combination with other anti-malarials composing an Artemisinin Combination Therapy (ACT. Low yield in the plant, and the added cost of secondary anti-malarials in the ACT, make artemisinin costly for the developing world. As an alternative, we compared the efficacy of oral delivery of the dried leaves of whole plant (WP A. annua to a comparable dose of pure artemisinin in a rodent malaria model (Plasmodium chabaudi. We found that a single dose of WP (containing 24 mg/kg artemisinin reduces parasitemia more effectively than a comparable dose of purified drug. This increased efficacy may result from a documented 40-fold increase in the bioavailability of artemisinin in the blood of mice fed the whole plant, in comparison to those administered synthetic drug. Synergistic benefits may derive from the presence of other anti-malarial compounds in A. annua. If shown to be clinically efficacious, well-tolerated, and compatible with the public health imperative of forestalling evolution of drug resistance, inexpensive, locally grown and processed A. annua might prove to be an effective addition to the global effort to reduce malaria morbidity and mortality.

  12. Molecular Modeling: A Powerful Tool for Drug Design and Molecular ...

    Indian Academy of Sciences (India)

    data. GENERAL I ARTICLE of programmable calculators (starting around 1956 with the introduction of Fortran), computers as visualization aids (around. 1970) .... ous applications of computer assisted molecular modeling tech- niques are .... thods are less complicated, fast, and are able to handle very large systems ...

  13. Antimalarial naphthoquinones from Nepenthes thorelii.

    Science.gov (United States)

    Likhitwitayawuid, K; Kaewamatawong, R; Ruangrungsi, N; Krungkrai, J

    1998-04-01

    Roots of Nepenthes thorelii yielded plumbagin, 2-methylnaphthazarin, octadecyl caffeate, isoshinanolone, and droserone. In addition, seven derivatives were prepared from plumbagin. Each of these natural and semisynthetic compounds was evaluated for in vitro antimalarial potential.

  14. Metallocene Antimalarials: The Continuing Quest

    OpenAIRE

    Blackie, Margaret A. L.; Chibale, Kelly

    2007-01-01

    Over the last decade, a significant body of research has been developed around the inclusion of a metallocene moiety into known antimalarial compounds. Ferroquine is the most successful of these compounds. Herein, we describe our contribution to metallocene antimalarials. Our approach has sought to introduce diversity sites in the side chain of ferroquine in order to develop a series of ferroquine derivatives. The replacement of the ferrocenyl moiety with ruthenocene has given rise to rutheno...

  15. The interaction of x-rays and antimalarials

    International Nuclear Information System (INIS)

    Geoghegan, D.S.; Skinner-Adams, T.; Davis, T.M.E.

    2001-01-01

    Full text: The radiation sensitivity of malaria parasites has three potential clinical applications, namely i) to prevent the transmission of malaria by blood transfusion, ii) as adjunctive therapy when a radioactive isotope is complexed to a conventional antimalarial drug, and iii) to attenuate the pathogenicity of specific parasite stages as part of the development of a vaccine. In the first two applications, detailed information relating to parasite radiosensitivity and the interaction of ionising radiation with antimalarials is of vital importance because dosimetry must allow for the exposure of normal cells. Malaria parasite cultures (Plasmodium falciparum) were exposed to a logarithmic series of concentrations of antimalarial agents and irradiated using a Siemens Stabilipan orthovoltage radiotherapy unit. The irradiation was performed at room temperature and ambient oxygen concentration. Control samples were also irradiated. The DNA synthesis in each culture was measured 48 hours post irradiation by using a 3 H-hypoxanthine incorporation assay. The antimalarials studied are: artesunate, quinine, retinol and chloroquine. The radiosensitivity of Plasmodium falciparum is not dependent on the strain of parasite with the dose required to inhibit 50% of DNA synthesis (ID 50 ) equal to 24.7 ± 3.0 Gy. This applies equally for the drug resistant and drug sensitive strains studied. Because the measured radiosensitivity is dependent on the sera oxygen concentration, the reported value for the ID 50 may not apply in hypoxic situations. The interaction of ionising radiation with the antimalarials shows synergy with retinol and choloquine, additivity with quinine and slight antagonism with artesunate. Radionuclide therapy may emerge as a novel treatment for malaria. If this does occur, then, although all strains appear to be equally radiosensitive, care must be taken when combining ionising radiation with existing antimalarials for the treatment of malaria. Copyright

  16. Developing a Molecular Roadmap of Drug-Food Interactions

    DEFF Research Database (Denmark)

    Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni

    2015-01-01

    in ∼ 1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global...... view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in Drug-Bank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing...... a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map....

  17. 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

    2015-01-01

    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. PMID:26014942

  18. In Vivo anti-malarial activities of Clerodendrum myricoides ...

    African Journals Online (AJOL)

    Background: Malaria caused by the parasite Plasmodium falciparum is an acute disease which kills an estimated 863,000 people per year according to the WHO report of 2009. The fight against malaria is faced with the occurrence of widespread resistance of P. falciparum. The search for plant-derived antimalarial drugs ...

  19. CNS adverse events associated with antimalarial agents. Fact or fiction?

    NARCIS (Netherlands)

    Phillips-Howard, P. A.; ter Kuile, F. O.

    1995-01-01

    CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too

  20. Antimalarial prescribing patterns in state hospitals and selected ...

    African Journals Online (AJOL)

    slowdown of progression to resistance could be achieved by improving prescribing practice, drug quality, and patient compliance. Objective: To determine the antimalarial prescribing pattern and to assess rational prescribing of chloroquine by prescribers in government hospitals and parastatals in Lagos State. Methods: ...

  1. Synthesis, and anti-malarial screening, of 1-diethylamino-4 ...

    African Journals Online (AJOL)

    Artemisinin and its derivatives have become antimalarial drugs of choice because they are effective against most stages in the life cycle of plasmodium and are safe for all, including pregnant women. World Health Organisation ... The target compound also had an LD50 of 330 mg/kg in mice by the oral route. A single dose ...

  2. Molecularly imprinted polymers as the future drug delivery devices.

    Science.gov (United States)

    Luliński, Piotr

    2013-01-01

    In recent years, the investigations of new drug delivery systems have been directed on the development of some "intelligent" drug delivery devices that are able to directly respond to the patient's individual needs. New drug delivery systems should maximize the efficiency of administrated therapeutic agents and improve the patient's quality of life. Introduction of the new drug delivery devices is an important scientific goal, which could be achieved by combining new technologies and intelligent biomaterials. Molecular imprinting technology has a high potential for the preparation of optimized drug delivery forms. Here, molecularly imprinted polymers (MIPs) are promising new materials for such purposes, but their application in this field is nowadays at a developing stage. In this review, the principles of molecular imprinting and the recognition-release mechanisms of polymeric matrices are discussed. The potential application of molecularly imprinted materials as the future drug delivery systems with various administering routes (transdermal, ocular or oral) are presented, and some future prospects for the imprinted polymers are outlined.

  3. Quinine conjugates and quinine analogues as potential antimalarial agents.

    Science.gov (United States)

    Jones, Rachel A; Panda, Siva S; Hall, C Dennis

    2015-06-05

    Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. Cajachalcone: An Antimalarial Compound from Cajanus cajan Leaf Extract

    Directory of Open Access Journals (Sweden)

    E. O. Ajaiyeoba

    2013-01-01

    Full Text Available Cajanus cajan L, a member of the family Fabaceae, was identified from the Nigerian antimalarial ethnobotany as possessing antimalarial properties. The bioassay-guided fractionation of the crude methanol extract of C. cajan leaves was done in vitro using the multiresistant strain of Plasmodium falciparum (K1 in the parasite lactate dehydrogenase assay. Isolation of compound was achieved by a combination of chromatographic techniques, while the structure of the compound was elucidated by spectroscopy. This led to the identification of a cajachalcone, 2′,6′-dihydroxy-4-methoxy chalcone, as the biologically active constituent from the ethyl acetate fraction. Cajachalcone had an IC50 value of 2.0 μg/mL (7.4 μM and could be a lead for anti-malarial drug discovery.

  5. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

    NARCIS (Netherlands)

    Rijpma, S.R.; Heuvel, J.J.; Velden, M. van der; Sauerwein, R.W.; Russel, F.G.; Koenderink, J.B.

    2014-01-01

    BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly

  6. Drug Repositioning by Kernel-Based Integration of Molecular Structure, Molecular Activity, and Phenotype Data

    Science.gov (United States)

    Wang, Yongcui; Chen, Shilong; Deng, Naiyang; Wang, Yong

    2013-01-01

    Computational inference of novel therapeutic values for existing drugs, i.e., drug repositioning, offers the great prospect for faster and low-risk drug development. Previous researches have indicated that chemical structures, target proteins, and side-effects could provide rich information in drug similarity assessment and further disease similarity. However, each single data source is important in its own way and data integration holds the great promise to reposition drug more accurately. Here, we propose a new method for drug repositioning, PreDR (Predict Drug Repositioning), to integrate molecular structure, molecular activity, and phenotype data. Specifically, we characterize drug by profiling in chemical structure, target protein, and side-effects space, and define a kernel function to correlate drugs with diseases. Then we train a support vector machine (SVM) to computationally predict novel drug-disease interactions. PreDR is validated on a well-established drug-disease network with 1,933 interactions among 593 drugs and 313 diseases. By cross-validation, we find that chemical structure, drug target, and side-effects information are all predictive for drug-disease relationships. More experimentally observed drug-disease interactions can be revealed by integrating these three data sources. Comparison with existing methods demonstrates that PreDR is competitive both in accuracy and coverage. Follow-up database search and pathway analysis indicate that our new predictions are worthy of further experimental validation. Particularly several novel predictions are supported by clinical trials databases and this shows the significant prospects of PreDR in future drug treatment. In conclusion, our new method, PreDR, can serve as a useful tool in drug discovery to efficiently identify novel drug-disease interactions. In addition, our heterogeneous data integration framework can be applied to other problems. PMID:24244318

  7. Influence of Polymer Molecular Weight on Drug-Polymer Solubility

    DEFF Research Database (Denmark)

    Knopp, Matthias Manne; Olesen, Niels Erik; Holm, Per

    2015-01-01

    In this study, the influence of polymer molecular weight on drug-polymer solubility was investigated using binary systems containing indomethacin (IMC) and polyvinylpyrrolidone (PVP) of different molecular weights. The experimental solubility in PVP, measured using a differential scanning...... calorimetry annealing method, was compared with the solubility calculated from the solubility of the drug in the liquid analogue N-vinylpyrrolidone (NVP). The experimental solubility of IMC in the low-molecular-weight PVP K12 was not significantly different from that in the higher molecular weight PVPs (K25......, K30, and K90). The calculated solubilities derived from the solubility in NVP (0.31-0.32 g/g) were found to be lower than those experimentally determined in PVP (0.38-0.40 g/g). Nevertheless, the similarity between the values indicates that the analogue solubility can provide valuable indications...

  8. Molecular basis of antifungal drug resistance in yeasts

    DEFF Research Database (Denmark)

    Morio, Florent; Jensen, Rasmus Hare; Le Pape, Patrice

    2017-01-01

    Besides inherent differences in in vitro susceptibilities, clinically-relevant yeast species may acquire resistance upon exposure to most antifungal drugs used in the clinic. In recent years, major fundamental research studies have been conducted to improve our understanding of the molecular basis......., in the context of antifungal drug resistance. Also included are the methods currently available for in vitro antifungal susceptibility testing and for molecular detection of mutations associated with resistance. Finally, the genetic drivers of antifungal resistance are discussed in light of the spectra...

  9. Molecular topology as a novel approach for drug discovery.

    Science.gov (United States)

    Gálvez, Jorge; Gálvez-Llompart, María; García-Domenech, Ramón

    2012-02-01

    Molecular topology (MT) has emerged in recent years as a powerful approach for the in silico generation of new drugs. One key part of MT is that, in the process of drug design/discovery, there is no need for an explicit knowledge of a drug's mechanism of action unlike other drug discovery methods. In this review, the authors introduce the topic by explaining briefly the most common methodology used today in drug design/discovery and address the most important concepts of MT and the methodology followed (QSAR equations, LDA, etc.). Furthermore, the significant results achieved, from this approach, are outlined and discussed. The results outlined herein can be explained by considering that MT represents a new paradigm in the field of drug design. This means that it is not only an alternative method to the conventional methods, but it is also independent, that is, it represents a pathway to connect directly molecular structure with the experimental properties of the compounds (particularly drugs). Moreover, the process can be realized also in the reverse pathway, that is, designing new molecules from their topological pattern, what opens almost limitless expectations in new drugs development, given that the virtual universe of molecules is much greater than that of the existing ones.

  10. Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request

    OpenAIRE

    Hogan, William R.; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

    2017-01-01

    Background The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outs...

  11. Prevalence of the molecular marker of chloroquine resistance ( pfcrt ...

    African Journals Online (AJOL)

    In line with the World Health Organization (WHO) guideline on chloroquine (CQ) resistance, CQ was withdrawn as the first-line antimalarial drug in Nigeria in 2005 as a result of ... We monitored the resistance pattern 5 years after withdrawal of CQ, using the pfcrt K76T mutation as a molecular marker for CQ resistance.

  12. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    Science.gov (United States)

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  13. Optical Molecular Imaging of Ultrasound-mediated Drug Delivery

    NARCIS (Netherlands)

    Derieppe, M.P.P.

    2015-01-01

    The goal of this PhD project was to develop optical molecular imaging methods to study drug delivery facilitated by ultrasound waves (US) and hyperthermia. Fibered confocal fluorescence microscopy (FCFM), together with dedicated image analysis, was used in vitro on a cell monolayer, and in vivo at

  14. Antimalarial activity of selected Ethiopian medicinal plants in mice

    Directory of Open Access Journals (Sweden)

    Eshetu M. Bobasa

    2018-02-01

    Full Text Available Context: Parasites are the leading killers in subtropical areas of which malaria took the lion share from protozoan diseases. Measuring the impact of antimalarial drug resistance is difficult, and the impact may not be recognized until it is severe, especially in high transmission areas. Aims: To evaluate the in vivo antimalarial activities of hydroalcoholic extracts of the roots of Piper capense and Adhatoda schimperiana, against Plasmodium berghei in mice. Methods: Four-day suppressive and curative test animal models were used to explore the antimalarial activities of the plants. 200, 400, and 600 mg/kg of each plant extract was administered to check the activities versus vehicle administered mice. Mean survival time and level of parasitemia were the major variables employed to compare the efficacy vs. negative control. Results: In both models the 400 and 600 mg/kg doses of Adhatoda schimperiana and the 600 mg/kg dose Piper capense. showed significant parasitemia suppression and increased in mean survival time at p≤0.05. The middle dose of Piper capense had a border line inhibition where the extracts were considered active when parasitemia was reduced by ≥ 30%. Conclusions: The hydroalcoholic extracts of the roots of Adhatoda schimperiana and Piper capense possess moderate antimalarial activities, which prove its traditional claims. Thus, further studies should be done to isolate the active constituents for future use in the modern drug discovery.

  15. Profiling of drug action using reporter mice and molecular imaging.

    Science.gov (United States)

    Rando, Gianpaolo; Biserni, Andrea; Ciana, Paolo; Maggi, Adriana

    2010-01-01

    Reporter mice associated to molecular imaging represent a major asset for the study of the spatio-temporal effects of drugs in living animals. The field is still relatively young and so far the number of animals genetically modified to express a given reporter gene ubiquitously and under the control of specific drugs is still limited. For a reporter animal the indispensable elements for the application to drug research and development are (i) the short life of the reporter enabling to have a clear view of the onset as well as the termination of drug effects, (ii) the generalized, drug-dependent activation of the reporter, and (iii) imaging modality suitable for high-throughput analysis. Because of its relative cheapness and ease to perform, in addition to all the above considerations, bioluminescence-based imaging is now regarded as the best imaging technology to be applied to the field of drug research. We show here the application of reporter mouse systems for drug screening in living animals in order to compare drug potency on target and specificity of action.

  16. Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties

    Directory of Open Access Journals (Sweden)

    Karène Urgin

    2017-01-01

    Full Text Available With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me2 or -N(Et2 in different positions (ortho, meta and para on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.

  17. Biotransformation and biocatalysis: roles and applications in the discovery of antimalarials.

    Science.gov (United States)

    Chigorimbo-Murefu, Nyaradzo T L; Njoroge, Mathew; Nzila, Alexis; Louw, Stefan; Masimirembwa, Collen; Chibale, Kelly

    2012-12-01

    Several strategies to discover new antimalarials have been proposed to augment and complement the conventional drug-discovery paradigm. One approach, which has not yet been fully exploited, is the use of drug biotransformation to identify new active molecules. This concept rests on the use of the biotransformation of drugs to their pharmacologically active metabolites. This approach has been used successfully in human chemotherapy, with the discovery and development of several metabolite-based drugs. This review looks at the contribution that biotransformations can play in antimalarial drug discovery.

  18. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials.

    Science.gov (United States)

    Dondorp, A M; Newton, P N; Mayxay, M; Van Damme, W; Smithuis, F M; Yeung, S; Petit, A; Lynam, A J; Johnson, A; Hien, T T; McGready, R; Farrar, J J; Looareesuwan, S; Day, N P J; Green, M D; White, N J

    2004-12-01

    To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia. Cross-sectional survey. Pharmacies and shops selling antimalarial drugs in Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand. Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality. Of the 188 tablet packs purchased which were labelled as 'artesunate' 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by 'Guilin Pharma', and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained active ingredient. An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999-2000. This is a serious threat to public health in the region.

  19. Molecular dynamics study on DNA nanotubes as drug delivery vehicle for anticancer drugs.

    Science.gov (United States)

    Liang, Lijun; Shen, Jia-Wei; Wang, Qi

    2017-05-01

    In recent years, self-assembled DNA nanotubes have emerged as a type of nano-biomaterials with great potential for biomedical applications. To develop universal nanocarriers for smart and targeted drug delivery from DNA nanotubes, the understanding of interaction mechanism between DNA nanotubes and drugs is essential. In this study, the interactions between anti-cancer drugs and DNA nanotubes were investigated via molecular dynamics simulation. Our simulation results demonstrated that the DNA nanotubes could serve as a good drug delivery material by absorption of anti-cancer drugs with π-π interactions. At high concentration of anti-cancer drugs, most of the drugs could be absorbed by DNA nanotubes. Therefore, it could greatly decrease the aggregation of anti-cancer drugs in aqueous solution. In addition, the stability of DNA nanotubes could be improved with the absorption of anti-cancer drugs. These findings greatly enhance the understanding of the interaction mechanism of DNA nanotubes and anti-cancer drugs. Our study suggests that DNA nanotubes are promising delivery vehicles by strong absorption of anti-cancer drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. [Novel drug composition ameliorating thrombosis and its molecular mechanisms].

    Science.gov (United States)

    Ning, Meng; Huang, Jing-Hui; Zhang, Yan-Fang; Cui, Wen-Yu; Wang, Hai

    2014-03-01

    To investigate the antithrombotic effects and its molecular mechanisms of prazosin combined with anisodamine (Ani). Isolated rat tail artery rings model was employed to evaluate the vasodilative effects of drugs, mice tail thrombosis model induced by carrageenan was used to study the antithrombotic effects and its molecular mechanisms of the drug composition. Among alpha1-adrenoreceptor antagonists, prazosin(Pra) had the greatest relaxation rate, which was (82.6 +/- 8.9)%, and the EC50 value was 0.44 micromol/L. The drug composition of anisodamine and prazosin of different doses could decrease the length of the tail thrombosis from (24.6 +/- 4.6)mm to (6.9 +/- 2.7)mm, and the rate of thrombosis was decreased from 86.6% to 50.0%. The drug composition could prolong the prothrombin time (PT) distinctively, but it had no effect on the activated partial thromboplastin time (APTT). It also could restrain the decrease of serum levels of tissue plasminogen activator (t-PA) and 6- Keto -PGF1alpha as well as the increase of type-1 plasminogen activator inhibitor (PAI-1) and thromboxane B2 (TXB2) in the mice. The drug composition formed by anisodamine and prazosin has good effects of relaxing extremities tiny blood vessels and it can fight against thrombosis, its antithrombotic mechanisms may be related to the influence of the extrinsic coagulation pathway, inhibition of platelet activation functions and the promotion of fibrinolysis function.

  1. Evaluation of chloroquine as a potent anti-malarial drug: issues of public health policy and healthcare delivery in post-war Liberia.

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    Massaquoi, Moses B F; Kennedy, Stephen B

    2003-02-01

    Chloroquine-resistant plasmodium falciparum malaria is a serious public health threat that is spreading rapidly across Sub-Saharan Africa. It affects over three quarters (80%) of malarial endemic countries. Of the estimated 300-500 million cases of malaria reported annually, the vast majority of malarial-related morbidities occur among young children in Africa, especially those concentrated in the remote rural areas with inadequate access to appropriate health care services. In Liberia, in vivo studies conducted between 1993 and 2000 observed varying degrees of plasmodium falciparum malaria infections that were resistant to chloroquine, including sulfadiazine-pyrimethamine. As the country emerges from a prolonged civil war, the health care delivery system may not be adequately prepared to implement an effective nation-wide malarial control strategy. As a result, the management of uncomplicated malaria in Liberia poses a significant public health challenge for the government-financed health care delivery system. Therefore, based on extensive literature review, we report the failure of chloroquine as an effective first-line drug for the treatment of uncomplicated plasmodium falciparum malaria in Liberia and recommend that national health efforts be directed at identifying alternative drug(s) to replace it.

  2. The acceptability of mass administrations of anti-malarial drugs as part of targeted malaria elimination in villages along the Thai–Myanmar border

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    Ladda Kajeechiwa

    2016-09-01

    Full Text Available Abstract Background A targeted malaria elimination project, including mass drug administrations (MDA of dihydroartemisinin/piperaquine plus a single low dose primaquine is underway in villages along the Thailand Myanmar border. The intervention has multiple components but the success of the project will depend on the participation of the entire communities. Quantitative surveys were conducted to study reasons for participation or non-participation in the campaign with the aim to identify factors associated with the acceptance and participation in the mass drug administrations. Methods The household heads in four study villages in which MDAs had taken place previously were interviewed between January 2014 and July 2015. Results 174/378 respondents (46 % completed three rounds of three drug doses each, 313/378 (83 % took at least three consecutive doses and 56/378 (15 % did not participate at all in the MDA. The respondents from the two villages (KNH and TPN were much more likely to participate in the MDA than respondents from the other two villages (HKT and TOT. The more compliant villages KNH and TPN had both an appearance of cohesive communities with similar demographic and ethnic backgrounds. By contrast the villages with low participation were unique. One village was fragmented following years of armed conflict and many respondents gave little inclination to cooperate with outsiders. The other village with low MDA coverage was characterised by a high percentage of short-term residents with little interest in community interventions. A universal reason for non-participation in the MDA applicable to all villages was an inadequate understanding of the intervention. Conclusions It is unlikely that community engagement can unite fragmented communities in participating in an intervention, which benefits the community. Understanding the purpose and the reasons underlying the intervention is an important pre-condition for participation. In the

  3. The in vitro antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with mefloquine/artesunate.

    Science.gov (United States)

    Chaijaroenkul, Wanna; Na-Bangchang, Kesara

    2014-03-01

    Multidrug resistance Plasmodium falciparum is the major health problem in Thailand. Discovery and development of new antimalarial drugs with novel modes of action is urgently required. The aim of the present study was to investigate the antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with the standard antimalarial drugs mefloquine and artesunate in chloroquine sensitive (3D7) and chloroquine resistant (K1) P. falciparum clones in vitro. Median (range) IC50 (drug concentration which produces 50% parasite growth inhibition) values of the 9-hydroxycalabaxanthone, α-mangostin, artesunate and mefloquine for 3D7 vs K1 clones were 1.5 (0.9-2.1) vs 1.2 (1.1-1.6) μM, 17.9 (15.7.0-20.0) vs 9.7 (6.0-14.0) μM, 1.0 (0.4-3.0) vs 1.7 (1.0-2.5) nM, and 13.3 (11.1-13.3) vs 7.1 (6.7-12.2) nM, respectively. Analysis of isobologram and combination index (CI) of 9-hydroxycalabaxanthone with artesunate or mefloquine showed synergistic and indifference antimalarial interaction, respectively. α-mangostin-artesunate combination exhibited a slight antagonistic effect of antimalarial interaction, whereas α-mangostin and mefloquine combination showed indifference interaction in both clones. The combination of 9-hydroxycalabaxanthone with α-mangostin showed the synergistic antimalarial interaction in both clones.

  4. Co-crystal formation between poly(ethylene glycol) and a small molecular drug griseofulvin.

    Science.gov (United States)

    Zhong, Zhi; Guo, Canxiong; Chen, Long; Xu, Jun; Huang, Yanbin

    2014-06-18

    Most of the pharmaceutical co-crystals are formed between drug molecules and small molecular compounds. Here, we demonstrated that a small molecular drug griseofulvin and poly(ethylene glycol) can also form co-crystals.

  5. Enhanced Molecular Dynamics Methods Applied to Drug Design Projects.

    Science.gov (United States)

    Ziada, Sonia; Braka, Abdennour; Diharce, Julien; Aci-Sèche, Samia; Bonnet, Pascal

    2018-01-01

    Nobel Laureate Richard P. Feynman stated: "[…] everything that living things do can be understood in terms of jiggling and wiggling of atoms […]." The importance of computer simulations of macromolecules, which use classical mechanics principles to describe atom behavior, is widely acknowledged and nowadays, they are applied in many fields such as material sciences and drug discovery. With the increase of computing power, molecular dynamics simulations can be applied to understand biological mechanisms at realistic timescales. In this chapter, we share our computational experience providing a global view of two of the widely used enhanced molecular dynamics methods to study protein structure and dynamics through the description of their characteristics, limits and we provide some examples of their applications in drug design. We also discuss the appropriate choice of software and hardware. In a detailed practical procedure, we describe how to set up, run, and analyze two main molecular dynamics methods, the umbrella sampling (US) and the accelerated molecular dynamics (aMD) methods.

  6. The effect of molecular shape on oligomerization of hydrophobic drugs: Molecular simulations of ciprofloxacin and nutlin

    Science.gov (United States)

    Li, Jianguo; Beuerman, Roger; Verma, Chandra

    2018-03-01

    Molecular aggregation plays a significant role in modulating the solubility, permeability, and bioactivity of drugs. The propensity to aggregate depends on hydrophobicity and on molecular shape. Molecular dynamics simulations coupled with enhanced sampling methods are used to explore the early stages of oligomerization of two drug molecules which have a strong aggregation propensity, but with contrasting molecule shapes: the antibiotic ciprofloxacin and the anticancer drug Nutlin-3A. The planar shape of ciprofloxacin induces the formation of stable oligomers at all cluster sizes. The aggregation of ciprofloxacin is driven by two-body interactions, and transferring one ciprofloxacin molecule to an existing cluster involves the desolvation of two faces and the concomitant hydrophobic interactions between the two faces; thus, the corresponding free energy of oligomerization weakly depends on the oligomer size. By contrast, Nutlin-3A has a star-shape and hence can only form stable oligomers when the cluster size is greater than 8. Free energy simulations further confirmed that the free energy of oligomer formation for Nutlin-3A becomes more favorable as the oligomer becomes larger. The aggregation of star-shaped Nutlin-3A results from many-body interactions and hence the free energy of cluster formation is strongly dependent on the size. The findings of this study provide atomistic insights into how molecular shape modulates the aggregation behavior of molecules and may be factored into the design of drugs or nano-particles.

  7. Analysis of genetic mutations associated with anti-malarial drug resistance in Plasmodium falciparum from the Democratic Republic of East Timor

    Science.gov (United States)

    de Almeida, Afonso; Arez, Ana Paula; Cravo, Pedro VL; do Rosário, Virgílio E

    2009-01-01

    Background In response to chloroquine (CQ) resistance, the policy for the first-line treatment of uncomplicated malaria in the Democratic Republic of East Timor (DRET) was changed in early 2000. The combination of sulphadoxine-pyrimethamine (SP) was then introduced for the treatment of uncomplicated falciparum malaria. Methods Blood samples were collected in two different periods (2003–2004 and 2004–2005) from individuals attending hospitals or clinics in six districts of the DRET and checked for Plasmodium falciparum infection. 112 PCR-positive samples were inspected for genetic polymorphisms in the pfcrt, pfmdr1, pfdhfr and pfdhps genes. Different alleles were interrogated for potential associations that could be indicative of non-random linkage. Results Overall prevalence of mutations associated with resistance to CQ and SP was extremely high. The mutant form of Pfcrt (76T) was found to be fixed even after five years of alleged CQ removal. There was a significant increase in the prevalence of the pfdhps 437G mutation (X2 = 31.1; p = 0.001) from the first to second survey periods. A non-random association was observed between pfdhfr51/pfdhps437 (p = 0.001) and pfdhfr 59/pfdhps 437 (p = 0.013) alleles. Conclusion Persistence of CQ-resistant mutants even after supposed drug withdrawal suggests one or all of the following: local P. falciparum may still be inadvertently exposed to the drug, that mutant parasites are being "imported" into the country, and/or reduced genetic diversity and low parasite transmission help maintain mutant haplotypes. The association between pfdhfr51/pfdhps437 and pfdhfr 59/pfdhps 437 alleles indicates that these are undergoing concomitant positive selection in the DRET. PMID:19358729

  8. Self-Medication with Antibiotics and Antimalarials in the Community of Silte Zone, South Ethiopia

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    Nasir Tajure Wabe

    2012-10-01

    Full Text Available AIM: Self-medication with antibiotics and antimalarials occurs among the population in Ethiopian. We studied to estimate the prevalence of self-medication with antibiotics and antimalarials in Ethiopia and evaluate factors associated with self-medications. METHODS: A cross-sectional study was conducted on 405 households, selected from Silte Zone in South Ethiopia, using a random sampling technique by employing a pretested questionnaire. Data were analyzed using SPSS for windows version 16.0. Chi-square test was used to observe the association of variables. RESULT: The prevalence of self-medication with antibiotics/ antimalarials in this study was 14.5%. Twenty seven (6.7% participants were self medicated with antibiotics, 2.7% used antimalarials drugs while 21 (5.2% used both. Level of monthly income and educational status significantly influence pattern of antibiotics and antimalarials self medication (P<0.05.The top three diseases that led to self medication in this study were headache (38.5%, fever (35.9%, and cough (14.1%. Among self-medicated antibiotics, Amoxicillin (13.5% followed by Ciprofloxacin (8.5% were the most commonly used class of drug. From antimalarials chloroquine (10.1% were highly abused. The main source of antibiotics /antimalarials was pharmacies (59.0% followed by shops (Kiosks (17.9%. The majority (20.5% of the respondents practiced self medication to avoid waiting time at health facilities. CONCLUSION: The prevalence of self-medication with anti-biotic/ antimalarials in the study community was low. Self medication tended to be higher in people with a higher education and those on higher monthly incomes. The major reason for self-medication is found to be to avoid waiting time at health facility. Community pharmacies are the major source drugs. [TAF Prev Med Bull 2012; 11(5.000: 529-536

  9. Metallocene Antimalarials: The Continuing Quest

    Science.gov (United States)

    Blackie, Margaret A. L.; Chibale, Kelly

    2008-01-01

    Over the last decade, a significant body of research has been developed around the inclusion of a metallocene moiety into known antimalarial compounds. Ferroquine is the most successful of these compounds. Herein, we describe our contribution to metallocene antimalarials. Our approach has sought to introduce diversity sites in the side chain of ferroquine in order to develop a series of ferroquine derivatives. The replacement of the ferrocenyl moiety with ruthenocene has given rise to ruthenoquine and a modest series of analogues. The reaction of ferroquine and selected analogues with Au(PPh3)NO3, Au(C6F5)(tht), and [Rh(COD)Cl2] has resulted in a series of heterobimetallic derivatives. In all cases, compounds have been evaluated for in vitro antiplasmodial activity in both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Preliminary structure-activity relationships have been delineated. PMID:18274662

  10. An alkaline comet assay study on the antimalarial drug atovaquone in human peripheral blood lymphocytes: a study based on clinically relevant concentrations.

    Science.gov (United States)

    Dinter, Domagoj; Gajski, Goran; Garaj-Vrhovac, Vera

    2013-01-01

    Atovaquone, a hydroxynaphthoquinone, is an anti-parasite drug, selectively targeting the mitochondrial respiratory chain of malaria parasite. It is used for both the treatment and prevention of malaria, usually in a fixed combination with proguanil. Although atovaquone has not often been associated with severe adverse reactions in the recommended dosages and has a relatively favorable side effect profile, the present study was undertaken to evaluate its cytogenotoxic potential towards human peripheral blood lymphocytes. Two different concentrations of atovaquone found in plasma when used in fixed-dose combination with proguanile hydrochloride were used with and without S9 metabolic activation: 2950 ng ml(-1) used for prophylactic treatment and 11 800 ng ml(-1) used in treatment of malaria. The results showed that lymphocyte viability was not affected after the treatment, suggesting that atovaquone was not cytotoxic in the given concentrations. With the alkaline comet assay we demonstrated that in human peripheral blood lymphocytes no significant changes in comet parameters occurred after the treatment. There were no differences in tested parameters with the addition of S9 metabolic activation, indicating that atovaquone either has no metabolite or it is not toxic in the given concentrations. Since no effects were observed after the treatment, it is to be concluded that atovaquone is safe from the aspect of genototoxicity in the recommended dosages. Copyright © 2011 John Wiley & Sons, Ltd.

  11. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

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    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  12. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    Science.gov (United States)

    Barbault, Florent; Maurel, François

    2015-10-01

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  13. ANTIMALARIALS PRESCRIPTION TO PATIENTS IN JOSINA MACHEL CENTRAL HOSPITAL. JANUARY-JULY 2014

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    Mateus Sebastião João Fernandes

    2015-07-01

    Full Text Available Malaria represents the main public health problem in Angola, being the leading cause of disease and death. The misuse of antimalarials can lead to an increase of drug resistance and undesired adverse reactions, among other issues, with a negative impact in patients and the National Health System. An observational, descriptive, cross-sectional study, of the Drug Use Study type, was conducted in patients with a confirmed diagnosis of malaria admitted at Josina Machel Central Hospital, to evaluate the quality of prescription of antimalarials. This prescription-indication study was conducted from January to July of 2014, in a sample of 151 patients admitted in the Medicine and Therapy Services. The adequacy of the prescription was assessed taking into account patients characteristics and the prescribed therapeutic regimen (drug, dose, posology and duration of treatment, using the therapeutic guidelines of the National Malaria Control Programme in Angola as reference. There was a high prevalence of inadequate prescriptions of antimalarials, which was observed in 70 out of 151 patients (46.4%. The inadequate prescription of antimalarials was more frequently observed in cases of complicated malaria and between patients admitted in the Medicine Services. The more frequent causes of antimalarials misuse were “unnecessary or inappropriate drug combinations” and “inadequate treatment”. The drugs more commonly misused were Quinine IV and Artemether IM.

  14. The application of molecular topology for ulcerative colitis drug discovery.

    Science.gov (United States)

    Bellera, Carolina L; Di Ianni, Mauricio E; Talevi, Alan

    2018-01-01

    Although the therapeutic arsenal against ulcerative colitis has greatly expanded (including the revolutionary advent of biologics), there remain patients who are refractory to current medications while the safety of the available therapeutics could also be improved. Molecular topology provides a theoretic framework for the discovery of new therapeutic agents in a very efficient manner, and its applications in the field of ulcerative colitis have slowly begun to flourish. Areas covered: After discussing the basics of molecular topology, the authors review QSAR models focusing on validated targets for the treatment of ulcerative colitis, entirely or partially based on topological descriptors. Expert opinion: The application of molecular topology to ulcerative colitis drug discovery is still very limited, and many of the existing reports seem to be strictly theoretic, with no experimental validation or practical applications. Interestingly, mechanism-independent models based on phenotypic responses have recently been reported. Such models are in agreement with the recent interest raised by network pharmacology as a potential solution for complex disorders. These and other similar studies applying molecular topology suggest that some therapeutic categories may present a 'topological pattern' that goes beyond a specific mechanism of action.

  15. Molecular Basis for Drug Resistance in HIV-1 Protease

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    Celia A. Schiffer

    2010-11-01

    Full Text Available HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

  16. In Vitro Drug Sensitivity Tests to Predict Molecular Target Drug Responses in Surgically Resected Lung Cancer.

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    Ryohei Miyazaki

    Full Text Available Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs and anaplastic lymphoma kinase (ALK inhibitors have dramatically changed the strategy of medical treatment of lung cancer. Patients should be screened for the presence of the EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4-ALK fusion gene prior to chemotherapy to predict their clinical response. The succinate dehydrogenase inhibition (SDI test and collagen gel droplet embedded culture drug sensitivity test (CD-DST are established in vitro drug sensitivity tests, which may predict the sensitivity of patients to cytotoxic anticancer drugs. We applied in vitro drug sensitivity tests for cyclopedic prediction of clinical responses to different molecular targeting drugs.The growth inhibitory effects of erlotinib and crizotinib were confirmed for lung cancer cell lines using SDI and CD-DST. The sensitivity of 35 cases of surgically resected lung cancer to erlotinib was examined using SDI or CD-DST, and compared with EGFR mutation status.HCC827 (Exon19: E746-A750 del and H3122 (EML4-ALK cells were inhibited by lower concentrations of erlotinib and crizotinib, respectively than A549, H460, and H1975 (L858R+T790M cells were. The viability of the surgically resected lung cancer was 60.0 ± 9.8 and 86.8 ± 13.9% in EGFR-mutants vs. wild types in the SDI (p = 0.0003. The cell viability was 33.5 ± 21.2 and 79.0 ± 18.6% in EGFR mutants vs. wild-type cases (p = 0.026 in CD-DST.In vitro drug sensitivity evaluated by either SDI or CD-DST correlated with EGFR gene status. Therefore, SDI and CD-DST may be useful predictors of potential clinical responses to the molecular anticancer drugs, cyclopedically.

  17. 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

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    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

  18. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

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    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  19. Implementation of a reference standard and proficiency testing programme by the World Wide Antimalarial Resistance Network (WWARN

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    Barnes Karen I

    2010-12-01

    Full Text Available Abstract Background The Worldwide Antimalarial Resistance Network (WWARN is a global collaboration to support the objective that anyone affected by malaria receives effective and safe drug treatment. The Pharmacology module aims to inform optimal anti-malarial drug selection. There is an urgent need to define the drug exposure - effect relationship for most anti-malarial drugs. Few anti-malarials have had their therapeutic blood concentration levels defined. One of the main challenges in assessing safety and efficacy data in relation to drug concentrations is the comparability of data generated from different laboratories. To explain differences in anti-malarial pharmacokinetics in studies with different measurement laboratories it is necessary to confirm the accuracy of the assay methods. This requires the establishment of an external quality assurance process to assure results that can be compared. This paper describes this process. Methods The pharmacology module of WWARN has established a quality assurance/quality control (QA/QC programme consisting of two separate components: 1. A proficiency testing programme where blank human plasma spiked with certified reference material (CRM in different concentrations is sent out to participating bioanalytical laboratories. 2. A certified reference standard programme where accurately weighed amounts of certified anti-malarial reference standards, metabolites, and internal standards are sent to participating bioanalytical and in vitro laboratories. Conclusion The proficiency testing programme is designed as a cooperative effort to help participating laboratories assess their ability to carry out drug analysis, resolve any potential problem areas and to improve their results - and, in so doing, to improve the quality of anti-malarial pharmacokinetic data published and shared with WWARN. By utilizing the same source of standards for all laboratories, it is possible to minimize bias arising from poor

  20. Antimalarial interaction of quinine and quinidine with clarithromycin.

    Science.gov (United States)

    Pandey, Swaroop Kumar; Dwivedi, Hemlata; Singh, Sarika; Siddiqui, Waseem Ahmad; Tripathi, Renu

    2013-03-01

    Quinine (QN) and quinidine (QND) have been commonly used as effective and affordable antimalarials for over many years. Quinine primarily is used for severe malaria treatment. However, plasmodia resistance to these drugs and poor patient compliance limits their administration to the patients. The declining sensitivity of the parasite to the drugs can thus be dealt with by combining with a suitable partner drug. In the present study QN/QND was assessed in combination with clarithromycin (CLTR), an antibiotic of the macrolide family. In vitro interactions of these drugs with CLTR against Plasmodium falciparum (P. falciparum) have shown a synergistic response with mean sum fractional inhibitory concentrations (ΣFICs) of ≤1 (0.85 ± 0.11 for QN + CLTR and 0.64 ± 0.09 for QND + CLTR) for all the tested combination ratios. Analysis of this combination of QN/QND with CLTR in mouse model against Plasmodium yoelii nigeriensis multi-drug resistant (P. yoelii nigeriensis MDR) showed that a dose of 200 mg/kg/day for 4 days of QN or QND produces 100% curative effect with 200 mg/kg/day for 7 days and 150 mg/kg/day for 7 days CLTR respectively, while the same dose of individual drugs could produce only up to a maximum 20% cure. It is postulated that CLTR, a CYP3A4 inhibitor, might have caused reduced CYP3A4 activity leading to increased plasma level of the QN/QND to produce enhanced antimalarial activity. Further, parasite apicoplast disruption by CLTR synergies the antimalarial action of QN and QND.

  1. Antimalarial natural products: a review

    Directory of Open Access Journals (Sweden)

    Faraz Mojab

    2012-03-01

    Results and Conclusion: There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures.

  2. Poisoning by anti-malarial drugs

    African Journals Online (AJOL)

    and tinnitus, a david@tibbutt.co.uk. 1 Chloroquine is a 4-aminoquinolone and comes as a number of salts mainly the phosphate and sulphate. Vasodilatation. •. (flushing sensation more obvious in a pale skin). This may be exacerbated by the vasodilatation caused by the malaria itself and so cause postural (orthostatic) ...

  3. Some Pharmacological Aspects of Antimalarial Drugs

    African Journals Online (AJOL)

    1974-06-15

    Jun 15, 1974 ... in the synthesis of folic acid. Both G-6-PD-deficient erythrocytes and the secondary tissue schizonts appear to have a similar enzyme defect involving the pentose-phosphate pathway, making them susceptible to oxidation damage by the quinoline-quinone metabolites of the. 8-aminoquinolines. (primaquin).

  4. (annonaceae) leaves-a potential antimalarial drug

    African Journals Online (AJOL)

    Xylopia species are widely available in West Africa. Xylopia parviflora (Benth) plant is used in folk medicine in the management of a number of ailments, one of these is the use of the leaves in the treatment of malaria fever for which a number of patients have reported its beneficial effects. This study was designed to ...

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

    Science.gov (United States)

    2011-01-01

    used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial

  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

    medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next

  7. Ethnobotanical perspective of antimalarial plants: traditional knowledge based study.

    Science.gov (United States)

    Qayum, Abdul; Arya, Rakesh; Lynn, Andrew M

    2016-02-04

    Considering the demand of antimalarial plants it has become essential to find and locate them for their optimal extraction. The work aims to find plants with antimalarial activities which were used by the local people; to raise the value of traditional knowledge system (TKS) prevalent in the study region; to compile characteristics of local plants used in malaria treatment (referred as antimalarial plants) and to have its spatial distribution analysis to establish a concept of geographical health. Antimalarial plants are listed based on literature survey and field data collected during rainy season, from 85 respondents comprised of different ethnic groups. Ethno-medicinal utilities of plants was extracted; botanical name, family, local name, part used, folklore, geographical location and image of plants were recorded after cross validating with existing literatures. The interview was trifurcated in field, Vaidya/Hakims and house to house. Graphical analysis was done for major plants families, plant part used, response of people and patients and folklore. Mathematical analysis was done for interviewee's response, methods of plant identification and people's preferences of TKS through three plant indices. Fifty-one plants belonging to 27 families were reported with its geographical attributes. It is found plant root (31.75 %) is used mostly for malaria treatment and administration mode is decoction (41.2 %) mainly. The study area has dominance of plants of family Fabaceae (7), Asteraceae (4), Acanthaceae (4) and Amaranthaceae (4). Most popular plants found are Adhatoda vasica, Cassia fistula and Swertia chirata while  % usage of TKS is 82.0 % for malaria cure. The research findings can be used by both scientific community and common rural people for bio-discovery of these natural resources sustainably. The former can extract the tables to obtain a suitable plant towards finding a suitable lead molecule in a drug discovery project; while the latter can meet their

  8. 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.

  9. Dependence of molecular properties on proteomic family for marketed oral drugs.

    Science.gov (United States)

    Vieth, Michal; Sutherland, Jeffrey J

    2006-06-15

    An association of drugs with their proteomic family reveals that molecular properties of drugs targeting proteases, lipid and peptide G-protein-coupled receptors (GPCRs), and nuclear hormone receptors significantly exceed limits for some properties in the "rule of five", while drugs targeting cytochrome P450s, biogenic amine GPCRs, and transporters have significantly lower values for certain properties. Also, the variation in drug targets appears to be a factor explaining increasing molecular weight over time.

  10. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    OpenAIRE

    Hubbard Alan E; Dorsey Grant; Gupta Vinay; Rosenthal Philip J; Greenhouse Bryan

    2010-01-01

    Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary elec...

  11. Antimalarial activity of medicinal plants from the Democratic Republic of Congo: A review.

    Science.gov (United States)

    Memvanga, Patrick B; Tona, Gaston L; Mesia, Gauthier K; Lusakibanza, Mariano M; Cimanga, Richard K

    2015-07-01

    Malaria is the most prevalent parasitic disease and the foremost cause of morbidity and mortality in the Democratic Republic of Congo. For the management of this disease, a large Congolese population recourses to traditional medicinal plants. To date the efficacy and safety of many of these plants have been validated scientifically in rodent malaria models. In order to generate scientific evidence of traditional remedies used in the Democratic Republic of Congo for the management of malaria, and show the potential of Congolese plants as a major source of antimalarial drugs, this review highlights the antiplasmodial and toxicological properties of the Congolese antimalarial plants investigated during the period of 1999-2014. In doing so, a useful resource for further complementary investigations is presented. Furthermore, this review may pave the way for the research and development of several available and affordable antimalarial phytomedicines. In order to get information on the different studies, a Google Scholar and PubMed literature search was performed using keywords (malaria, Congolese, medicinal plants, antiplasmodial/antimalarial activity, and toxicity). Data from non-indexed journals, Master and Doctoral dissertations were also collected. Approximately 120 extracts and fractions obtained from Congolese medicinal plants showed pronounced or good antiplasmodial activity. A number of compounds with interesting antiplasmodial properties were also isolated and identified. Some of these compounds constituted new scaffolds for the synthesis of promising antimalarial drugs. Interestingly, most of these extracts and compounds possessed high selective activity against Plasmodium parasites compared to mammalian cells. The efficacy and safety of several plant-derived products was confirmed in mice, and a good correlation was observed between in vitro and in vivo antimalarial activity. The formulation of several plant-derived products also led to some clinical trials

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

    Science.gov (United States)

    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 (substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    Full Text Available Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC, are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both

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

    Science.gov (United States)

    Littrell, Megan; Gatakaa, Hellen; Phok, Sochea; Allen, Henrietta; Yeung, Shunmay; Chuor, Char Meng; Dysoley, Lek; Socheat, Duong; Spiers, Angus; White, Chris; Shewchuk, Tanya; Chavasse, Desmond; O'Connell, Kathryn A

    2011-10-31

    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. 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. 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. While data on the anti-malarial market shows favourable progress towards replacing

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

    Directory of Open Access Journals (Sweden)

    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

  17. Stevens-Johnson syndrome associated with Malarone antimalarial prophylaxis.

    Science.gov (United States)

    Emberger, Michael; Lechner, Arno Michael; Zelger, Bernhard

    2003-07-01

    To the best of our knowledge, Stevens-Johnson syndrome (SJS) has not been reported previously as an adverse reaction to Malarone, which is a combination of atovaquone and proguanil hydrochloride used for antimalarial prophylaxis and therapy. We describe a 65-year-old patient who had SJS with typical clinical and histopathological findings associated with the use of Malarone prophylaxis for malaria. This report should alert physicians to this severe cutaneous reaction, and Malarone should be added to the list of drugs that can potentially cause SJS.

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

    Directory of Open Access Journals (Sweden)

    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

  19. A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

    Science.gov (United States)

    Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

    2011-01-01

    Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

  20. Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols.

    Directory of Open Access Journals (Sweden)

    Juliana B R Corrêa Soares

    Full Text Available BACKGROUND: The parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN, quinidine (QND and quinacrine (QCR in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day from the 11(th to 17(th day after infection caused significant decreases in worm burden (39%-61% and egg production (42%-98%. Hz formation was significantly inhibited (40%-65% in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms. CONCLUSIONS: The overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a

  1. In Vitro Chemosensitization of Plasmodium falciparum to Antimalarials by Verapamil and Probenecid▿

    OpenAIRE

    Masseno, Victor; Muriithi, Steven; Nzila, Alexis

    2009-01-01

    We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.

  2. In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid.

    Science.gov (United States)

    Masseno, Victor; Muriithi, Steven; Nzila, Alexis

    2009-07-01

    We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.

  3. 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.

  4. Synthesis and evaluation of antimalarial activity of curcumin derivatives; Sintese e avaliacao da atividade antimalarica de compostos derivados da curcumina

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa [Universidade Federal de Juiz de Fora (UFSJ), MG (Brazil). Instituto de Ciencias Exatas. Departamento de Quimica; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla, E-mail: varotti@ufsj.edu.br [Universidade Federal de Sao Joao Del Rei (UFSJ), MG (Brazil). Centro de Ciencias da Saude; and others

    2014-05-15

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC{sub 50} values ranging from 1.7 to 15.2 μg mL{sup -1}), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  5. Prediction models for drug-induced hepatotoxicity by using weighted molecular fingerprints

    OpenAIRE

    Kim, Eunyoung; Nam, Hojung

    2017-01-01

    Background Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. Results In this study, we used 881 bits of molecular fingerpri...

  6. Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

    OpenAIRE

    Burkhart, Keith K.; Abernethy, Darrell; Jackson, David

    2015-01-01

    Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was al...

  7. Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design.

    Science.gov (United States)

    Albanaz, Amanda T S; Rodrigues, Carlos H M; Pires, Douglas E V; Ascher, David B

    2017-06-01

    Mutations introduce diversity into genomes, leading to selective changes and driving evolution. These changes have contributed to the emergence of many of the current major health concerns of the 21st century, from the development of genetic diseases and cancers to the rise and spread of drug resistance. The experimental systematic testing of all mutations in a system of interest is impractical and not cost-effective, which has created interest in the development of computational tools to understand the molecular consequences of mutations to aid and guide rational experimentation. Areas covered: Here, the authors discuss the recent development of computational methods to understand the effects of coding mutations to protein function and interactions, particularly in the context of the 3D structure of the protein. Expert opinion: While significant progress has been made in terms of innovative tools to understand and quantify the different range of effects in which a mutation or a set of mutations can give rise to a phenotype, a great gap still exists when integrating these predictions and drawing causality conclusions linking variants. This often requires a detailed understanding of the system being perturbed. However, as part of the drug development process it can be used preemptively in a similar fashion to pharmacokinetics predictions, to guide development of therapeutics to help guide the design and analysis of clinical trials, patient treatment and public health policy strategies.

  8. In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa

    Directory of Open Access Journals (Sweden)

    Eberlin Marcos N

    2011-05-01

    Full Text Available Abstract Background To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. Methods Crude extract (CE was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7 and -resistant (S20 strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. Results At non-toxic concentrations, the 100% ethanolic (F4 and 50% methanolic (F5 fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. Conclusions The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.

  9. An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

    Directory of Open Access Journals (Sweden)

    Chun-Bing Chen

    2018-01-01

    Full Text Available Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS/drug-induced hypersensitivity syndrome (DIHS, or Stevens–Johnson syndrome (SJS/toxic epidermal necrolysis (TEN. Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs. The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

  10. An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

    Science.gov (United States)

    Abe, Riichiro; Pan, Ren-You; Wang, Chuang-Wei

    2018-01-01

    Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity. PMID:29651444

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

    Science.gov (United States)

    Shewchuk, Tanya; O'Connell, Kathryn A; Goodman, Catherine; Hanson, Kara; Chapman, Steven; Chavasse, Desmond

    2011-10-31

    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. 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. 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 project aims to disseminate findings widely for decision

  12. 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

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

    Science.gov (United States)

    2011-01-01

    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 project aims to disseminate

  14. 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.

  15. 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

    Directory of Open Access Journals (Sweden)

    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

  16. Epidemiological models for the spread of anti-malarial resistance

    Directory of Open Access Journals (Sweden)

    Antia R

    2003-02-01

    Full Text Available Abstract Background The spread of drug resistance is making malaria control increasingly difficult. Mathematical models for the transmission dynamics of drug sensitive and resistant strains can be a useful tool to help to understand the factors that influence the spread of drug resistance, and they can therefore help in the design of rational strategies for the control of drug resistance. Methods We present an epidemiological framework to investigate the spread of anti-malarial resistance. Several mathematical models, based on the familiar Macdonald-Ross model of malaria transmission, enable us to examine the processes and parameters that are critical in determining the spread of resistance. Results In our simplest model, resistance does not spread if the fraction of infected individuals treated is less than a threshold value; if drug treatment exceeds this threshold, resistance will eventually become fixed in the population. The threshold value is determined only by the rates of infection and the infectious periods of resistant and sensitive parasites in untreated and treated hosts, whereas the intensity of transmission has no influence on the threshold value. In more complex models, where hosts can be infected by multiple parasite strains or where treatment varies spatially, resistance is generally not fixed, but rather some level of sensitivity is often maintained in the population. Conclusions The models developed in this paper are a first step in understanding the epidemiology of anti-malarial resistance and evaluating strategies to reduce the spread of resistance. However, specific recommendations for the management of resistance need to wait until we have more data on the critical parameters underlying the spread of resistance: drug use, spatial variability of treatment and parasite migration among areas, and perhaps most importantly, cost of resistance.

  17. Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection [v1; ref status: indexed, http://f1000r.es/51s

    Directory of Open Access Journals (Sweden)

    Veljko Veljkovic

    2015-02-01

    Full Text Available The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD. Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.

  18. Antimalarial work in China: a historical perspective.

    Science.gov (United States)

    Yip, K

    1998-06-01

    Systematic scientific studies of malaria in China did not begin until the 1920s. The persistence of misconceptions about the disease and the absence of political stability, funds and trained personnel were obstacles to any large scale antimalarial campaigns. In the 1920s and 30s, antimalarial efforts involved epidemiologic studies, environmental alterations, and treatment of patients. During the Sino-Japanese War when the Chinese government relocated inland, China's antimalarial work focused on the control of the disease, especially in the western and southwestern provinces. After the founding of the People's Republic of China in 1949, nationwide antimalarial campaigns were initiated and enforced by the central government which also promoted intersectoral and interregional cooperation. Together with the building of a preventive and anti-epidemic infrastructure and health care system as well as the training of personnel, the government used techniques of mass mobilization to launch programs of vector control and mass therapy. Provinces were also organized into antimalarial regional alliances to facilitate malaria control and surveillance.

  19. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei.

    Science.gov (United States)

    Ramli, Norazsida; Ahamed, Pakeer Oothuman Syed; Elhady, Hassan Mohamed; Taher, Muhammad

    2014-10-01

    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. This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Acute oral toxicity dose at 5000 mg/kg was conducted to evaluate the safety of this extract. Twenty mice were divided into control and experimental group. All the mice were observed for signs of toxicity, mortality, weight changes and histopathological changes. Antimalarial activity of different extract doses of 50, 200, 400 and 1000 mg/kg were tested in vivo against Plasmodium berghei infections in mice (five mice for each group) during early, established and residual infections. The acute oral toxicity test revealed that no mortality or evidence of adverse effects was seen in the treated mice. The extract significantly reduced the parasitemia by the 50 (P = 0.000), 200 (P = 0.000) and 400 mg/kg doses (P = 0.000) in the in vivo prophylactic assay. The percentage chemo-suppression was calculated as 83.33% for 50 mg/kg dose, 75.62% for 200 mg/kg dose and 90.74% for 400 mg/kg dose. Body weight of all treated groups; T1, T2, T3 and T4 also showed enhancement after 7 days posttreatment. Statistically no reduction of parasitemia calculated for curative and suppressive test. Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection.

  20. Molecular detection methods of resistance to antituberculosis drugs in Mycobacterium tuberculosis.

    Science.gov (United States)

    Brossier, F; Sougakoff, W

    2017-09-01

    Molecular methods predict drug resistance several weeks before phenotypic methods and enable rapid implementation of appropriate therapeutic treatment. We aimed to detail the most representative molecular tools used in routine practice for the rapid detection of resistance to antituberculosis drugs among Mycobacterium tuberculosis strains. The molecular diagnosis of resistance to antituberculosis drugs in clinical samples or from in vitro cultures is based on the detection of the most common mutations in the genes involved in the development of resistance in M. tuberculosis strains (encoding either protein targets of antibiotics, or antibiotic activating enzymes) by commercial molecular kits or by sequencing. Three hypotheses could explain the discrepancies between the genotypic results and the phenotypic drug susceptibility testing results: a low percentage of resistant mutants precluding the detection by genotypic methods on the primary culture; a low level of resistance not detected by phenotypic testing; and other resistance mechanisms not yet characterized. Molecular methods have varying sensitivity with regards to detecting antituberculosis drug resistance; that is why phenotypic susceptibility testing methods are mandatory for detecting antituberculosis drug-resistant isolates that have not been detected by molecular methods. The questionable ability of existing phenotypic and genotypic drug susceptibility testing to properly classify strains as susceptible or resistant, and at what level of resistance, was raised for several antituberculosis agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. ANTIMALARIALS PRESCRIPTION TO PATIENTS IN JOSINA MACHEL CENTRAL HOSPITAL. JANUARY-JULY 2014

    OpenAIRE

    Mateus Sebastião João Fernandes; Boaventura Moura; Héctor Lara Fernández; Vladimir Calzadilla Moreira; Lúcia Gomes Fraga

    2015-01-01

    Malaria represents the main public health problem in Angola, being the leading cause of disease and death. The misuse of antimalarials can lead to an increase of drug resistance and undesired adverse reactions, among other issues, with a negative impact in patients and the National Health System. An observational, descriptive, cross-sectional study, of the Drug Use Study type, was conducted in patients with a confirmed diagnosis of malaria admitted at Josina Machel Central Hospital, to eva...

  2. ISOLATION AND PRESENCE OF ANTIMALARIAL ACTIVITIES OF MARINE SPONGE Xestospongia sp.

    OpenAIRE

    Murtihapsari Murtihapsari; Apriani Sulu Parubak; Bertha Mangallo; Wiwied Ekasari; Puji Budi Asih; Ayu Indah Lestari

    2013-01-01

    Plasmodium falciparum, the agent of malignant malaria, is one of mankind's most severe scourges, mainly in the tropic world. Efforts to develop preventive vaccines or remedial drugs are handicapped by the parasite's rapid evolution of drug resistance. Here, we presented an advance work on examination of antimalarial component from marine life of Xestospongia sp., the study is based on hexane extraction method. The premier result, we obtained five fractions. Among these five fractions, the fou...

  3. Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

    Science.gov (United States)

    Drawnel, Faye Marie; Zhang, Jitao David; Küng, Erich; Aoyama, Natsuyo; Benmansour, Fethallah; Araujo Del Rosario, Andrea; Jensen Zoffmann, Sannah; Delobel, Frédéric; Prummer, Michael; Weibel, Franziska; Carlson, Coby; Anson, Blake; Iacone, Roberto; Certa, Ulrich; Singer, Thomas; Ebeling, Martin; Prunotto, Marco

    2017-05-18

    Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik

    2016-01-01

    The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R...... are useful for understanding drug metabolism....

  5. Antimalarial properties of South African medicinal plants

    CSIR Research Space (South Africa)

    Pillay, P

    2007-01-01

    Full Text Available of structure-activity derivatives around these simplified structures is currently under way. CONCLUSIONS The study identified a number of promising South African medicinal plants for further investigation as plant-based antimalarial agents. The overall... as potential sources of antimalarial lead compounds. REFERENCES Clarkson, C., Maharaj, V.J., Crouch, N.R., Grace, O.M., Pillay, P., Matsabisa, M.G., Bhagwandin, N., Smith, P.J., Folb, P.I., 2004. In vitro antiplasmodial activity of medicinal plants native...

  6. Antimalarial plants used by indigenous people of the Upper Rio Negro in Amazonas, Brazil.

    Science.gov (United States)

    Kffuri, Carolina Weber; Lopes, Moisés Ahkʉtó; Ming, Lin Chau; Odonne, Guillaume; Kinupp, Valdely Ferreira

    2016-02-03

    This is the first intercultural report of antimalarial plants in this region. The aim of this study was to document the medicinal plants used against malaria by indigenous people in the Upper Rio Negro region and to review the literature on antimalarial activity and traditional use of the cited species. Participant observation, semi-structured interviews, and ethnobotanical walks were conducted with 89 informants in five indigenous communities between April 2010 and November 2013 to obtain information on the use of medicinal plants against malaria. We reviewed academic databases for papers published in scientific journals up to January 2014 in order to find works on ethnopharmacology, ethnobotany, and antimalarial activity of the species cited. Forty-six plant species belonging to 24 families are mentioned. Fabaceae (17.4%), Arecaceae (13.0%) and Euphorbiaceae (6.5%) account together for 36.9% of these species. Only seven plant species showed a relatively high consensus. Among the plant parts, barks (34.0%) and roots (28.0%) were the most widely used. Of the 46 species cited, 18 (39.1%) have already been studied for their antimalarial properties according to the literature, and 26 species (56.5%) have no laboratory essays on antimalarial activity. Local traditional knowledge of the use of antimalarials is still widespread in indigenous communities of the Upper Rio Negro, where 46 plants species used against malaria were recorded. Our studies highlight promising new plants for future studies: Glycidendron amazonicum, Heteropsis tenuispadix, Monopteryx uaucu, Phenakospermum guianensis, Pouteria ucuqui, Sagotia brachysepala and notably Aspidosperma schultesii, Ampelozizyphus amazonicus, Euterpe catinga, E. precatoria, Physalis angulata, Cocos nucifera and Swartzia argentea with high-use consensus. Experimental validation of these remedies may help in developing new drugs for malaria. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Molecular detection of drug resistance in microbes by isotopic techniques: The IAEA experience

    International Nuclear Information System (INIS)

    Dar, L.; Boussaha, A.; Padhy, A.K.; Khan, B.

    2003-01-01

    The International Atomic Energy Agency (IAEA) supports various programmes on the uses of radionuclide techniques in the management of human communicable diseases. An important issue, being addressed through several technology transfer projects, is the detection of drug resistance in microbes by radioisotope based molecular-biology diagnostic procedures. The techniques employed include dot blot hybridisation with P-32 labelled oligonucleotide probes to detect point mutations, associated with drug resistance, in microbial genes amplified by the polymerase chain reaction (PCR). Molecular methods have been used for the detection of drug resistance in the malarial parasite, Plasmodium falciparum, and in Mycobacterium tuberculosis. Radioisotope based molecular-biology methods have been demonstrated to have comparative advantages in being sensitive, specific, cost-effective, and suitable for application to large-scale molecular surveillance for drug resistance. (author)

  8. Ameliorative antimalarial effects of the combination of rutin and swertiamarin on malarial parasites

    Directory of Open Access Journals (Sweden)

    Divya Shitlani

    2016-06-01

    Full Text Available Objective: To ameliorate the antimalarial activity via the combination of rutin (flavonoid and swertiamarin (glycoside. Methods: The antimalarial effects were assessed by in vitro and in vivo methodology. In vitro antiplasmodial activity was assessed by using Plasmodium falciparum cultured media and determined the IC 50 value of individual drugs and their combinations. In in vivo methodology, antimalarial effects of rutin, swertiamarin (200–280 mg/kg/day, p.o. and their combination in 1:1, 1:2 and 2:1 ratios were investigated early and established malaria infections using Swiss albino mice infected with Plasmodium berghei. Chloroquine phosphate (5 mg/kg/day, p.o. was used as the standard drug. Results: IC 50 values of the rutin and swertiamarin via in vitro study revealed (9.50 ± 0.29 µg/ mL and (8.17 ± 0.17 µg/mL respectively. Whereas, the combination in 1:1 ratio [IC50 of (5.51 ± 0.18 µg/mL] showed better antiplasmodial activity against Plasmodium falciparum. In vivo results showed that rutin and swertiamarin had chemosuppressant effects in a dose-dependent manner, whereas, combination in 1:1 ratio possessed potential antimalarial activity similar to chloroquine phosphate. The drug interaction between rutin and swertiamarin revealed the synergistic effect on 1:1 ratio and additive effect on 1:2 and 2:1 ratios. Conclusions: The results of the in vitro and in vivo study clearly indicate that the combination (1:1 of rutin and swertiamarin showed potential antimalarial activity rather than an individual of each and their combinations 1:2 and 2:1.

  9. Anti-malarial treatment outcomes in Ethiopia: a systematic review and meta-analysis.

    Science.gov (United States)

    Gebreyohannes, Eyob Alemayehu; Bhagavathula, Akshaya Srikanth; Seid, Mohammed Assen; Tegegn, Henok Getachew

    2017-07-03

    Ethiopia is among countries with a high malaria burden. There are several studies that assessed the efficacy of anti-malarial agents in the country and this systematic review and meta-analysis was performed to obtain stronger evidence on treatment outcomes of malaria from the existing literature in Ethiopia. A systematic literature search using the preferred reporting items for systematic review and meta-analysis (PRISMA) statement was conducted on studies from Pubmed, Google Scholar, and ScienceDirect databases to identify published and unpublished literature. Comprehensive meta-analysis software was used to perform all meta-analyses. The Cochrane Q and the I 2 were used to evaluate heterogeneity of studies. Random effects model was used to combine studies showing heterogeneity of Cochrane Q p  50. Twenty-one studies were included in the final analysis with a total number of 3123 study participants. Treatment outcomes were assessed clinically and parasitologically using World Health Organization guidelines. Adequate clinical and parasitological response was used to assess treatment success at the 28th day. Overall, a significant high treatment success of 92.9% (95% CI 89.1-96.6), p Ethiopia, but associated with high rates of adverse drug reactions (ADRs). However, these ADRs were not serious enough to discontinue anti-malarial treatment. The results of this study suggest that the current anti-malarial medications are effective and safe; however, greater priority should be placed on the discovery of new anti-malarial drugs to achieve successful outcomes as resistance seems inevitable since cases of anti-malarial drug resistance have been reported from other areas of the world.

  10. Medicinal Chemistry and Molecular Modeling: An Integration to Teach Drug Structure-Activity Relationship and the Molecular Basis of Drug Action

    Science.gov (United States)

    Carvalho, Ivone; Borges, Aurea D. L.; Bernardes, Lilian S. C.

    2005-01-01

    The use of computational chemistry and the protein data bank (PDB) to understand and predict the chemical and molecular basis involved in the drug-receptor interactions is discussed. A geometrical and chemical overview of the great structural similarity in the substrate and inhibitor is provided.

  11. Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

    OpenAIRE

    Chen, Jiezhong; Huang, Xu-Feng; Shao, Renfu; Chen, Chen; Deng, Chao

    2017-01-01

    Antipsychotic drugs (APDs) are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treat...

  12. Drug delivery to the kidneys and the bladder with the low molecular weight protein lysozyme

    NARCIS (Netherlands)

    Kok, Robbert J.; Haas, Marijke; Moolenaar, Frits; de Zeeuw, Dick; Meijer, Dirk K.F.

    1998-01-01

    The low molecular weight protein (LMWP) lysozyme is a suitable drug carrier for renal drug targeting. When the tubular reabsorption of a can be prevented, the protein will be excreted in the urine. In this way, lysozyme (LZM) conjugates might also be used as carriers for targeting to the urinary

  13. Drug delivery to the kidneys and the bladder with the low molecular weight protein lysozyme

    NARCIS (Netherlands)

    Kok, RJ; Haas, M; Moolenaar, F; de Zeeuw, D; Meijer, DKF

    1998-01-01

    The low molecular weight protein (LMWP) lysozyme is a suitable drug carrier for renal drug targeting. When the tubular reabsorption of a LMWP can be prevented, the protein will be excreted in the urine. In this way lysozyme (LZM) conjugates might also be used as carriers for targeting to the urinary

  14. Access to artesunate-amodiaquine, quinine and other anti-malarials: policy and markets in Burundi

    Directory of Open Access Journals (Sweden)

    Dismas Baza

    2011-02-01

    Full Text Available Abstract Background Malaria is the leading cause of morbidity and mortality in post-conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate-amodiaquine (AS-AQ as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non-governmental (NGO retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti-malarials. Methods Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO, a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment of AS-AQ, quinine and other anti-malarials were calculated. Results Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti-malarials were mainly found in the private outlets (38.9% compared to public (4.2% and NGO (0% outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu. Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu, private and NGO sectors (both US$1.61 or 2,000 FBu. Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors

  15. Design, Synthesis and Testing of Novel Antimalarial

    Science.gov (United States)

    2006-05-05

    of P. falciparum Strains Tested ............................. 27 Figure 17 – Antimalarial Data of Chloroquine and Mefloquine ...vitro tests were performed by Dr. Lucia Gerena at the Walter Reed Army Institute of Research. 27 D6 W2 TM91-C235 Resistance Mefloquine ...Chloroquine Mefloquine Halofantrine Pyrimethamine Chloroquine Quinine Folate Antagonists Susceptibility Chloroquine Mefloquine

  16. Development of novel drug delivery prototypes devices for targeted delivery drug therapy at the molecular level in aqueous media.

    Science.gov (United States)

    George, Roy; Oberhozer, Theunis Gerhardus; Perchyonok, Victoria Tamara

    2011-09-01

    A novel approach in target specific molecular prototype drug delivery system concerns the attempt to employ radical affording substances (RAS) or radical quenching substances (RQS) as prodrugs able to produce irreversible damage on the desired target and therefore to stimulate cellular apoptosis. However, radical species generated can react quickly within the chemical environment prior to reaching its proper site of action. In this short communication, we report our investigations towards developing two alternative novel, simple, flexible and effective drug delivery systems that provide optimal dosage of drugs precisely where and when needed and therefore achieve and sustain a complex delivery profile. We have demonstrated the application of two effective molecular prototype delivery systems able to harness free radical reactivity within the laboratory where biological processes can be studied and controlled, leading to the prevention of disease and the development of new treatments for disease states mediated by free radicals.

  17. Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds.

    Science.gov (United States)

    Brandão, Geraldo Célio; Rocha Missias, Franciele C; Arantes, Lucas Miquéias; Soares, Luciana Ferreira; Roy, Kuldeep K; Doerksen, Robert J; Braga de Oliveira, Alaide; Pereira, Guilherme Rocha

    2018-02-10

    Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC 50 123.5 μM) and selectivity index (SI) values in the range of 4.5-197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between -9.375 and -14.55 units, compared to -9.137 for lapachol and -12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Targeting the treatment of drug abuse with molecular imaging

    International Nuclear Information System (INIS)

    Schiffer, Wynne K.; Liebling, Courtney N.B.; Patel, Vinal; Dewey, Stephen L.

    2007-01-01

    Although imaging studies in and of themselves have significant contributions to the study of human behavior, imaging in drug abuse has a much broader agenda. Drugs of abuse bind to molecules in specific parts of the brain in order to produce their effects. Positron emission tomography (PET) provides a unique opportunity to track this process, capturing the kinetics with which an abused compound is transported to its site of action. The specific examples discussed here were chosen to illustrate how PET can be used to map the regional distribution and kinetics of compounds that may or may not have abuse liability. We also discussed some morphological and functional changes associated with drug abuse and different stages of recovery following abstinence. PET measurements of functional changes in the brain have also led to the development of several treatment strategies, one of which is discussed in detail here. Information such as this becomes more than a matter of academic interest. Such knowledge can provide the bases for anticipating which compounds may be abused and which may not. It can also be used to identify biological markers or changes in brain function that are associated with progression from drug use to drug abuse and also to stage the recovery process. This new knowledge can guide legislative initiatives on the optimal duration of mandatory treatment stays, promoting long-lasting abstinence and greatly reducing the societal burden of drug abuse. Imaging can also give some insights into potential pharmacotherapeutic targets to manage the reinforcing effects of addictive compounds, as well as into protective strategies to minimize their toxic consequences

  19. Targeting the treatment of drug abuse with molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Schiffer, Wynne K. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)], E-mail: wynne@bnl.gov; Liebling, Courtney N.B.; Patel, Vinal; Dewey, Stephen L. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)

    2007-10-15

    Although imaging studies in and of themselves have significant contributions to the study of human behavior, imaging in drug abuse has a much broader agenda. Drugs of abuse bind to molecules in specific parts of the brain in order to produce their effects. Positron emission tomography (PET) provides a unique opportunity to track this process, capturing the kinetics with which an abused compound is transported to its site of action. The specific examples discussed here were chosen to illustrate how PET can be used to map the regional distribution and kinetics of compounds that may or may not have abuse liability. We also discussed some morphological and functional changes associated with drug abuse and different stages of recovery following abstinence. PET measurements of functional changes in the brain have also led to the development of several treatment strategies, one of which is discussed in detail here. Information such as this becomes more than a matter of academic interest. Such knowledge can provide the bases for anticipating which compounds may be abused and which may not. It can also be used to identify biological markers or changes in brain function that are associated with progression from drug use to drug abuse and also to stage the recovery process. This new knowledge can guide legislative initiatives on the optimal duration of mandatory treatment stays, promoting long-lasting abstinence and greatly reducing the societal burden of drug abuse. Imaging can also give some insights into potential pharmacotherapeutic targets to manage the reinforcing effects of addictive compounds, as well as into protective strategies to minimize their toxic consequences.

  20. Molecular weight-dependent degradation and drug release of surface-eroding poly(ethylene carbonate)

    DEFF Research Database (Denmark)

    Bohr, Adam; Wang, Yingya; Harmankaya, Necati

    2017-01-01

    Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough...... physicochemical characterization of diverse PEC (molecular weights: 85, 110, 133, 174 and 196 kDa), the degradation and drug release behavior of rifampicin- and bovine serum albumin-loaded PEC films was investigated in vitro (in the presence and absence of cholesterol esterase), in cell culture (RAW264.......7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half...

  1. Bioactive compounds fractionated from endophyte Streptomyces SUK 08 with promising ex-vivo antimalarial activity

    Directory of Open Access Journals (Sweden)

    Noraziah Mohamad Zin

    2017-12-01

    Full Text Available Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract. Methods: The activities of SUK 08 crude extract were evaluated by using the Plasmodium lactate dehydrogenase assay and synchronization test against rodent malaria parasite Plasmodium berghei, instead of human malarial parasite Plasmodium falciparum. The cytotoxicity of the crude extract was determined by MTT assay. The crude extract was analyzed by thin-layer chromatography and gas chromatography–mass spectrophotometry. Results: The ethyl acetate crude extract showed very promising antimalarial activity with IC50 of 1.25 mg/mL. The synchronization tests showed that ethyl acetate extraction could inhibit all stages of the Plasmodium life cycle, but it was most effective at the Plasmodium ring stage. On the basis of a MTT assay on Chang Liver cells, ethyl acetate and ethanol demonstrated IC50 values of >1.0 mg/mL. The IC50 of parasitemia at 5% and 30% for this extract was lower than chloroquine. Thin-layer chromatography, with 1: 9 ratio of ethyl acetate: hexane, was used to isolate several distinct compounds. Based on gas chromatography–mass spectrophotometry analysis, three core structures were identified as cyclohexane, butyl propyl ester, and 2,3-heptanedione. Structurally, these compounds were similar to currently available antimalarial drugs. Conclusions: The results suggest that compounds isolated from Streptomyces SUK 08 are viable antimalarial drug candidates that require further investigations. Keywords: Butyl–propyl–ester, Cyclohexane, 2,3-Heptanedione, Endophyte, Streptomyces, Antimalarial

  2. Molecular Analysis of Multi-Drug Resistance (MDR) in ...

    African Journals Online (AJOL)

    The recent emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis has become an area of great concern. This occurs as a result of inadequate treatment management of tuberculosis which provides a selective pressure that favours the emergence of resistant mutants with enhanced infectiousness.

  3. High Fidelity Drug Repurposing, Molecular Profiling, and Cell Reprogramming

    Science.gov (United States)

    2016-09-01

    the research community and, ultimately, directly to patients. For example, while family history , PSA profile and an abnormal digital rectal exam are...e.g. active surveillance, radical prostatectomy, radiation or hormonal /chemo therapies). CRCs are perfect for medium and high throughput drug

  4. Multi-drug resistance and molecular pattern of erythromycin and ...

    African Journals Online (AJOL)

    The appearance and dissemination of penicillin resistant and macrolide resistant Streptococcus pneumoniae strains has caused increasing concern worldwide. The aim of this study was to survey drug resistance and genetic characteristics of macrolide and penicillin resistance in S. pneumoniae. This is a cross-sectional ...

  5. Interventions to improve the use of antimalarials in south-east Asia: an overview.

    Science.gov (United States)

    Gomes, M; Wayling, S; Pang, L

    1998-01-01

    There are few drugs for malaria, and those which are available for use are subject to rapid development of resistance. Curiously, little effort has been made to improve drug use in malaria-endemic countries and to assess the benefits of such improvements. Advances can be made in public understanding of the value of ingesting a full regimen of antimalarials, in order to achieve complete cure, and in improving simple technologies (blister packaging) to achieve the same result. Better efforts can be made to reduce the availability of fake or substandard drugs in the marketplace. In this article, we describe the outcome of a concerted effort to improve drug compliance and drug quality in an area of multidrug resistance for malaria. These research efforts, guided by the Task Force for Improved Use of Antimalarials, characterized the problems in drug compliance in South-East Asia, and developed interventions to improve drug use in the various countries. Interventions involved drug packaging, public information campaigns, and assessments of drug quality. Results show that blister packaging worked best to improve drug compliance and that the increased cost of packaged medication did not limit its use. Drug quality was a major problem in unregulated countries and should be improved.

  6. Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

    Directory of Open Access Journals (Sweden)

    H. M. Adnan Hameed

    2018-04-01

    Full Text Available Tuberculosis (TB is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and total drug-resistant tuberculosis (TDR-TB, due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

  7. Molecular docking, spectroscopic studies and quantum calculations on nootropic drug.

    Science.gov (United States)

    Uma Maheswari, J; Muthu, S; Sundius, Tom

    2014-04-05

    A systematic vibrational spectroscopic assignment and analysis of piracetam [(2-oxo-1-pyrrolidineacetamide)] have been carried out using FT-IR and FT-Raman spectral data. The vibrational analysis was aided by an electronic structure calculation based on the hybrid density functional method B3LYP using a 6-311G++(d,p) basis set. Molecular equilibrium geometries, electronic energies, IR and Raman intensities, and harmonic vibrational frequencies have been computed. The assignments are based on the experimental IR and Raman spectra, and a complete assignment of the observed spectra has been proposed. The UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies and the maximum absorption wavelengths λmax were determined by the time-dependent DFT (TD-DFT) method. The geometrical parameters, vibrational frequencies and absorption wavelengths were compared with the experimental data. The complete vibrational assignments are performed on the basis of the potential energy distributions (PED) of the vibrational modes in terms of natural internal coordinates. The simulated FT-IR, FT-Raman, and UV spectra of the title compound have been constructed. Molecular docking studies have been carried out in the active site of piracetam by using Argus Lab. In addition, the potential energy surface, HOMO and LUMO energies, first-order hyperpolarizability and the molecular electrostatic potential have been computed. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Molecular weight-dependent degradation and drug release of surface-eroding poly(ethylene carbonate).

    Science.gov (United States)

    Bohr, Adam; Wang, Yingya; Harmankaya, Necati; Water, Jorrit J; Baldursdottír, Stefania; Almdal, Kristoffer; Beck-Broichsitter, Moritz

    2017-06-01

    Poly(ethylene carbonate) (PEC) is a unique biomaterial showing significant potential for controlled drug delivery applications. The current study investigated the impact of the molecular weight on the biological performance of drug-loaded PEC films. Following the preparation and thorough physicochemical characterization of diverse PEC (molecular weights: 85, 110, 133, 174 and 196kDa), the degradation and drug release behavior of rifampicin- and bovine serum albumin-loaded PEC films was investigated in vitro (in the presence and absence of cholesterol esterase), in cell culture (RAW264.7 macrophages) and in vivo (subcutaneous implantation in rats). All investigated samples degraded by means of surface erosion (mass loss, but constant molecular weight), which was accompanied by a predictable, erosion-controlled drug release pattern. Accordingly, the obtained in vitro degradation half-lives correlated well with the observed in vitro half-times of drug delivery (R 2 =0.96). Here, the PEC of the highest molecular weight resulted in the fastest degradation/drug release. When incubated with macrophages or implanted in animals, the degradation rate of PEC films superimposed the results of in vitro incubations with cholesterol esterase. Interestingly, SEM analysis indicated a distinct surface erosion process for enzyme-, macrophage- and in vivo-treated polymer films in a molecular weight-dependent manner. Overall, the molecular weight of surface-eroding PEC was identified as an essential parameter to control the spatial and temporal on-demand degradation and drug release from the employed delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    Science.gov (United States)

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations.

    Science.gov (United States)

    Jain, Vaibhav; Maiti, Prabal K; Bharatam, Prasad V

    2016-09-28

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH 2 ) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH 2 ) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH 2 ) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  11. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    Science.gov (United States)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  12. Antimalarial efficacy of hydroxyethylapoquinine (SN-119) and its derivatives.

    Science.gov (United States)

    Sanders, Natalie G; Meyers, David J; Sullivan, David J

    2014-01-01

    Quinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC50) of 100 to 200 nM against Plasmodium falciparum quinine-sensitive strain 3D7 (IC50, 56 nM). Only HEAQD demonstrated activity against quinine-tolerant P. falciparum strains Dd2 and INDO with IC50s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC50 of 313 nM. In the lethal mouse malaria model Plasmodium berghei ANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC50 ≥ 90 μM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC50s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quinine in vitro and in vivo for Plasmodium inhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.

  13. 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.

  14. Malaria healthcare policy change in Kenya: implications on sales and marketing of antimalarials.

    Science.gov (United States)

    Ngure, Peter K; Nyaoke, Lorraine; Minja, David

    2012-03-01

    Malaria healthcare policy change in Kenya aimed at improving the control of malaria but faced a number of challenges in implementation related to marketing of the drugs. This research investigated the effect of the change of the national malaria policy on drug sales and strategic marketing responses of antimalarial pharmaceutical companies in Kenya. A descriptive cross-sectional design was employed to describe the existing state of antimalarials market in Kenya after the change of the malaria healthcare policy. Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recorded a 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by all the companies. Further, SPs (which had been replaced as first-line therapy for malaria) registered good sales. In most cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs and generic antimalarial medicines exceeded that of Coartem® for most distributors. The most common change made to marketing strategies by distributors (62.5%) was to increase imports of antimalarials. A total of 40% of the manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the fact that continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence of malaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensure drugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the national guidelines.

  15. Unique molecular landscapes in cancer: implications for individualized, curated drug combinations.

    Science.gov (United States)

    Wheler, Jennifer; Lee, J Jack; Kurzrock, Razelle

    2014-12-15

    With increasingly sophisticated technologies in molecular biology and "omic" platforms to analyze patients' tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next-generation sequencing. Among 57 consecutive patients, no two had the same molecular portfolio. Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill-suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a "mismatch" between our traditional clinical trials system that selects patients based on common characteristics to evaluate a drug (drug-centric approach) and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach). ©2014 American Association for Cancer Research.

  16. Molecularly imprinted polymers based drug delivery devices: a way to application in modern pharmacotherapy. A review.

    Science.gov (United States)

    Luliński, Piotr

    2017-07-01

    This review presents the current status of molecularly imprinted polymers (MIPs) for drug delivery, in particular the studies that focus on biocompatibility, cytotoxicity, and in vitro or in vivo behavior of MIPs. It also shows the limitations that hamper the introduction of MIPs to pharmacotherapy and prevent this class of polymers from commercialization. MIPs are promising materials in the construction of drug delivery devices because they can provide improved delivery profiles or longer release times and deliver the drugs in the feedback regulated way, which is extremely important in modern pharmacotherapy. Here, a brief overview of the imprinting process and a concise description of drug release mechanisms from the imprinted materials will be presented followed by the discussion of potential MIP drug delivery devices for ocular, dermal, intravenous and oral routes of administration. Finally, future prospects for imprinted drug delivery forms will be outlined. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Electroporation of Skin Stratum Corneum Lipid Bilayer and Molecular Mechanism of Drug Transport: A Molecular Dynamics Study.

    Science.gov (United States)

    Gupta, Rakesh; Rai, Beena

    2018-04-30

    Skin electroporation has been used significantly to increase the drug permeation. However, molecular mechanism, which resulted in enhancement of flux through skin, is still not known. In this study, extensive atomistic molecular dynamics simulation of skin lipids (made up of ceramide (CER), cholesterol (CHOL) and free fatty acid (FFA)) have been performed at various external electric field. We show for the first time the pore formation in the skin lipid bilayer during the electroporation. We show the effect of applied external electrical field on the pore formation dynamics in lipid bilayer of different size and composition. The pore formation and resealing kinetics were different and was found to be highly dependent on the composition of skin lipid bilayer. The pore formation time decreased with increase in the bilayer size. The pore sustaining electric field was found to be in the range of 0.20-0.25 V/nm for equimolar CER, CHOL and FFA lipid bilayer. The skin lipid bilayer (1:1:1), sealed itself within 20 ns after the removal of external electric field. We also present the molecular mechanism of enhancement of drug permeation in the presence of external field as compared to the passive diffusion. The molecular level understanding obtained here could help in optimizing/designing the electroporation experiments for effective drug delivery. For a given skin composition and size of drug molecule, the combination of pore formation time and pore growth model can be used to know aproiri the desired electric field and time for application of electric field.

  18. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity.

    Science.gov (United States)

    Rijpma, Sanna R; van den Heuvel, Jeroen J M W; van der Velden, Maarten; Sauerwein, Robert W; Russel, Frans G M; Koenderink, Jan B

    2014-09-13

    Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins. The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1-4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins. A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine. Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials

  19. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica.

    Science.gov (United States)

    Chinchilla, Misael; Valerio, Idalia; Sánchez, Ronald; Mora, Víctor; Bagnarello, Vanessa; Martínez, Laura; Gonzalez, Antonieta; Vanegas, Juan Carlos; Apestegui, Alvaro

    2012-06-01

    Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biol6gica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9 microg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  20. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica

    Directory of Open Access Journals (Sweden)

    Misael Chinchilla

    2012-06-01

    Full Text Available Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB, were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae; Xanthosoma undipes (Araceae; Iriartea deltoidea (Arecaceae; Neurolaena lobata (Asteraceae; Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae; Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae; Hampea appendiculata (Malvaceae; Ruagea glabra, Guarea glabra (Meliaceae; Psidium guajava (Myrtaceae; Bocconia frutescens (Papaveraceae; Piper friedrichsthalii (Piperaceae; Clematis dioica (Ranunculaceae; Prunus annularis (Rosaceae; Siparuna thecaphora (Siparunaceae; Solanum arboreum, Witheringia solanácea (Solanaceae; Ticodendrum incognitum (Ticodendraceae; Heliocarpus appendiculatus (Tiliaceae and Myriocarpa longipes (Urticaceae. We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  1. Synthesis and antimalarial activity evaluation of 3-(3-(7-chloroquinolin-4-ylaminopropyl-1,3-thiazinan-4-one derivatives

    Directory of Open Access Journals (Sweden)

    Mukesh Kumar Kumawat

    2016-09-01

    Full Text Available Some novel derivatives of 3-(3-(7-chloroquinolin-4-ylaminopropyl-1,3-thiazinan-4-one were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro antimalarial activity against chloroquine sensitive strain of Plasmodium falciparum (RKL-2 employing chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities towards the parasite in comparison to the standard. It was found that antimalarial activity of 3-(3-(7-chloroquinolin-4-ylaminopropyl-2-(4-bromophenyl-1,3-thiazinan-4-one was marginally superior than all the compounds evaluated.

  2. Self-medication with antibiotics and antimalarials in the community of Khartoum State, Sudan.

    Science.gov (United States)

    Awad, Abdelmoneim; Eltayeb, Idris; Matowe, Lloyd; Thalib, Lukman

    2005-08-12

    To estimate the prevalence of self medication with antibiotics and antimalarials in Khartoum State, Sudan and evaluate factors associated with self medication. A pre-tested questionnaire was used to collect data from a sample of 600 households, (1750 adult persons), selected from three cities in Khartoum State, Sudan, using a multistage stratified clustered sampling. One thousand two hundred and ninety three (73.9%) of the study population had used antibiotics or antimalarials without a prescription within one month prior to the study. Eight hundred and forty one (48.1%) of the respondents agreed that they have used antibiotics, 43.4% used antimalarials, while 17.5% used both. Self medication with either antibiotics/ antimalarials was found to be significantly associated with age, income, gender and level of education. Overall, self medication with any antibiotics or antimalarials was least common among the > or = 60 years compared to youngest age group (OR: 0.07; 0.04 -0.11) and most common among the female gender (OR: 1.8; 1.4 -2.4), the middle income group (OR: 3.7; 2.6-5.3) and the university graduates. Self medication with antibiotic was found to be significantly higher among females (OR: 1.5; 1.16-1.87), middle aged respondents aged 40-59 (OR: 2.1; 1.5-3.0) compared to younger respondents. Lower income and higher level of education was also found to be significantly associated with the increase risk of self medicating with antibiotic. Increase risk for self medication with antimalarials were, however, found to be significantly associated with male gender and younger age group of self-medication was financial constraints. The main source of medicines was the private pharmacies, which were regarded as a cheaper alternative to other primary healthcare sources. The prevalence of self-medication with antibiotics/antimalarials in Khartoum State, Sudan is alarmingly high. Self medication behaviour varies significantly with a number of socio-economic characteristics

  3. Vibrational spectroscopy modeling of a drug in molecular solvents and enzymes

    Science.gov (United States)

    Devereux, Christian J.; Fulfer, Kristen D.; Zhang, Xiaoliu; Kuroda, Daniel G.

    2017-09-01

    Modeling of drugs in enzymes is of immensurable value to many areas of science. We present a theoretical study on the vibrational spectroscopy of Rilpivirine, a HIV reverse transcriptase inhibitor, in conventional solvents and in clinically relevant enzymes. The study is based on vibrational spectroscopy modeling of the drug using molecular dynamics simulations, DFT frequency maps, and theory. The modeling of the infrared lineshape shows good agreement with experimental data for the drug in molecular solvents where the local environment motions define the vibrational band lineshape. On the other hand, the theoretical description of the drug in the different enzymes does not match previous experimental findings indicating that the utilized methodology might not apply to heterogeneous environments. Our findings show that the lack of reproducibility might be associated with the development of the frequency map which does not contain all of the possible interactions observed in such systems.

  4. Molecular biological studies on the human radioresistance and drug resistance

    International Nuclear Information System (INIS)

    Kim, Chang Min; Hong, Weon Seon

    1992-04-01

    We irradiated the MKN45 and PC14 cell lines with 500 rads and also established the adriamycin-resistant and cis-platinum resistant cell line. The genomic DNA and total RNA were extracted and subjected to the Southern and Northern analysis using various probes including heat shock protein 70, MDR1, fos, TGFb etc. The mRNA transcript was increased 1 hour after the irradiation and sustained during the 48 hours and returned to the level of pre-irradiation. No significant change was observed with the drug resistant cell lines at the level of gene dosage. We suggest that the marked increase of the hsp70 transcript is very important finding and is believed to be a good candidate for the modulation of the cellular response to irradiation and the radioresistance. (Author)

  5. Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

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    Jiezhong Chen

    2017-11-01

    Full Text Available Antipsychotic drugs (APDs are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1 APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2 APD-induced obesity can result in high levels of free fatty acids (FFA and inflammation, which can also cause insulin resistance. (3 APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

  6. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  7. 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

    Science.gov (United States)

    Guimarães, Daniel Silqueira Martins; da Fonseca, Amanda Luisa; Batista, Ronan; Comar, Moacyr; de Oliveira, Alaíde Braga; Taranto, Alex Gutterres; Varotti, Fernando de Pilla

    2015-01-01

    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. PMID:25946251

  8. 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.

  9. 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.

    Science.gov (United States)

    Guimarães, Daniel Silqueira Martins; Fonseca, Amanda Luisa da; Batista, Ronan; Comar Junior, Moacyr; Oliveira, Alaíde Braga de; Taranto, Alex Gutterres; Varotti, Fernando de Pilla

    2015-04-01

    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.

  10. Fast Metabolic Response to Drug Intervention Through Analysis on a Miniaturized, Highly Integrated Molecular Imaging System

    OpenAIRE

    Wang, Jun; Hwang, Kiwook; Braas, Daniel; Dooraghi, Alex; Nathanson, David; Campbell, Dean O.; Gu, Yuchao; Sandberg, Troy; Mischel, Paul; Radu, Caius; Chatziioannou, Arion F.; Phelps, Michael E.; Christofk, Heather; Heath, James R.

    2013-01-01

    We report on a radiopharmaceutical imaging platform designed to capture the kinetics of cellular responses to drugs. Methods: A portable in vitro molecular imaging system comprising a microchip and a β-particle imaging camera permitted routine cell-based radioassays of small numbers of either suspended or adherent cells. We investigated the kinetics of responses of model lymphoma and glioblastoma cancer cell lines to ^(18)F-FDG uptake after drug exposure. Those responses were correlated with ...

  11. [From Purkinje's pharmacologic observations to molecular drug interactions].

    Science.gov (United States)

    Kvĕtina, J

    1998-11-01

    The 650th anniversary of the foundation of Charles University (7 April 1348) in Prague has initiated a number of historical surveys of the subjects which has been taught at the University for a longer period of time. The disciplines connected with pharmacotherapy were being developed in an empirical conception at the University from the second half of the 14th century but the beginnings of experimental drug research date as late as the mid-19th century. The present survey of the history of "the sciences of medicaments" therefore attempts to outline in short entries the developmental stages of pharmaceutical and pharmacological investigations in the territory of Bohemia and Moravia in about recent 150 years. The arrangement of data is chronological; in the part covering the second half of the 20th century the research of a predominantly exploratory character (universities and academic institutions and their representatives) and research aimed primarily to innovate medicaments (research institutions of pharmaceutical industry and clinical pharmacology and some of their representatives) are treated separately.

  12. High adherence to antimalarials and antibiotics under integrated community case management of illness in children less than five years in eastern Uganda.

    Directory of Open Access Journals (Sweden)

    Joan N Kalyango

    Full Text Available BACKGROUND: Development of resistance to first line antimalarials led to recommendation of artemisinin based combination therapies (ACTs. High adherence to ACTs provided by community health workers (CHWs gave reassurance that community based interventions did not increase the risk of drug resistance. Integrated community case management of illnesses (ICCM is now recommended through which children will access both antibiotics and antimalarials from CHWs. Increased number of medicines has been shown to lower adherence. OBJECTIVE: To compare adherence to antimalarials alone versus antimalarials combined with antibiotics under ICCM in children less than five years. METHODS: A cohort study was nested within a cluster randomized trial that had CHWs treating children less than five years with antimalarials and antibiotics (intervention areas and CHWs treating children with antimalarials only (control areas. Children were consecutively sampled from the CHWs' registers in the control areas (667 children; and intervention areas (323 taking antimalarials only and 266 taking antimalarials plus antibiotics. The sampled children were visited at home on day one and four of treatment seeking. Adherence was assessed using self reports and pill counts. RESULTS: Adherence in the intervention arm to antimalarials alone and antimalarials plus antibiotics arm was similar (mean 99% in both groups but higher than adherence in the control arm (antimalarials only (mean 96%. Forgetfulness (38% was the most cited reason for non-adherence. At adjusted analysis: absence of fever (OR = 3.3, 95%CI =1.6-6.9, seeking care after two or more days (OR = 2.2, 95%CI = 1.3-3.7, not understanding instructions given (OR = 24.5, 95%CI = 2.7-224.5, vomiting (OR = 2.6, 95%CI = 1.2-5.5, and caregivers' perception that the child's illness was not severe (OR = 2.0, 95%CI = 1.1-3.8 were associated with non-adherence. CONCLUSIONS: Addition of antibiotics to antimalarials did not lower adherence

  13. In vitro antioxidant and antimalarial activities of leaves, pods and bark extracts of Acacia nilotica (L.) Del.

    Science.gov (United States)

    Sadiq, Muhammad Bilal; Tharaphan, Pattamon; Chotivanich, Kesinee; Tarning, Joel; Anal, Anil Kumar

    2017-07-18

    The emergence of drug resistant malaria is threatening our ability to treat and control malaria in the Southeast Asian region. There is an urgent need to develop novel and chemically diverse antimalarial drugs. This study aimed at evaluating the antimalarial and antioxidant potentials of Acacia nilotica plant extracts. The antioxidant activities of leaves, pods and bark extracts were determined by standard antioxidant assays; reducing power capacity, % lipid peroxidation inhibition and ferric reducing antioxidant power assay. The antimalarial activities of plant extracts against Plasmodium falciparum parasites were determined by the 48 h schizont maturation inhibition assay. Further confirmation of schizonticide activity of extracts was made by extending the incubation period up to 96 h after removing the plant extract residues from parasites culture. Inhibition assays were analyzed by dose-response modelling. In all antioxidant assays, leaves of A. nilotica showed higher antioxidant activity than pods and bark. Antimalarial IC 50 values of leaves, pods and bark extracts were 1.29, 4.16 and 4.28 μg/ml respectively, in the 48 h maturation assay. The IC 50 values determined for leaves, pods and bark extracts were 3.72, 5.41 and 5.32 μg/ml respectively, after 96 h of incubation. All extracts inhibited the development of mature schizont, indicating schizonticide activity against P. falciparum. A. nilotica extracts showed promising antimalarial and antioxidant effects. However, further investigation is needed to isolate and identify the active components responsible for the antimalarial and antioxidant effects.

  14. Toxicology and drug delivery by cucurbit[n]uril type molecular containers.

    Science.gov (United States)

    Hettiarachchi, Gaya; Nguyen, Duc; Wu, Jing; Lucas, Derick; Ma, Da; Isaacs, Lyle; Briken, Volker

    2010-05-06

    Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system. In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB[7] molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target. Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.

  15. [Economic Loss of Remaining Contents in Molecular Target Drug Preparation and the Simulation for Cost Saving].

    Science.gov (United States)

    Usami, Eiseki; Kimura, Michio; Fukuoka, Tomohiro; Okada, Kazutomo; Yoshimura, Tomoaki

    2016-06-01

    While preparing an anticancer drug, even if it is an expensive molecular target drug, the remainder is not divided and saved for use in other patients; instead, it is discarded, resulting in waste of medical resources. In this study, we examined the economic loss in terms of medical costs by calculating the discarded amounts of 12 commonly used molecular target drugs at Ogaki Municipal Hospital, Japan between January 2012 and December 2014. We found, on average, that drugs valued at ¥ 52,593,182 were discarded annually. In particular, the discarded amounts of relatively expensive drugs, such as bevacizumab, bortezomib, and rituximab, were valued at ¥ 16,646,300, ¥ 15,866,289, and ¥ 8,401,324, respectively. Among these, the average amount of waste per administration of bortezomib was particularly expensive, at a cost of ¥ 67,325. Bortezomib is a commonly used treatment, resulting in excessive cumulative discarded cost. In an effort to save cost, we should consider using small capacity standard injections. Development of a simulation that used the remaining drug contents from only 1 day showed that bevacizumab alone accounts for an average cost saving of ¥1 2,542,191(75.3%) per year. This study suggests that effectively utilizing the remaining drug contents would ensure efficient use of medical resources, thereby reducing economic losses.

  16. Population Genetics and Drug Resistance Markers: An Essential for Malaria Surveillance in Pakistan

    International Nuclear Information System (INIS)

    Raza, A.; Beg, M.A.

    2013-01-01

    Plasmodium (P.) vivax is the prevalent malarial species accounting for 70% of malaria cases in Pakistan. However, baseline epidemiological data on P. vivax population structure and drug resistance are lacking from Pakistan. For population structure studies, molecular genetic markers, circumsporozoite protein (csp) and merozoite surface protein-1 (msp-1) are considered useful as these play an important role in P. vivax survival under immune and environmental pressure. Furthermore, these genes have also been identified as suitable candidates for vaccine development. While efforts for effective vaccine are underway, anti-malarial agents remain the mainstay for control. Evidence of resistance against commonly used anti-malarial agents, particularly Sulphadoxine-Pyrimethamine (SP) is threatening to make this form of control defunct. Therefore, studies on drug resistance are necessary so that anti-malarial treatment strategies can be structured and implemented accordingly by the Malaria Control Program, Pakistan. This review aims to provide information on genetic markers of P. vivax population structure and drug resistance and comment on their usefulness in molecular surveillance and control. (author)

  17. Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

    Directory of Open Access Journals (Sweden)

    Alaíde Braga de Oliveira

    2009-08-01

    Full Text Available Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

  18. The counterfeit anti-malarial is a crime against humanity: a systematic review of the scientific evidence

    Science.gov (United States)

    2014-01-01

    Background The counterfeiting of anti-malarials represents a form of attack on global public health in which fake and substandard anti-malarials serve as de facto weapons of mass destruction, particularly in resource-constrained endemic settings, where malaria causes nearly 660,000 preventable deaths and threatens millions of lives annually. It has been estimated that fake anti-malarials contribute to nearly 450,000 preventable deaths every year. This crime against humanity is often underestimated or ignored. This study attempts to describe and characterize the direct and indirect effects of counterfeit anti-malarials on public health, clinical care and socio-economic conditions. Methods A search was performed using key databases, WHO documents, and English language search engines. Of 262 potential articles that were identified using a fixed set of criteria, a convenience sample of 105 appropriate articles was selected for this review. Results Artemisinin-based combination therapy (ACT) is an important tool in the fight against malaria, but a sizable number of patients are unable to afford to this first-line treatment. Consequently, patients tend to procure cheaper anti-malarials, which may be fake or substandard. Forensic palynology reveals that counterfeits originate in Asia. Fragile drug regulations, ineffective law-enforcement agencies and corruption further burden ailing healthcare facilities. Substandard/fake anti-malarials can cause (a) economic sabotage; (b) therapeutic failure; (c) increased risk of the emergence and spread of resistant strains of Plasmodium falciparum and Plasmodium vivax; (d) an undermining of trust/confidence in healthcare stakeholders/systems; and, (e) serious side effects or death. Conclusion Combating counterfeit anti-malarials is a complex task due to limited resources and poor techniques for the detection and identification of fake anti-malarials. This situation calls for sustainable, global, scientific research and policy change

  19. The counterfeit anti-malarial is a crime against humanity: a systematic review of the scientific evidence.

    Science.gov (United States)

    Karunamoorthi, Kaliyaperumal

    2014-06-02

    The counterfeiting of anti-malarials represents a form of attack on global public health in which fake and substandard anti-malarials serve as de facto weapons of mass destruction, particularly in resource-constrained endemic settings, where malaria causes nearly 660,000 preventable deaths and threatens millions of lives annually. It has been estimated that fake anti-malarials contribute to nearly 450,000 preventable deaths every year. This crime against humanity is often underestimated or ignored. This study attempts to describe and characterize the direct and indirect effects of counterfeit anti-malarials on public health, clinical care and socio-economic conditions. A search was performed using key databases, WHO documents, and English language search engines. Of 262 potential articles that were identified using a fixed set of criteria, a convenience sample of 105 appropriate articles was selected for this review. Artemisinin-based combination therapy (ACT) is an important tool in the fight against malaria, but a sizable number of patients are unable to afford to this first-line treatment. Consequently, patients tend to procure cheaper anti-malarials, which may be fake or substandard. Forensic palynology reveals that counterfeits originate in Asia. Fragile drug regulations, ineffective law-enforcement agencies and corruption further burden ailing healthcare facilities. Substandard/fake anti-malarials can cause (a) economic sabotage; (b) therapeutic failure; (c) increased risk of the emergence and spread of resistant strains of Plasmodium falciparum and Plasmodium vivax; (d) an undermining of trust/confidence in healthcare stakeholders/systems; and, (e) serious side effects or death. Combating counterfeit anti-malarials is a complex task due to limited resources and poor techniques for the detection and identification of fake anti-malarials. This situation calls for sustainable, global, scientific research and policy change. Further, responsible stakeholders in

  20. PBCA-based polymeric microbubbles for molecular imaging and drug delivery

    NARCIS (Netherlands)

    Koczera, Patrick; Appold, Lia; Shi, Yang; Liu, Mengjiao; Dasgupta, Anshuman; Pathak, Vertika; Ojha, Tarun; Fokong, Stanley; Wu, Zhuojun; Van Zandvoort, Marc; Iranzo, Olga; Kuehne, Alexander J C; Pich, Andrij; Kiessling, Fabian; Lammers, Twan

    2017-01-01

    Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. We describe different types of targeted and drug-loaded poly(n-butyl cyanoacrylate) (PBCA) MB, and demonstrate their suitability for multiple biomedical applications, including molecular US imaging and US-mediated

  1. Clinical and Molecular Epidemiology of Infective Endocarditis in Intravenous Drug Users

    Directory of Open Access Journals (Sweden)

    Pei-Jiuan Chao

    2009-12-01

    Conclusion: Our results suggest that coinfection with hepatitis C was common in intravenous drug users with IE, and that molecular patterns of MRSA isolates had high similarity. SCCmec type III, which is usually hospital-acquired, could have caused the community-associated MRSA endocarditis in our patients.

  2. Molecular Docking of Enzyme Inhibitors: A Computational Tool for Structure-Based Drug Design

    Science.gov (United States)

    Rudnitskaya, Aleksandra; Torok, Bela; Torok, Marianna

    2010-01-01

    Molecular docking is a frequently used method in structure-based rational drug design. It is used for evaluating the complex formation of small ligands with large biomolecules, predicting the strength of the bonding forces and finding the best geometrical arrangements. The major goal of this advanced undergraduate biochemistry laboratory exercise…

  3. Fulminant hepatic failure following marijuana drug abuse: Molecular adsorbent recirculation system therapy

    Directory of Open Access Journals (Sweden)

    G Swarnalatha

    2013-01-01

    Full Text Available Marijuana is used for psychoactive and recreational purpose. We report a case of fulminant hepatic failure following marijuana drug abuse who recovered following artificial support systems for acute liver failure. There is no published literature of management of marijuana intoxication with molecular adsorbent recirculation system (MARS. MARS is effective and safe in patients with fulminant hepatic failure following marijuana intoxication.

  4. The impact of treatment density and molecular weight for fractional laser-assisted drug delivery

    DEFF Research Database (Denmark)

    Haak, Christina S; Bhayana, Brijesh; Farinelli, William A

    2012-01-01

    treatment density (% of skin occupied by channels) and molecular weight (MW) for fractional CO(2) laser-assisted drug delivery. AFXL substantially increased intra- and transcutaneous delivery of polyethylene glycols (PEGs) in a MW range from 240 to 4300 Da (Nuclear Magnetic Resonance, p...

  5. Micellar solubilization of poorly water-soluble drugs: effect of surfactant and solubilizate molecular structure.

    Science.gov (United States)

    Vinarov, Zahari; Katev, V; Radeva, D; Tcholakova, S; Denkov, N D

    2018-04-01

    This study aims to clarify the role of surfactant and drug molecular structures on drug solubility in micellar surfactant solutions. (1) Rationale for surfactant selection is provided; (2) the large data set can be used for validation of the drug solubility parameters used in oral absorption models. Equilibrium solubility of two hydrophobic drugs and one model hydrophobic steroid in micellar solutions of 19 surfactants was measured by HPLC. The drug solubilization locus in the micelles was assessed by UV spectrometry. Danazol is solubilized much more efficiently than fenofibrate by ionic surfactants due to ion-dipole interactions between the charged surfactant head groups and the polar steroid backbone. Drug solubilization increases linearly with the increase of hydrophobic chain length for all studied surfactant types. Addition of 1-3 ethylene oxide (EO) units in the head group of dodecyl sulfate surfactants reduces significantly the solubilization of both studied drugs and decreases linearly the solubilization locus polarity of fenofibrate. The locus of fenofibrate solubilization is in the hydrophobic core of nonionic surfactant micelles and in the palisade layer of ionic surfactant micelles. Highest drug solubility can be obtained by using surfactants molecules with long chain length coupled with hydrophilic head group that provides additional drug-surfactant interactions (i.e. ion-dipole) in the micelles.

  6. In vitro EFFICACY OF ACT DRUGS ON Plasmodium falciparum ...

    African Journals Online (AJOL)

    userpc

    Resistance of P. falciparum to the common and cheap antimalarial drugs chloroquine and sulpadoxyne-pyrimethamine has a profound public health impact in malaria endemic areas like Nigeria. This increasing drug resistance has necessitated change in antimalarial therapy in. Africa. In view of this, the World Health.

  7. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin.

    Science.gov (United States)

    Elf, S; Lin, R; Xia, S; Pan, Y; Shan, C; Wu, S; Lonial, S; Gaddh, M; Arellano, M L; Khoury, H J; Khuri, F R; Lee, B H; Boggon, T J; Fan, J; Chen, J

    2017-01-12

    The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.

  8. 4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies.

    Science.gov (United States)

    Kumar, Deepak; Khan, Shabana I; Tekwani, Babu L; Ponnan, Prija; Rawat, Diwan S

    2015-01-07

    A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. New active drugs against liver stages of Plasmodium predicted by molecular topology.

    NARCIS (Netherlands)

    Mahmoudi, N.; Garcia-Domenech, R.; Galvez, J.; Farhati, K.; Franetich, J.F.; Sauerwein, R.W.; Hannoun, L.; Derouin, F.; Danis, M.; Mazier, D.

    2008-01-01

    We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of Plasmodium yoelii in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices

  10. In vitro antimalarial activity of extracts of three plants used in the traditional medicine of India.

    Science.gov (United States)

    Bhat, G P; Surolia, N

    2001-10-01

    In an attempt to search for new antimalarial drugs, we studied plants used by traditional healers of southwest India to treat malaria. Aqueous and organic solvent extracts obtained from specific parts of the plants Swertia chirata, Carica papaya, and Citrus sinensis were tested on malaria strain Plasmodium falciparum FCK 2 in vitro. The temperatures of extraction were the same as that used by the traditional healers in their plant preparations. Visual evaluation of the antimalarial activity of the plant extracts on thin blood smears was followed by quantification of the activity by use of [35S]-methionine incorporation into parasite proteins to determine the value that inhibits 50% (IC50). Among the 3 plants tested, 2 had significant inhibitory effect on P. falciparum in vitro.

  11. A “reverse pharmacology” approach for developing an anti-malarial phytomedicine

    Directory of Open Access Journals (Sweden)

    Diakite Chiaka

    2011-03-01

    Full Text Available Abstract A “reverse pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “reverse pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.

  12. In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

    Directory of Open Access Journals (Sweden)

    Valter F de Andrade-Neto

    2007-06-01

    Full Text Available In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae, the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae, respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae, all presented significant in vitro inhibition (more active than quinine and chloroquine of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.

  13. Development of Antibody–Drug Conjugates Using DDS and Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Masahiro Yasunaga

    2017-09-01

    Full Text Available Antibody-drug conjugate (ADC, as a next generation of antibody therapeutics, is a combination of an antibody and a drug connected via a specialized linker. ADC has four action steps: systemic circulation, the enhanced permeability and retention (EPR effect, penetration within the tumor tissue, and action on cells, such as through drug delivery system (DDS drugs. An antibody with a size of about 10 nm has the same capacity for passive targeting as some DDS carriers, depending on the EPR effect. In addition, some antibodies are capable of active targeting. A linker is stable in the bloodstream but should release drugs efficiently in the tumor cells or their microenvironment. Thus, the linker technology is actually a typical controlled release technology in DDS. Here, we focused on molecular imaging. Fluorescent and positron emission tomography (PET imaging is useful for the visualization and evaluation of antibody delivery in terms of passive and active targeting in the systemic circulation and in tumors. To evaluate the controlled release of the ADC in the targeted area, a mass spectrometry imaging (MSI with a mass microscope, to visualize the drug released from ADC, was used. As a result, we succeeded in confirming the significant anti-tumor activity of anti-fibrin, or anti-tissue factor-ADC, in preclinical settings by using DDS and molecular imaging.

  14. Facilitating adverse drug event detection in pharmacovigilance databases using molecular structure similarity: application to rhabdomyolysis

    Science.gov (United States)

    Vilar, Santiago; Harpaz, Rave; Chase, Herbert S; Costanzi, Stefano; Rabadan, Raul

    2011-01-01

    Background Adverse drug events (ADE) cause considerable harm to patients, and consequently their detection is critical for patient safety. The US Food and Drug Administration maintains an adverse event reporting system (AERS) to facilitate the detection of ADE in drugs. Various data mining approaches have been developed that use AERS to detect signals identifying associations between drugs and ADE. The signals must then be monitored further by domain experts, which is a time-consuming task. Objective To develop a new methodology that combines existing data mining algorithms with chemical information by analysis of molecular fingerprints to enhance initial ADE signals generated from AERS, and to provide a decision support mechanism to facilitate the identification of novel adverse events. Results The method achieved a significant improvement in precision in identifying known ADE, and a more than twofold signal enhancement when applied to the ADE rhabdomyolysis. The simplicity of the method assists in highlighting the etiology of the ADE by identifying structurally similar drugs. A set of drugs with strong evidence from both AERS and molecular fingerprint-based modeling is constructed for further analysis. Conclusion The results demonstrate that the proposed methodology could be used as a pharmacovigilance decision support tool to facilitate ADE detection. PMID:21946238

  15. In vivo antimalarial and cytotoxic properties of Annona senegalensis ...

    African Journals Online (AJOL)

    The in vivo animal antimalarial and in vitro cytotoxic activities of the methanol extract of Annona senegalensis Pers. (Annonaceae) was investigated in this study. The in vivo antimalarial activity of the methanol extract against Plasmodium berghei was assessed using the 4-day suppressive test procedure. The extract of A.

  16. Antimalarial Anthrone and Chromone from the Leaf Latex of Aloe ...

    African Journals Online (AJOL)

    In Ethiopian traditional medicine, the leaf latex of Aloe debranan Chrstian is used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the leaf latex of A. debrana was tested for its in vivo antimalarial activity, in a 4-day suppressive assay ...

  17. In vivo Antimalarial Activity of Methanol and Water Extracts of ...

    African Journals Online (AJOL)

    Conclusions: The possible active compounds responsible for the observed chemosupression may be flavonoids, terpeneoids and anthraquinones which are present in the extract. This is the first report on the in vivo antimalarial activity of E. thorifolium. Keywords: Antimalarial, Eryngium thorifolium, Plasmodium berghei, ...

  18. Antimalarial Activity of Ultra-Short Peptides

    Directory of Open Access Journals (Sweden)

    María Yolanda Rios

    2009-12-01

    Full Text Available Ultra-short peptides 1-9 were designed and synthesized with phenylalanine, ornithine and proline amino acid residues and their effect on antimalarial activity was analyzed. On the basis of the IC50 data for these compounds, the effects of nature, polarity, and amino acid sequence on Plasmodium berghei schizont cultures were analyzed too. Tetrapeptides Phe-Orn-Phe-Orn (4 and Lys-Phe-Phe-Orn (5 showed a very important activity with IC50 values of 3.31 and 2.57 μM, respectively. These two tetrapeptides are candidates for subsequent in vivo assays and SARS investigations.

  19. In Vivo Antimalarial Activity of the Solvent Fractions of Fruit Rind and Root of Carica papaya Linn (Caricaceae) against Plasmodium berghei in Mice

    Science.gov (United States)

    Kebebe, Dereje; Mulisa, Eshetu; Gashe, Fanta

    2017-01-01

    Background Currently, antimalarial drug resistance poses a serious challenge. This stresses the need for newer antimalarial compounds. Carica papaya is used traditionally and showed in vitro antimalarial activity. This study attempted to evaluate in vivo antimalarial activity of C. papaya in mice. Methods In vivo antimalarial activity of solvent fractions of the plant was carried out against early P. berghei infection in mice. Parasitemia, temperature, PCV, and body weight of mice were recorded. Windows SPSS version 16 (one-way ANOVA followed by Tukey's post hoc test) was used for data analysis. Results The pet ether and chloroform fractions of C. papaya fruit rind and root produced a significant (p papaya fruit rind in the highest dose (400 mg/kg/day). Only 400 mg/kg/day dose of chloroform fraction of C. papaya root exhibited a parasite suppression effect (48.11%). But, methanol fraction of the plant parts produced less chemosuppressive effect. Conclusion Pet ether fraction of C. papaya fruit rind had the highest antimalarial activity and could be a potential source of lead compound. Further study should be done to show the chemical and metabolomic profile of active ingredients. PMID:29391947

  20. PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists.

    Science.gov (United States)

    Canfield, C J; Milhous, W K; Ager, A L; Rossan, R N; Sweeney, T R; Lewis, N J; Jacobus, D P

    1993-07-01

    A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)- imidocarbonimidic diamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.

  1. Self-medication practices with antibiotics and antimalarials among Sudanese undergraduate university students.

    Science.gov (United States)

    Awad, Abdelmoneim I; Eltayeb, Idris B

    2007-07-01

    In many developing countries, up to 60-80% of health problems are self-medicated. To estimate the prevalence of self-medication with antibiotics and/or antimalarials and identify factors promoting such use among university students in Sudan. A descriptive cross-sectional study was performed, using a pretested questionnaire on a sample of 1300 students selected from 5 universities in Khartoum State, Sudan. Eight hundred ninety-one (79.5%; 95% CI 77.0 to 81.8) students from the study population had used antibiotics or antimalarials without a prescription within 1-2 months prior to the study. Four hundred ninety (55%; 95% CI 51.7 to 58.3) of the respondents stated that they had used antibiotics, 39 (4.4%; 95% CI 3.2 to 6.0) had used antimalarials, and 362 (40.6%; 95% CI 37.4 to 43.9) had used both. Overall, self-medication with antibiotics or antimalarials was significantly more common among students 21 years of age or older compared with those 20 years of age or younger (OR 1.55; 95% CI 1.15 to 2.09; p = 0.004) and among students attending private universities compared with those attending public universities (OR 1.42; 95% CI 1.04 to 1.95; p = 0.028). Self-medication with antibiotics followed a similar pattern, which was significantly more common among students 21 years of age or older (OR 1.36; 95% CI 1.03 to 1.81; p = 0.03) and private university respondents (OR 1.52; 95% CI 1.15 to 2.02; p = 0.003). Self-medication with antimalarials was found to be significantly less common among females (OR 0.76; 95% CI 0.59 to 0.97; p = 0.028) and higher among the 21 years or older age group (OR 1.84; 95% CI 1.42 to 2.40; p self-medication was the respondents' previous experiences with similar ailments. The main source of drugs was community pharmacies. The prevalence of self-medication with antibiotics/antimalarials among undergraduate university students in Khartoum State is high. Our findings highlight the need for planning interventions to promote the judicious use of

  2. Rapid molecular diagnostics for multi-drug resistant tuberculosis in India.

    Science.gov (United States)

    Ramachandran, Rajeswari; Muniyandi, M

    2018-03-01

    Rapid molecular diagnostic methods help in the detection of TB and Rifampicin resistance. These methods detect TB early, are accurate and play a crucial role in reducing the burden of drug resistant tuberculosis. Areas covered: This review analyses rapid molecular diagnostic tools used in the diagnosis of MDR-TB in India, such as the Line Probe Assay and GeneXpert. We have discussed the burden of MDR-TB and the impact of recent diagnostic tools on case detection and treatment outcomes. This review also discusses the costs involved in establishing these new techniques in India. Expert commentary: Molecular methods have considerable advantages for the programmatic management of drug resistant TB. These include speed, standardization of testing, potentially high throughput and reduced laboratory biosafety requirements. There is a desperate need for India to adopt modern, rapid, molecular tools with point-of-care tests being currently evaluated. New molecular diagnostic tests appear to be cost effective and also help in detecting missing cases. There is enough evidence to support the scaling up of these new tools in India.

  3. Computational models to assign biopharmaceutics drug disposition classification from molecular structure.

    Science.gov (United States)

    Khandelwal, Akash; Bahadduri, Praveen M; Chang, Cheng; Polli, James E; Swaan, Peter W; Ekins, Sean

    2007-12-01

    We applied in silico methods to automatically classify drugs according to the Biopharmaceutics Drug Disposition Classification System (BDDCS). Models were developed using machine learning methods including recursive partitioning (RP), random forest (RF) and support vector machine (SVM) algorithms with ChemDraw, clogP, polar surface area, VolSurf and MolConnZ descriptors. The dataset consisted of 165 training and 56 test set molecules. RF model 3, RP model 1, and SVM model 1 can correctly predict 73.1, 63.6 and 78.6% test compounds in classes 1, 2 and 3, respectively. Both RP and SVM models can be used for class 4 prediction. The inclusion of consensus analysis resulted in improved test set predictions for class 2 and 4 drugs. The models can be used to predict BDDCS class for new compounds from molecular structure using readily available molecular descriptors and software, representing an area where in silico approaches could aid the pharmaceutical industry in speeding drugs to the patient and reducing costs. This could have significant applications in drug discovery to identify molecules that may have future developability issues.

  4. Mapping of Drug-like Chemical Universe with Reduced Complexity Molecular Frameworks.

    Science.gov (United States)

    Kontijevskis, Aleksejs

    2017-04-24

    The emergence of the DNA-encoded chemical libraries (DEL) field in the past decade has attracted the attention of the pharmaceutical industry as a powerful mechanism for the discovery of novel drug-like hits for various biological targets. Nuevolution Chemetics technology enables DNA-encoded synthesis of billions of chemically diverse drug-like small molecule compounds, and the efficient screening and optimization of these, facilitating effective identification of drug candidates at an unprecedented speed and scale. Although many approaches have been developed by the cheminformatics community for the analysis and visualization of drug-like chemical space, most of them are restricted to the analysis of a maximum of a few millions of compounds and cannot handle collections of 10 8 -10 12 compounds typical for DELs. To address this big chemical data challenge, we developed the Reduced Complexity Molecular Frameworks (RCMF) methodology as an abstract and very general way of representing chemical structures. By further introducing RCMF descriptors, we constructed a global framework map of drug-like chemical space and demonstrated how chemical space occupied by multi-million-member drug-like Chemetics DNA-encoded libraries and virtual combinatorial libraries with >10 12 members could be analyzed and mapped without a need for library enumeration. We further validate the approach by performing RCMF-based searches in a drug-like chemical universe and mapping Chemetics library selection outputs for LSD1 targets on a global framework chemical space map.

  5. ATS drugs molecular structure representation using refined 3D geometric moment invariants

    Czech Academy of Sciences Publication Activity Database

    Pratama, S. F.; Muda, A. K.; Choo, J. H.; Flusser, Jan; Abraham, A.

    2017-01-01

    Roč. 55, č. 10 (2017), s. 1951-1963 ISSN 0259-9791 R&D Projects: GA ČR GA15-16928S Institutional support: RVO:67985556 Keywords : 3D moment invariants * Geometric moment invariants * ATS drugs * Molecular similarity * Molecular descriptors Subject RIV: JD - Computer Applications, Robotics OBOR OECD: Computer sciences, information science, bioinformathics (hardware development to be 2.2, social aspect to be 5.8) Impact factor: 1.308, year: 2016 http://library.utia.cas.cz/separaty/2017/ZOI/flusser-0479217.pdf

  6. Spectroscopic and molecular docking studies on the interaction of antiviral drug nevirapine with calf thymus DNA.

    Science.gov (United States)

    Moghadam, Neda Hosseinpour; Salehzadeh, Sadegh; Shahabadi, Nahid

    2017-09-02

    The interaction of calf thymus DNA with nevirapine at physiological pH was studied by using absorption, circular dichroism, viscosity, differential pulse voltammetry, fluorescence techniques, salt effect studies and computational methods. The drug binds to ct-DNA in a groove binding mode, as shown by slight variation in the viscosity of ct-DNA. Furthermore, competitive fluorimetric studies with Hoechst 33258 indicate that nevirapine binds to DNA via groove binding. Moreover, the structure of nevirapine was optimized by DFT calculations and was used for the molecular docking calculations. The molecular docking results suggested that nevirapine prefers to bind on the minor groove of ct-DNA.

  7. Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.

    Science.gov (United States)

    Engleman, Eric A; Katner, Simon N; Neal-Beliveau, Bethany S

    2016-01-01

    Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission

  8. Sharing individual patient and parasite-level data through the WorldWide Antimalarial Resistance Network platform: A qualitative case study [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Elizabeth Pisani

    2017-08-01

    Full Text Available Background: Increasingly, biomedical researchers are encouraged or required by research funders and journals to share their data, but there's very little guidance on how to do that equitably and usefully, especially in resource-constrained settings. We performed an in-depth case study of one data sharing pioneer: the WorldWide Antimalarial Resistance Network (WWARN. Methods: The case study included a records review, a quantitative analysis of WAARN-related publications, in-depth interviews with 47 people familiar with WWARN, and a witness seminar involving a sub-set of 11 interviewees. Results: WWARN originally aimed to collate clinical, in vitro, pharmacological and molecular data into linked, open-access databases intended to serve as a public resource to guide antimalarial drug treatment policies. Our study describes how WWARN navigated challenging institutional and academic incentive structures, alongside funders' reluctance to invest in capacity building in malaria-endemic countries, which impeded data sharing. The network increased data contributions by focusing on providing free, online tools to improve the quality and efficiency of data collection, and by inviting collaborative authorship on papers addressing policy-relevant questions that could only be answered through pooled analyses. By July 1, 2016, the database included standardised data from 103 molecular studies and 186 clinical trials, representing 135,000 individual patients. Developing the database took longer and cost more than anticipated, and efforts to increase equity for data contributors are on-going. However, analyses of the pooled data have generated new methods and influenced malaria treatment recommendations globally. Despite not achieving the initial goal of real-time surveillance, WWARN has developed strong data governance and curation tools, which are now being adapted relatively quickly for other diseases. Conclusions: To be useful, data sharing requires

  9. In vivo antimalarial activity of the endophytic actinobacteria, Streptomyces SUK 10.

    Science.gov (United States)

    Baba, Mohd Shukri; Zin, Noraziah Mohamad; Hassan, Zainal Abidin Abu; Latip, Jalifah; Pethick, Florence; Hunter, Iain S; Edrada-Ebel, RuAngelie; Herron, Paul R

    2015-12-01

    Endophytic bacteria, such as Streptomyces, have the potential to act as a source for novel bioactive molecules with medicinal properties. The present study was aimed at assessing the antimalarial activity of crude extract isolated from various strains of actinobacteria living endophytically in some Malaysian medicinal plants. Using the four day suppression test method on male ICR strain mice, compounds produced from three strains of Streptomyces (SUK8, SUK10, and SUK27) were tested in vivo against Plasmodium berghei PZZ1/100 in an antimalarial screen using crude extracts at four different concentrations. One of these extracts, isolated from Streptomyces SUK10 obtained from the bark of Shorea ovalis tree, showed inhibition of the test organism and was further tested against P. berghei-infected mice for antimalarial activity at different concentrations. There was a positive relationship between the survival of the infected mouse group treated with 50 µg/kg body weight (bw) of ethyl acetate-SUK10 crude extract and the ability to inhibit the parasites growth. The parasite inhibition percentage for this group showed that 50% of the mice survived for more than 90 days after infection with the parasite. The nucleotide sequence and phylogenetic tree suggested that Streptomyces SUK10 may constitute a new species within the Streptomyces genus. As part of the drug discovery process, these promising finding may contribute to the medicinal and pharmaceutical field for malarial treatment.

  10. Collaborative health and enforcement operations on the quality of antimalarials and antibiotics in southeast Asia.

    Science.gov (United States)

    Yong, Yuk Lin; Plançon, Aline; Lau, Yen Hui; Hostetler, Dana M; Fernández, Facundo M; Green, Michael D; Sounvoravong, Sourisak; Nara, Suon; Boravann, Mam; Dumrong, Thitikornkovit; Bangsawan, Nurjaya; Low, Min Yong; Lim, Chin-Chin; Ai, Ruth Lee Choo; Newton, Paul N

    2015-06-01

    Counterfeit (or falsified) and substandard medicines pose a major public health risk. We describe the findings of Operation Storm I and II conducted in 2008-2009 to combat counterfeit medicines through partnership between national customs, Drug Regulatory Agencies (DRAs), and police in Cambodia, Indonesia, Laos, Myanmar, Singapore, Thailand, and Vietnam. Samples were obtained from seizures and market surveillance by national DRAs. Laboratory analysis using spectroscopic and chromatographic techniques and examination of packaging were performed. Ninety-three suspect antibiotics and 95 antimalarial samples were collected. Of the 93 antibiotics, 29 (31%) had % active pharmaceutical ingredient content (%API) 115% (including one counterfeit). Of the 95 antimalarials, 30 (32%) had %API 115% API (including one counterfeit). A significant minority of samples, antimalarials (13%) and antibiotics (15%), were collected in plastic bags with minimal or no labeling. Of 20 ampicillin samples, 13 (65%) contained INTERPOL), World Health Organization (WHO), and laboratories facilitated a platform for discussions and intelligence sharing, helping to improve each participating country's capacity to combat poor-quality medicines. © The American Society of Tropical Medicine and Hygiene.

  11. Amino acids as co-amorphous stabilizers for poorly water-soluble drugs--Part 2: molecular interactions.

    Science.gov (United States)

    Löbmann, Korbinian; Laitinen, Riikka; Strachan, Clare; Rades, Thomas; Grohganz, Holger

    2013-11-01

    The formation of co-amorphous drug-drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs--low molecular weight excipient blends--have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Drug design based on x-ray diffraction and steered molecular dynamics

    Czech Academy of Sciences Publication Activity Database

    Hašek, Jindřich; Skálová, Tereza; Dohnálek, Jan; Dušková, Jarmila; Petroková, Hana; Vondráčková, Eva; Zimmermann, K.

    2005-01-01

    Roč. 12, č. 3 (2005), s. 208-210 ISSN 1211-5894. [VUFB Conference on Modern Methods in Synthesis and Analysis of Active Pharmaceutical Substances /5./. Praha, 23.11.2005-24.11.2005] R&D Projects: GA AV ČR KJB4050312 Institutional research plan: CEZ:AV0Z40500505 Keywords : drug design * X-ray diffraction * steered molecular dynamics Subject RIV: CF - Physical ; Theoretical Chemistry

  13. Chemoinformatic Analysis of Combinatorial Libraries, Drugs, Natural Products and Molecular Libraries Small Molecule Repository

    OpenAIRE

    Singh, Narender; Guha, Rajarshi; Giulianotti, Marc; Pinilla, Clemencia; Houghten, Richard; Medina-Franco, Jose L.

    2009-01-01

    A multiple criteria approach is presented, that is used to perform a comparative analysis of four recently developed combinatorial libraries to drugs, Molecular Libraries Small Molecule Repository (MLSMR) and natural products. The compound databases were assessed in terms of physicochemical properties, scaffolds and fingerprints. The approach enables the analysis of property space coverage, degree of overlap between collections, scaffold and structural diversity and overall structural novelty...

  14. Modern drug design: the implication of using artificial neuronal networks and multiple molecular dynamic simulations

    Science.gov (United States)

    Yakovenko, Oleksandr; Jones, Steven J. M.

    2018-01-01

    We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource (https://drugdesigndata.org/). The challenge was focused on the ligands of the farnesoid X receptor (FXR), a highly flexible nuclear receptor of the cholesterol derivative chenodeoxycholic acid. FXR is considered an important therapeutic target for metabolic, inflammatory, bowel and obesity related diseases (Expert Opin Drug Metab Toxicol 4:523-532, 2015), but in the context of this competition it is also interesting due to the significant ligand-induced conformational changes displayed by the protein. To deal with these conformational changes we employed multiple simulations of molecular dynamics (MD). Our MD-based protocols were top-ranked in estimating the free energy of binding of the ligands and FXR protein. Our approach was ranked second in the prediction of the binding poses where we also combined MD with molecular docking and artificial neural networks. Our approach showed mediocre results for high-throughput scoring of interactions.

  15. Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.

    Science.gov (United States)

    Scafidi, Joseph; Ritter, Jonathan; Talbot, Brooke M; Edwards, Jorge; Chew, Li-Jin; Gallo, Vittorio

    2018-04-15

    Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers. Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 78(8); 2081-95. ©2018 AACR . ©2018 American Association for Cancer Research.

  16. Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries small molecule repository.

    Science.gov (United States)

    Singh, Narender; Guha, Rajarshi; Giulianotti, Marc A; Pinilla, Clemencia; Houghten, Richard A; Medina-Franco, Jose L

    2009-04-01

    A multiple criteria approach is presented, that is used to perform a comparative analysis of four recently developed combinatorial libraries to drugs, Molecular Libraries Small Molecule Repository (MLSMR) and natural products. The compound databases were assessed in terms of physicochemical properties, scaffolds, and fingerprints. The approach enables the analysis of property space coverage, degree of overlap between collections, scaffold and structural diversity, and overall structural novelty. The degree of overlap between combinatorial libraries and drugs was assessed using the R-NN curve methodology, which measures the density of chemical space around a query molecule embedded in the chemical space of a target collection. The combinatorial libraries studied in this work exhibit scaffolds that were not observed in the drug, MLSMR, and natural products databases. The fingerprint-based comparisons indicate that these combinatorial libraries are structurally different than current drugs. The R-NN curve methodology revealed that a proportion of molecules in the combinatorial libraries is located within the property space of the drugs. However, the R-NN analysis also showed that there are a significant number of molecules in several combinatorial libraries that are located in sparse regions of the drug space.

  17. Clarithromycin enhances the antimalarial efficacy of mefloquine via its increased bioavailability and disrupting P. falciparum apicoplast.

    Science.gov (United States)

    Gunjan, S; Singh, S K; Chauhan, B S; Pandey, S K; Ahmad, H; Dwivedi, A K; Tripathi, R

    2015-09-01

    Many important drugs like mefloquine are not being used because of the development of resistance and other related issues. In the present study, we aimed to control drug resistance by using combination therapy and tried to understand the mechanism involved. We have explored in vitro interaction of clarithromycin (CLTR), and mefloquine (MQ) against Pf3D7 and PfK1 strains. Bioavailability of MQ in parasitized RBC lysate was checked in the presence/absence of CLTR using HPLC method. Further tufA mRNA/protein expression was investigated to know the effect of both drugs on apicoplast by using qPCR and Western blotting. MQ and CLTR inhibited growth of Pf3D7 and PfK1. CLTR showed its delayed antimalarial effect by its low IC50 values in the second cycle which indicates its effect on apicoplast. Downregulation of tufA expression on both mRNA and protein level supports this hypothesis. MQ and CLTR showed synergism/additiveness (mean ∑FICs = 0.89 and 1.26) against Pf3D7 and PfK1 respectively. It is evidenced from HPLC data that CLTR might have reduced metabolism of MQ in Plasmodium falciparum, leading to increased levels of MQ to produce enhanced antimalarial activity. The metabolism of CLTR is also reduced may be due to competitive metabolism of MQ via CYP3A4. The present study reveals that broad spectrum biological activities (i.e. antimalarial and antiviral) of MQ can be saved by using suitable partner drug like CLTR. This study also shows that CLTR increases the concentration of MQ and disrupts the apicoplast. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. High content live cell imaging for the discovery of new antimalarial marine natural products.

    Science.gov (United States)

    Cervantes, Serena; Stout, Paige E; Prudhomme, Jacques; Engel, Sebastian; Bruton, Matthew; Cervantes, Michael; Carter, David; Tae-Chang, Young; Hay, Mark E; Aalbersberg, William; Kubanek, Julia; Le Roch, Karine G

    2012-01-03

    The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. © 2011 Cervantes et al; licensee BioMed Central Ltd.

  19. Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents.

    Science.gov (United States)

    Devender, Nalmala; Gunjan, Sarika; Chhabra, Stuti; Singh, Kartikey; Pasam, Venkata Reddy; Shukla, Sanjeev K; Sharma, Abhisheak; Jaiswal, Swati; Singh, Sunil Kumar; Kumar, Yogesh; Lal, Jawahar; Trivedi, Arun Kumar; Tripathi, Renu; Tripathi, Rama Pati

    2016-02-15

    In a quest to discover new drugs, we have synthesized a series of novel β-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 μM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 μM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  20. Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development.

    Science.gov (United States)

    Tomar, Dheeraj S; Kumar, Sandeep; Singh, Satish K; Goswami, Sumit; Li, Li

    2016-01-01

    Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored.

  1. Prediction of drug-packaging interactions via molecular dynamics (MD) simulations.

    Science.gov (United States)

    Feenstra, Peter; Brunsteiner, Michael; Khinast, Johannes

    2012-07-15

    The interaction between packaging materials and drug products is an important issue for the pharmaceutical industry, since during manufacturing, processing and storage a drug product is continuously exposed to various packaging materials. The experimental investigation of a great variety of different packaging material-drug product combinations in terms of efficacy and safety can be a costly and time-consuming task. In our work we used molecular dynamics (MD) simulations in order to evaluate the applicability of such methods to pre-screening of the packaging material-solute compatibility. The solvation free energy and the free energy of adsorption of diverse solute/solvent/solid systems were estimated. The results of our simulations agree with experimental values previously published in the literature, which indicates that the methods in question can be used to semi-quantitatively reproduce the solid-liquid interactions of the investigated systems. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Molecularly imprinted polymers for the detection of illegal drugs and additives: a review.

    Science.gov (United States)

    Xiao, Deli; Jiang, Yue; Bi, Yanping

    2018-04-04

    This review (with 154 refs.) describes the current status of using molecularly imprinted polymers in the extraction and quantitation of illicit drugs and additives. The review starts with an introduction into some synthesis methods (lump MIPs, spherical MIPs, surface imprinting) of MIPs using illicit drugs and additives as templates. The next section covers applications, with subsections on the detection of illegal additives in food, of doping in sports, and of illicit addictive drugs. A particular focus is directed towards current limitations and challenges, on the optimization of methods for preparation of MIPs, their applicability to aqueous samples, the leakage of template molecules, and the identification of the best balance between adsorption capacity and selectivity factor. At last, the need for convincing characterization methods, the lack of uniform parameters for defining selectivity, and the merits and demerits of MIPs prepared using nanomaterials are addressed. Strategies are suggested to solve existing problems, and future developments are discussed with respect to a more widespread use in relevant fields. Graphical abstract This review gives a comprehensive overview of the advances made in molecularly imprinting of polymers for use in the extraction and quantitation of illicit drugs and additives. Methods for syntheses, highlighted applications, limitations and current challenges are specifically addressed.

  3. Mecanismos moleculares de acción de algunas drogas inmunosupresoras Molecular mechanisms of action of some immunosuppresive drugs

    Directory of Open Access Journals (Sweden)

    Ana C. Liberman

    2008-12-01

    Full Text Available Los tratamientos utilizados para desordenes inmunológicos son de origen empírico, utilizando drogas inmunosupresoras identificadas a través de la selección de un gran número de compuestos naturales y sintéticos. Las drogas inmunosupresoras son ampliamente utilizadas en tratamientos clínicos de desordenes autoinmunes, en la prevención de rechazo a transplantes así como también en desordenes de carácter no autoinmune tales como las alergias. El diseño de las terapias inmunosupresoras está basado en controlar una respuesta inmune exacerbada. La base fisiopatológica de este concepto es en modular la acción de células mononucleares, siendo el principal punto de control las células T. Estas drogas inhiben la función normal de protección del sistema inmune llevando a la aparición de complicaciones en las terapias de inmunosupresión. Las drogas inmunosupresoras tienen diferentes blancos en el proceso de inmunidad celular. Según su modo de acción pueden clasificarse en cuatro categorías: drogas antinflamatorias de la familia de los corticosteroides, inmunosupresoras específicas inhibidoras de la calcineurina, citotóxicas o antiproliferativas y anticuerpos específicos. En este trabajo describimos el mecanismo de acción molecular de agentes inmunosupresores tales como, esteroides, ciclosporina, tacrolimo, azatioprina, ciclofosfamida, sirolimus, mofetil mecofenolato, leflunomida y anticuerpos específicos, para contribuir a la comprensión de cómo utilizar y mejorar estos agentes.A number of natural and synthetic substances are used in the treatment of immunological disorders. The immunosuppressive drugs are widely utilized in clinical treatments of autoimmune disorders, in the prevention of transplant rejection as well as in non-autoimmune diseases such as allergy. The design of immunosuppressive therapies is based on the control of the exacerbated immune response. The pathophysiologic mean of this concept is to modulate the

  4. Grid-based Continual Analysis of Molecular Interior for Drug Discovery, QSAR and QSPR.

    Science.gov (United States)

    Potemkin, Andrey V; Grishina, Maria A; Potemkin, Vladimir A

    2017-01-01

    In 1979, R.D.Cramer and M.Milne made a first realization of 3D comparison of molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (Dynamic Lattice- Oriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities. Then, in 1988, the method which was called CoMFA (Comparative Molecular Field Analysis) was introduced and the appropriate software became commercially available. Since 1988, a lot of 3D QSAR methods, algorithms and their modifications are introduced for solving of virtual drug discovery problems (e.g., CoMSIA, CoMMA, HINT, HASL, GOLPE, GRID, PARM, Raptor, BiS, CiS, ConGO,). All the methods can be divided into two groups (classes):1. Methods studying the exterior of molecules; 2) Methods studying the interior of molecules. A series of grid-based computational technologies for Continual Molecular Interior analysis (CoMIn) are invented in the current paper. The grid-based analysis is fulfilled by means of a lattice construction analogously to many other grid-based methods. The further continual elucidation of molecular structure is performed in various ways. (i) In terms of intermolecular interactions potentials. This can be represented as a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are well known continual functions and their values can be determined in all lattice points for a molecule. (ii) In the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum

  5. ANTIMALARIAL COMPOUNDS FROM ENDOPHYTIC FUNGI OF BROTOWALI (Tinaspora crispa L

    Directory of Open Access Journals (Sweden)

    Elfita Elfita

    2011-07-01

    Full Text Available The term endophytic refers to a bacteria or a fungi microorganism that colonizes interior organs of plants, but does not have pathogenic effects on its host. In their symbiotic association, the host plant protects and feeds the endophytic, which ";in return"; produces bioactive metabolites to enhance the growth and compotitiveness of the host and to protect it from herbivores and plant pathogens. Plants with ethnobotanical history, for example brotowali (Tinaspora crispa L, are likely candidates to find bioactive compounds. Two alkaloids have been isolated from endophytic fungi of brotowali. The molecular structures of the isolated compounds were determined based on spectroscopic data, including UV, IR, NMR 1D and 2D spectrum. The compounds were determined as: 7- hydroxy-3,4,5-trimethyl-6-on-2,3,4,6-tetrahydroisoquinoline-8-carboxylic acid (1 and 2,5-dihydroxy-1-(hydroxymethylpyridin-4-on (2. The compound has antimalarial activity against Plasmodium falciparum 3D7, with IC50 values 0,129 µM and 0,127 µM.

  6. Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug-Polymer-Polymer Ternary Solution.

    Science.gov (United States)

    Prasad, Dev; Chauhan, Harsh; Atef, Eman

    2016-03-07

    We are reporting a synergistic effect of combined Eudragit E100 and PVP K90 in precipitation inhibition of indomethacin (IND) in solutions at low polymer concentration, a phenomenon that has significant implications on the usefulness of developing novel ternary solid dispersion of poorly soluble drugs. The IND supersaturation was created by cosolvent technique, and the precipitation studies were performed in the absence and the presence of individual and combined PVP K90 and Eudragit E100. The studies were also done with PEG 8000 as a noninteracting control polymer. A continuous UV recording of the IND absorption was used to observe changes in the drug concentration over time. The polymorphic form and morphology of precipitated IND were characterized by Raman spectroscopy and scanning electron microscopy. The change in the chemical shift in solution (1)H NMR was used as novel approach to probe IND-polymer interactions. Molecular modeling was used for calculating binding energy between IND-polymer as another indication of IND-polymer interaction. Spontaneous IND precipitation was observed in the absence of polymers. Eudragit E100 showed significant inhibitory effect on nuclei formation due to stronger interaction as reflected in higher binding energy and greater change in chemical shift by NMR. PVP K90 led to significant crystal growth inhibition due to adsorption on growing IND crystals as confirmed by modified crystal habit of precipitate in the presence of PVP K90. Combination of polymers resulted in a synergistic precipitation inhibition and extended supersaturation. The NMR confirmed interaction between IND-Eudragit E100 and IND-PVP K90 in solution. The combination of polymers showed similar peak shift albeit using lower polymer concentration indicating stronger interactions. The results established the significant synergistic precipitation inhibition effect upon combining Eudragit E100 and PVP K90 due to drug-polymer interaction.

  7. Augmentation of the Differentiation Response to Antitumor Antimalarials

    National Research Council Canada - National Science Library

    Rahim, Rayhana

    2003-01-01

    .... We have shown that the quinoline antimalarials chloroquine (CO) and hydroxychioroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-10A cells...

  8. Unambiguous Synthesis and Prophylactic Antimalarial Activities of Imidazolidinedione Derivatives

    National Research Council Canada - National Science Library

    Zhang, Quan; Guan, Jian; Sacci, John; Ager, Arba; Ellis, William; Mihlhous, Wilbur; Kyle, Dennis; Lin, Ai J

    2005-01-01

    .... To search for compounds with good oral efficacy, a series of carbamate derivatives of the active components were prepared by the new procedure, many of which showed profound causal prophylactic antimalarial activity against Plasmodium yoelil in mouse by oral administration.

  9. Pharmacological screening of some traditionally-used antimalarial ...

    African Journals Online (AJOL)

    Pharmacological screening of some traditionally-used antimalarial plants from the Democratic Republic of Congo compared to their ecological taxonomic equivalence in Madagascar. KN Ngbolua, H Rafatro, H Rakotoarimanana, US Ratsimamanga, V Mudogo, PT Mpiana, DST Tshibangu ...

  10. In Vivo Antimalarial Activities of Plants Used in Ethiopian Traditional ...

    African Journals Online (AJOL)

    In Vivo Antimalarial Activities of Plants Used in Ethiopian Traditional Medicine, Delomenna, Southeast Ethiopia. Ashenafi Asefa, Kelbassa Urga, Mulugeta Guta, Waleleng Mekonene, Daniel Melaku, Kise Mudie, Tesgayae Kidanemariam ...

  11. Simple field assays to check quality of current artemisinin-based antimalarial combination formulations.

    Directory of Open Access Journals (Sweden)

    Jean-Robert Ioset

    Full Text Available INTRODUCTION: Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT for use as first line treatment against malaria. This class of drugs is now first-line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. METHODS AND FINDINGS: Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5-dimethoxybenzenediazonium chloride hemi (zinc chloride salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP--artesunate/amodiaquine, Coartem--artemether/lumefantrine and Duocortexcin--dihydroartemisinin/piperaquine. The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. CONCLUSIONS: Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible

  12. Simple field assays to check quality of current artemisinin-based antimalarial combination formulations.

    Science.gov (United States)

    Ioset, Jean-Robert; Kaur, Harparkash

    2009-09-30

    Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin) derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO) has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT) for use as first line treatment against malaria. This class of drugs is now first-line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5-dimethoxybenzenediazonium chloride hemi (zinc chloride) salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP--artesunate/amodiaquine, Coartem--artemether/lumefantrine and Duocortexcin--dihydroartemisinin/piperaquine). The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible, inexpensive and, have successfully resulted in detecting two

  13. In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

    Directory of Open Access Journals (Sweden)

    Adeleke Clement Adebajo

    2014-08-01

    Full Text Available Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED50 values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED50 value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED50 of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED50 = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05 more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity.

  14. Molecular Modeling of Interaction between Diabetic Drug and Antioxidant in Controlling Sucrose

    Science.gov (United States)

    Rakesh, Leela; Lee, Choon

    2009-09-01

    This article examined the possible protective effect of N-acetylcysteine (NAC) taurine, quercetin and Syringaldehyde dendritic antioxidants against the oxidative stress induced by diabetic or pre-diabetic patient case due to high sucrose intake by computer simulation. We also compared these results with the well-known diabetic drugs glizipid and Avandia. Towards this understanding we undertook a molecular level computer model in order to study the molecular interaction between high sugar content with antioxidant by varying ratios of sucrose molecules with and without the presence of diabetic drugs. From our study it shows that with the presence of various antioxidant combinations diabetics drugs could be much more beneficial to the patients in terms of its side effects such a heart attack. Many interesting results have been obtained by this study. The application of this driving force may be used to predict the feasibility and benefit in order to understand the high-sucrose diet-induced obesity, which certainly would bring new insights on obesity-related adverse control and may possibly suggest the impact of N-acetylcysteine and syringaldehyde in such cases. Hyperglycemia is an important predictor of cardiovascular mortality in patients with diabetes. We also investigated the hypothesis that diabetes or acute hyperglycemia attenuates the reduction of myocardial infarct size produced by activation of mitochondrial ATP-regulated potassium (KATP) channels. The results indicate that diabetes/hyperglycemia impairs activation of mitochondrial KATP channels.

  15. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    International Nuclear Information System (INIS)

    Rehman, F.U.; Khan, M.F.; Khan, G.M.; Khan, H.; Khan, I.U.

    2010-01-01

    Metal complexes are famous for a wide array of chemotherapeutic effects. The current study was designed to synthesize and evaluate unexplored chemotherapeutic effects of Cu (II) and Nickel (II) complexes of the non-steroidal anti-inflammatory drug diclofenac. Nickel complex exhibited significant leishmanicidal activity against Lieshmania major, while the copper complex was found to possess low activity against the same pathogen. Both of the complexes revealed low antibacterial activities and were interestingly failed to produce any considerable antimalarial activity against Plasmodium falciparum 3D7. Selective leishmanicidal activities of Nickel (II) complex of diclofenac needs further improvement to be developed as potential new metal-based leishmanicidal agent.(author)

  16. Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp

    OpenAIRE

    Laurent, Dominique; Jullian, Valérie; Parenty, A.; Knibiehler, M.; Dorin, D.; Schmitt, S.; Lozach, O.; Lebouvier, N.; Frostin, M.; Alby, F.; Maurel, Séverine; Doerig, C.; Meijer, L.; Sauvain, Michel

    2006-01-01

    As part of our search for new antimalarial drugs, we have screened for inhibitors of Pfnek-1, a protein kinase of Plasmodium falciparum, in south Pacific marine sponges. On the basis of a preliminary screening, the ethanolic crude extract of a new species of Xestospongia collected in Vanuatu was selected for its promising activity. A bioassay-guided fractionation led us to isolate xestoquinone which inhibits Pfnek-1 with an IC50 around 1 mu M. Among a small panel of plasmodial protein kinases...

  17. Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

    International Nuclear Information System (INIS)

    Mai, Binh Khanh; Li, Mai Suan

    2011-01-01

    Highlights: → We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. → It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. → We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. → The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.

  18. Nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs.

    Science.gov (United States)

    Huang, Wei; Chen, Liqing; Kang, Lin; Jin, Mingji; Sun, Ping; Xin, Xin; Gao, Zhonggao; Bae, You Han

    2017-06-01

    Anticancer therapy has always been a vital challenge for the development of nanomedicine. Repeated single therapeutic agent may lead to undesirable and severe side effects, unbearable toxicity and multidrug resistance due to complex nature of tumor. Nanomedicine-based combination anticancer therapy can synergistically improve antitumor outcomes through multiple-target therapy, decreasing the dose of each therapeutic agent and reducing side effects. There are versatile combinational anticancer strategies such as chemotherapeutic combination, nucleic acid-based co-delivery, intrinsic sensitive and extrinsic stimulus combinational patterns. Based on these combination strategies, various nanocarriers and drug delivery systems were engineered to carry out the efficient co-delivery of combined therapeutic agents for combination anticancer therapy. This review focused on illustrating nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs for synergistically improving anticancer efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance.

    Science.gov (United States)

    Carey, Maureen A; Papin, Jason A; Guler, Jennifer L

    2017-07-19

    Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. Here, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood. Using this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.

  20. Defining desirable natural product derived anticancer drug space: optimization of molecular physicochemical properties and ADMET attributes

    Directory of Open Access Journals (Sweden)

    Deepika Singh

    2016-06-01

    Full Text Available As part of our endeavor to enhance survival of natural product derived drug candidates and to guide the medicinal chemist to design higher probability space for success in the anti cancer drug development area, we embarked on a detailed study of the property space for a collection of natural product derived anti cancer molecules. We carried out a comprehensive analysis of properties for 24 natural products derived anti cancer drugs including clinical development candidates and a set of 27 natural products derived anti cancer lead compounds. In particular, we focused on understanding the interplay among eight physicochemical properties including like partition coefficient (log P, distribution coefficient at pH=7.4 (log D, topological polar surface area (TPSA, molecular weight (MW, aqueous solubility (log S, number of hydrogen bond acceptors (HBA, number of hydrogen bond donors (HBD and number of rotatable bonds (nRot crucial for drug design and  relationships between physicochemical properties, ADME (absorption, distribution, metabolism, and elimination attributes, and in silico toxicity profile for these two sets of compounds. This analysis provides guidance for the chemist to modify the existing natural product scaffold or designing of new anti cancer molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

  1. Prediction models for drug-induced hepatotoxicity by using weighted molecular fingerprints.

    Science.gov (United States)

    Kim, Eunyoung; Nam, Hojung

    2017-05-31

    Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. In this study, we used 881 bits of molecular fingerprint and used as features describing presence or absence of each substructure of compounds. Then, the Bayesian probability of each substructure was calculated and labeled (positive or negative for DILI), and a weighted fingerprint was determined from the ratio of DILI-positive to DILI-negative probability values. Using weighted fingerprint features, the prediction models were trained and evaluated with the Random Forest (RF) and Support Vector Machine (SVM) algorithms. The constructed models yielded accuracies of 73.8% and 72.6%, AUCs of 0.791 and 0.768 in cross-validation. In independent tests, models achieved accuracies of 60.1% and 61.1% for RF and SVM, respectively. The results validated that weighted features helped increase overall performance of prediction models. The constructed models were further applied to the prediction of natural compounds in herbs to identify DILI potential, and 13,996 unique herbal compounds were predicted as DILI-positive with the SVM model. The prediction models with weighted features increased the performance compared to non-weighted models. Moreover, we predicted the DILI potential of herbs with the best performed model, and the prediction results suggest that many herbal compounds could have potential to be DILI. We can thus infer that taking natural products without detailed references about the relevant pathways may be dangerous. Considering the frequency of use of compounds in natural herbs and their increased application in drug development, DILI labeling

  2. Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

    International Nuclear Information System (INIS)

    Ofulla, A.V.O.

    1995-01-01

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3 H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC 50 s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC 50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC 50 73.36 ± 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 (± 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs

  3. Using rapid diagnostic tests as source of malaria parasite DNA for molecular analyses in the era of declining malaria prevalence

    DEFF Research Database (Denmark)

    Ishengoma, Deus S; Lwitiho, Sudi; Madebe, Rashid A

    2011-01-01

    Malaria prevalence has recently declined markedly in many parts of Tanzania and other sub-Saharan African countries due to scaling-up of control interventions including more efficient treatment regimens (e.g. artemisinin-based combination therapy) and insecticide-treated bed nets. Although...... continued molecular surveillance of malaria parasites is important to early identify emerging anti-malarial drug resistance, it is becoming increasingly difficult to obtain parasite samples from ongoing studies, such as routine drug efficacy trials. To explore other sources of parasite DNA, this study...

  4. A Survey of Antimalarial Drug Use Practices among Urban Dwellers ...

    African Journals Online (AJOL)

    One hundred and twenty five (125) (35.71) of the respondents frequently experienced malaria attack and practiced self-medication. One hundred and fifteen (115) (32.86%) of the respondents treated their malaria episode with Sulphadoxine-Pyrimethamine (SP) combination while 90 (25.71%) of the respondents frequently ...

  5. EVALUATION OF ANTIMALARIAL DRUGS IN INDONESIA, 1981 - 1995

    Directory of Open Access Journals (Sweden)

    Emiliana Tjitra

    2012-09-01

    Full Text Available Telah dilakukan evaluasi obat-obat antimalaria in-vitro dan in-vivo untuk menentukan pola resistensi dan memanfaatkan data ini untuk melakukan sistem pengamatan yang efektif. Semua penelitian pengobatan dan pencegahan malaria di lapangan dan rumah sakit dalam kurun waktu 1981 - 1995 ditelaah. Pertama kali kasus resistensi P. falciparum terhadap klorokuin ditemukan di Kalimantan Timur pada tahun 1973, dan telah menyebar ke seluruh (27 propinsi Indonesia dengan derajat RI - RIIL Pada saat ini, resistensi Riil telah didapatkan di 20 propinsi, sedangkan pada tahun 1981-1985 hanya di 4 propinsi. Kasus malaria vivaks resisten klorokuin dilaporkan pertama kali dari Sumatera Utara (P. Nias pada tahun 1991, dan kemudian ditemukan di Irian Jaya (41%, Sumatera Utara (13%, Nusa Tenggara Timur (8%, Sulawesi Utara (2% dan Jakarta (laporan kasus yang didapatkan dari transfusi darah. Malaria falsiparum yang tercatat resisten sulfadoksin-pirimetamin didapatkan di 11 propinsi dengan derajat RI - RII. P. falciparum resisten in-vitro juga didapatkan terhadap kina (6 propinsi, meflokuin (5 propinsi dan amodiakuin (4 propinsi. Beberapa obat antimalaria baru (meflokuin, halofantrin dan derivat artemisinin telah diteliti dan ternyata efektif untuk pengobatan malaria tanpa komplikasi. Penelitian pencegahan menunjukkan angka pencegahan untuk klorokuin 41-92%, sulfadoksin- pirimetamin 98%, primakuin 89-92%, doksisiklin 99% dan meflokuin 100 %. Efek samping obat-obat antimalaria tersebut umumnya ringan. Di Indonesia, penyebaran malaria falsiparum resisten klorokuin R1II dan malaria falsiparum resisten multidrug merupakan masalah kesehatan masyarakat yang serius dan tantangan dalam pengobatan. Demikian pula kehadiran malaria vivaks resisten klorokuin menimbulkan masalah baru yang lain. Oleh sebab itu obat-obat antimalaria yang didistribusikan sebaiknya dikemas per paket untuk dosis obat pengobatan yang lengkap dengan keterangan cara minum obat yang jelas. Dengan demikian dapat dicegah pemberian dosis pengobatan yang tidak cukup dan berkembangnya resistensi obat. Selama obat antimalaria baru belum tersedia di Indonesia, perlu dilakukan penelitian perbaikan efikasi obat antimalaria yang sudah ada. Obat pencegahan alternatif yang aman dan efektif untuk anak-anak, ibu hamil dan menyusui juga perlu diteliti.

  6. Research Article Antimalarial Drugs for Pediatrics - Prescribing and ...

    African Journals Online (AJOL)

    Erah

    2011-03-23

    Mar 23, 2011 ... parents of children seeking malaria treatment were also interviewed at the public hospitals. Results: A ... The annual incidence rate is 400–500/1,000 people, and this number doubles for children less than five years of age [1]. It is estimated that over 1% .... remaining 78 (39%) refused to dispense the.

  7. Evaluation of French Guiana traditional antimalarial remedies.

    Science.gov (United States)

    Bertani, S; Bourdy, G; Landau, I; Robinson, J C; Esterre, Ph; Deharo, E

    2005-04-08

    In order to evaluate the antimalarial potential of traditional remedies used in French Guiana, 35 remedies were prepared in their traditional form and screened for blood schizonticidal activity in vitro on Plasmodium falciparum chloroquine re4sistant strain (W2). Some of these extracts were screened in vivo against Plasmodium yoelii rodent malaria. Ferriprotoporphyrin inhibition test was also performed. Four remedies, widely used among the population as preventives, were able to inhibit more than 50% of the parasite growth in vivo at around 100 mg/kg: Irlbachia alata (Gentiananceae), Picrolemma pseudocoffea (Simaroubaceae), Quassia amara (Simaroubaceae), Tinospora crispa (Menispermaceae) and Zanthoxylum rhoifolium (Rutaceae). Five remedies displayed an IC50 in vitro < 10 microg/ml: Picrolemma pseudocoffea, Pseudoxandra cuspidata (Annonaceae) and Quassia amara leaves and stem, together with a multi-ingredient recipe. Two remedies were more active than a Cinchona preparation on the ferriprotoporphyrin inhibition test: Picrolemma pseudocoffea and Quassia amara. We also showed that a traditional preventive remedy, made from Geissospermum argenteum bark macerated in rum, was able to impair the intrahepatic cycle of the parasite. For the first time, traditional remedies from French Guiana have been directly tested on malarial pharmacological assays and some have been shown to be active.

  8. Ultrasound in Radiology: from Anatomic, Functional, Molecular Imaging to Drug Delivery and Image-Guided Therapy

    Science.gov (United States)

    Klibanov, Alexander L.; Hossack, John A.

    2015-01-01

    During the past decade, ultrasound has expanded medical imaging well beyond the “traditional” radiology setting - a combination of portability, low cost and ease of use makes ultrasound imaging an indispensable tool for radiologists as well as for other medical professionals who need to obtain imaging diagnosis or guide a therapeutic intervention quickly and efficiently. Ultrasound combines excellent ability for deep penetration into soft tissues with very good spatial resolution, with only a few exceptions (i.e. those involving overlying bone or gas). Real-time imaging (up to hundreds and thousands frames per second) enables guidance of therapeutic procedures and biopsies; characterization of the mechanical properties of the tissues greatly aids with the accuracy of the procedures. The ability of ultrasound to deposit energy locally brings about the potential for localized intervention encompassing: tissue ablation, enhancing penetration through the natural barriers to drug delivery in the body and triggering drug release from carrier micro- and nanoparticles. The use of microbubble contrast agents brings the ability to monitor and quantify tissue perfusion, and microbubble targeting with ligand-decorated microbubbles brings the ability to obtain molecular biomarker information, i.e., ultrasound molecular imaging. Overall, ultrasound has become the most widely used imaging modality in modern medicine; it will continue to grow and expand. PMID:26200224

  9. Molecular epidemiology of drug-resistant Plasmodium falciparum in Benguela province, Angola.

    Science.gov (United States)

    Foumane Ngane, Vincent; Allico Djaman, Joseph; Culeux, Cécile; Piette, Nathalie; Carnevale, Pierre; Besnard, Patrick; Fortes, Filomeno; Basco, Leonardo K; Tahar, Rachida

    2015-03-14

    The malaria situation has been worsening in Angola, partly due to armed conflict until the recent past and drug-resistant Plasmodium falciparum. Malaria transmission is heterogeneous within the country, and data on drug-resistant malaria in different parts of the country are incomplete. The aim of the present study was to evaluate resistance to 4-aminoquinolines and antifolate drugs in P. falciparum isolates collected in Benguela province, central Angola, using molecular markers. Fingerprick capillary blood was collected from asymptomatic children aged less than 15 years old during a household survey in and around Balombo town in 2010-2011. Samples were screened for P. falciparum by nested PCR. Molecular markers (P. falciparum dihydrofolate reductase [pfdhfr], P. falciparum dihydropteroate synthase [pfdhps], P. falciparum chloroquine resistance transporter [pfcrt], and P. falciparum multidrug-resistance gene 1 [pfmdr1]) were sequenced to determine the key codons associated with drug resistance. A total of 60 blood samples were positive for P. falciparum. Most isolates with successful PCR amplification had mutant pfdhfr alleles, with either double mutant AICNI (69%) or triple mutant AIRNI (21%) haplotypes. A16V, S108T, and I164L substitutions were not found. Many of the isolates were carriers of either SGKAA (60%) or AGKAA (27%) pfdhps haplotype. K540E substitution was absent. There were only two pfcrt haplotypes: wild-type CVMNK (11%) and mutant CVIET (89%). Wild-type pfmdr1 NYSND haplotype was found in 19% of the isolates, whereas single mutant pfmdr1 YYSND and NFSND haplotypes occurred in 48% and 11%, respectively. Double mutant pfmdr1 haplotypes (YFSND and YYSNY) occurred rarely. The results suggest that the high prevalence of mutant pfcrt CVIET haplotype is in agreement with low clinical efficacy of chloroquine observed in earlier studies and that the double pfdhfr mutant AICNI and single pfdhps mutant SGKAA are currently the predominant haplotypes associated

  10. Mammaglobin as a potential molecular target for breast cancer drug delivery

    Directory of Open Access Journals (Sweden)

    Fleming Timothy P

    2009-03-01

    Full Text Available Abstract Background Mammaglobin (MAM has been used as a specific molecular marker for breast cancer diagnosis. Recently, several groups of researchers proposed a number of therapeutic strategies targeting this molecule. Some of the strategies are based upon an essential but not demonstrated hypothesis – mammaglobin is associated with the surface of breast cancer cells, which strongly disputes the therapeutic strategies. Results We conducted a computer-based predictive analysis and identified a small fragment at the N-end of MAM as a potential transmembrane domain. We provided several evidences to demonstrate the presence of the membrane-associated MAM. We isolated the membrane protein components from known MAM positive breast cancer cells (MDA-MB361 and MDA-MB415. We showed that about 22–64% of MAM proteins, depending upon the types of the cancer cells, directly attached on the membrane of breast cancer cells, by Western blotting assays. To directly visualize the presence of the membrane-bound MAM protein, we incubated the MAM positive cancer cells with FITC labeled anti-MAM antibody, and observed clear fluorescent signals on the surface of the cells. In studying the MAM protein distribution in human breast cancer tissues, we first identified two immunostain patterns that are associated with the membrane-bound MAM: the membrane stain pattern and luminary surface stain pattern. To test whether the membrane-associated MAM can serve as a molecular target for drug delivery, we conjugated anti-MAM antibody to human low-density lipoprotein (LDL and loaded doxorubicin (Dox in the core of LDL. Specific binding and cytotoxicity of the MAM targeted and Dox loaded LDL was tested in the MAM positive breast cancer cells in vitro. Conclusion We first showed that some of MAM protein directly associated with the surface of breast cancer cells. The membrane-associated MAM protein may be utilized as a useful molecular marker for breast cancer targeted drug

  11. Investigating the Interaction Pattern and Structural Elements of a Drug-Polymer Complex at the Molecular Level.

    Science.gov (United States)

    Nie, Haichen; Mo, Huaping; Zhang, Mingtao; Song, Yang; Fang, Ke; Taylor, Lynne S; Li, Tonglei; Byrn, Stephen R

    2015-07-06

    Strong associations between drug and polymeric carriers are expected to contribute to higher drug loading capacities and better physical stability of amorphous solid dispersions. However, molecular details of the interaction patterns and underlying mechanisms are still unclear. In the present study, a series of amorphous solid dispersions of clofazimine (CLF), an antileprosy drug, were prepared with different polymers by applying the solvent evaporation method. When using hypromellose phthalate (HPMCP) as the carrier, the amorphous solid dispersion system exhibits not only superior drug loading capacity (63% w/w) but also color change due to strong drug-polymer association. In order to further explain these experimental observations, the interaction between CLF and HPMCP was investigated in a nonpolar volatile solvent system (chloroform) prior to forming the solid dispersion. We observed significant UV/vis and (1)H NMR spectral changes suggesting the protonation of CLF and formation of ion pairs between CLF and HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate the strength of associations between drug and polymers, as well as the molecular mobility of CLF. Finally, by correlating the experimental values with quantum chemistry calculations, we demonstrate that the protonated CLF is binding to the carboxylate group of HPMCP as an ion pair and propose a possible structural model of the drug-polymer complex. Understanding the drug and carrier interaction patterns from a molecular perspective is critical for the rational design of new amorphous solid dispersions.

  12. Molecular Docking Assessment of Efficacy of Different Clinically Used Arsenic Chelator Drugs

    Directory of Open Access Journals (Sweden)

    Durjoy Majumder

    2013-01-01

    Full Text Available Arsenic contamination of ground water has become a global problem affecting specially, south-east Asian countries like Bangladesh and eastern parts of India. It also affects South America and some parts of the US. Different organs of the physiological system are affected due to contamination of inorganic arsenic in water. Animal studies with different chelators are not very conclusive as far as the multi/differential organ effect(s of arsenic is concerned. Our docking study establishes the molecular rationale of blood test for early detection of arsenic toxicity; as arsenic has a high affinity to albumin, a plasma protein and actin, a structural protein of all cells including Red Blood Cells. This study also shows that there is a little possibility of male reproductive organs toxicity by different forms of inorganic arsenic; however, female reproductive system is very much susceptible to sodium-arsenite. Through comparative analysis regarding the chelating effectiveness among the available arsenic chelator drugs, meso-2,3 dimercaptosuccinic acid (DMSA and in some cases lipoic acid is the most preferred choice of drug for removing of arsenic deposits. This computational method actually reinforces the clinical finding regarding DMSA as the most preferred drug in removal of arsenic deposits from majority of the human tissues.

  13. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

    Directory of Open Access Journals (Sweden)

    Khodakarim Nastaran

    2010-05-01

    Full Text Available Abstract Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain and CY27 (chloroquine-sensitive strain, using the parasite lactate dehydrogenase (pLDH assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain. Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy, Solanum surattense (Burm.f. and Prosopis juliflora (Sw. showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time.

  14. Quinoline hybrids and their antiplasmodial and antimalarial activities.

    Science.gov (United States)

    Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

    2017-10-20

    Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    di Nuzzo L

    2014-05-01

    Full Text Available Luigi di Nuzzo,1 Rosamaria Orlando,2 Carla Nasca,1 Ferdinando Nicoletti1,31Department of Physiology and Pharmacology, Sapienza University of Rome, 2IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, 3IRCCS Neuromed, Pozzilli, ItalyAbstract: New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12, laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1 the regulation of the immune system; 2 the permeability of the blood–brain barrier; and 3 the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism.Keywords: demyelinating diseases, pharmacotherapy, fingolimod, dimethyl fumarate, laquinimod, teriflunomide

  16. A novel in silico approach to drug discovery via computational intelligence.

    Science.gov (United States)

    Hecht, David; Fogel, Gary B

    2009-04-01

    A computational intelligence drug discovery platform is introduced as an innovative technology designed to accelerate high-throughput drug screening for generalized protein-targeted drug discovery. This technology results in collections of novel small molecule compounds that bind to protein targets as well as details on predicted binding modes and molecular interactions. The approach was tested on dihydrofolate reductase (DHFR) for novel antimalarial drug discovery; however, the methods developed can be applied broadly in early stage drug discovery and development. For this purpose, an initial fragment library was defined, and an automated fragment assembly algorithm was generated. These were combined with a computational intelligence screening tool for prescreening of compounds relative to DHFR inhibition. The entire method was assayed relative to spaces of known DHFR inhibitors and with chemical feasibility in mind, leading to experimental validation in future studies.

  17. Electrochemical microfluidic chip based on molecular imprinting technique applied for therapeutic drug monitoring.

    Science.gov (United States)

    Liu, Jiang; Zhang, Yu; Jiang, Min; Tian, Liping; Sun, Shiguo; Zhao, Na; Zhao, Feilang; Li, Yingchun

    2017-05-15

    In this work, a novel electrochemical detection platform was established by integrating molecularly imprinting technique with microfluidic chip and applied for trace measurement of three therapeutic drugs. The chip foundation is acrylic panel with designed grooves. In the detection cell of the chip, a Pt wire is used as the counter electrode and reference electrode, and a Au-Ag alloy microwire (NPAMW) with 3D nanoporous surface modified with electro-polymerized molecularly imprinted polymer (MIP) film as the working electrode. Detailed characterization of the chip and the working electrode was performed, and the properties were explored by cyclic voltammetry and electrochemical impedance spectroscopy. Two methods, respectively based on electrochemical catalysis and MIP/gate effect were employed for detecting warfarin sodium by using the prepared chip. The linearity of electrochemical catalysis method was in the range of 5×10 -6 -4×10 -4 M, which fails to meet clinical testing demand. By contrast, the linearity of gate effect was 2×10 -11 -4×10 -9 M with remarkably low detection limit of 8×10 -12 M (S/N=3), which is able to satisfy clinical assay. Then the system was applied for 24-h monitoring of drug concentration in plasma after administration of warfarin sodium in rabbit, and the corresponding pharmacokinetic parameters were obtained. In addition, the microfluidic chip was successfully adopted to analyze cyclophosphamide and carbamazepine, implying its good versatile ability. It is expected that this novel electrochemical microfluidic chip can act as a promising format for point-of-care testing via monitoring different analytes sensitively and conveniently. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. A network-based classification model for deriving novel drug-disease associations and assessing their molecular actions.

    Directory of Open Access Journals (Sweden)

    Min Oh

    Full Text Available The growing number and variety of genetic network datasets increases the feasibility of understanding how drugs and diseases are associated at the molecular level. Properly selected features of the network representations of existing drug-disease associations can be used to infer novel indications of existing drugs. To find new drug-disease associations, we generated an integrative genetic network using combinations of interactions, including protein-protein interactions and gene regulatory network datasets. Within this network, network adjacencies of drug-drug and disease-disease were quantified using a scored path between target sets of them. Furthermore, the common topological module of drugs or diseases was extracted, and thereby the distance between topological drug-module and disease (or disease-module and drug was quantified. These quantified scores were used as features for the prediction of novel drug-disease associations. Our classifiers using Random Forest, Multilayer Perceptron and C4.5 showed a high specificity and sensitivity (AUC score of 0.855, 0.828 and 0.797 respectively in predicting novel drug indications, and displayed a better performance than other methods with limited drug and disease properties. Our predictions and current clinical trials overlap significantly across the different phases of drug development. We also identified and visualized the topological modules of predicted drug indications for certain types of cancers, and for Alzheimer's disease. Within the network, those modules show potential pathways that illustrate the mechanisms of new drug indications, including propranolol as a potential anticancer agent and telmisartan as treatment for Alzheimer's disease.

  19. Biological activity, quantitative structure–activity relationship analysis, and molecular docking of xanthone derivatives as anticancer drugs

    Science.gov (United States)

    Miladiyah, Isnatin; Jumina, Jumina; Haryana, Sofia Mubarika; Mustofa, Mustofa

    2018-01-01

    Background Xanthone derivatives have a wide range of pharmacological activities, such as those involving antibacterial, antiviral, antimalarial, anthelmintic, anti-inflammatory, antiprotozoal, and anticancer properties. Among these, we investigated the anticancer properties of xanthone. This research aimed to analyze the biological activity of ten novel xanthone derivatives, to investigate the most contributing-descriptors for their cytotoxic activities, and to examine the possible mechanism of actions of xanthone compound through molecular docking. Materials and methods The cytotoxic tests were carried out on WiDR and Vero cell lines, by a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay method. The structural features required for xanthone’s anticancer activity were conducted by using the semi-empirical Austin Model-1 method, and continued with quantitative structure-activity relationship (QSAR) analysis using BuildQSAR program. The study of the possible mechanism of actions of the selected xanthone compound was done through molecular docking with PLANTS. Results The three novel xanthone derivatives (compounds 5, 7, and 8) exhibited cytotoxic activity with compound 5 showed the highest degree of cytotoxicity at concentration 9.23 µg/mL (37.8 µM). The following best equation model was obtained from the BuildQSAR calculation: log 1/IC50 = −8.124 qC1 −35.088 qC2 −6.008 qC3 + 1.831 u + 0.540 logP −9.115 (n = 10, r = 0.976, s = 0.144, F = 15.920, Q2 = 0.651, SPRESS = 0.390). This equation model generated 15 proposed new xanthone compounds with better-predicted anticancer activities. A molecular docking study of compound 5 showed that xanthone formed binding interactions with some receptors involved in cancer pathology, including telomerase, tumor-promoting inflammation (COX-2), and cyclin-dependent kinase-2 (CDK2) inhibitor. Conclusion The results suggested that compound 5 showed the best cytotoxic activity among the xanthone

  20. Engineering Botulinum Neurotoxin C1 as a Molecular Vehicle for Intra-Neuronal Drug Delivery.

    Science.gov (United States)

    Vazquez-Cintron, Edwin J; Beske, Phillip H; Tenezaca, Luis; Tran, Bao Q; Oyler, Jonathan M; Glotfelty, Elliot J; Angeles, Christopher A; Syngkon, Aurelia; Mukherjee, Jean; Kalb, Suzanne R; Band, Philip A; McNutt, Patrick M; Shoemaker, Charles B; Ichtchenko, Konstantin

    2017-02-21

    Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD 50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm.

  1. In-vitro dissolution rate and molecular docking studies of cabergoline drug with β-cyclodextrin

    Science.gov (United States)

    Shanmuga priya, Arumugam; Balakrishnan, Suganya bharathi; Veerakanellore, Giri Babu; Stalin, Thambusamy

    2018-05-01

    The physicochemical properties and dissolution profile of cabergoline drug (CAB) with β-cyclodextrin (β-CD) inclusion complex were investigated by the UV spectroscopy. The inclusion complex has used to calculate the stability constant and gives the stoichiometry molar ratio is 1:1 between CAB and β-CD. The phase solubility diagram and the aqueous solubility of CAB (60%) was found to be enhanced by β-CD. In addition, the phase solubility profile of CAB with β-CD was classified as AL-type. Binary systems of CAB with β-CD were prepared by Physical mixture, Kneading and solvent evaporation methods. The solid-state properties of the inclusion complex were characterized by Fourier transformation-infrared spectroscopy, Differential scanning calorimetry, Powder X-ray diffractometric patterns and Scanning electron microscopic techniques. Theoretically, β-CD and CAB inclusion complex obtained by molecular docking studies, it is in good correlation with the results obtained through experimental methods using the Schrödinger software program. In-vitro dissolution profiles of the inclusion complexes were carried out and obvious increase in dissolution rate was observed when compared with pure CAB drug and the complexes.

  2. ISOLATION AND PRESENCE OF ANTIMALARIAL ACTIVITIES OF MARINE SPONGE Xestospongia sp.

    Directory of Open Access Journals (Sweden)

    Murtihapsari Murtihapsari

    2013-12-01

    Full Text Available Plasmodium falciparum, the agent of malignant malaria, is one of mankind's most severe scourges, mainly in the tropic world. Efforts to develop preventive vaccines or remedial drugs are handicapped by the parasite's rapid evolution of drug resistance. Here, we presented an advance work on examination of antimalarial component from marine life of Xestospongia sp., the study is based on hexane extraction method. The premier result, we obtained five fractions. Among these five fractions, the fourth has the most potent inhibitory against the growth of P. falciparum 3D7 with an IC50: 7.13 µg/mL. A compiled spectrum analysis, FTIR, 1H-NMR and GC-MS, revealed that the fourth fraction consisted abundantly of two secondary metabolites such as flavonoids and triterpenoids. Finally, our results suggest a plausible structure rooted to the base of ibuprofen.

  3. Molecular modeling and multispectroscopic studies of the interaction of hepatitis B drug, adefovir dipivoxil with human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Shahabadi, Nahid, E-mail: nahidshahabadi@yahoo.com [Department of Chemistry, Faculty of Science, Razi University, Kermanshah (Iran, Islamic Republic of); Medical Biology Research Center (MBRC) Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Falsafi, Monireh [Department of Chemistry, Faculty of Science, Razi University, Kermanshah (Iran, Islamic Republic of); Hadidi, Saba [Department of Chemistry, Faculty of Science, Razi University, Kermanshah (Iran, Islamic Republic of); Medical Biology Research Center (MBRC) Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of)

    2015-11-15

    The interaction of hepatitis B drug, adefovir dipivoxil with human serum albumin (HSA) was studied by using UV–vis, fluorometric, circular dichroism (CD) and molecular docking techniques. The results indicated that the binding of the drug to HSA caused fluorescence quenching through static quenching mechanism with binding constant of 1.3×103 M{sup −1}. The thermodynamic parameters indicated that the hydrophobic force contacts are the major forces in the stability of protein-drug complex (ΔH>0 and ΔS>0). The displacement experiments using the site probes viz., warfarin and ibuprofen showed that adefovir dipivoxil could bind to the site III of HSA. The results of CD and UV–vis spectroscopy indicated that the binding of the drug induced some conformational changes in HSA. Furthermore, the study of molecular docking also confirmed binding of adefovir dipivoxil to the site III of HSA by hydrophobic interaction. - Highlights: • The interaction of adefovir dipivoxil, drug for the treatment of HIV and HBV with human serum albumin (HSA) is investigated. • The drug bound to HSA by hydrophobic force and induced some conformational changes in HSA. • The study of molecular docking showed that adefovir dipivoxil could bind to the site III of HSA mainly.

  4. Molecular modeling and multispectroscopic studies of the interaction of hepatitis B drug, adefovir dipivoxil with human serum albumin

    International Nuclear Information System (INIS)

    Shahabadi, Nahid; Falsafi, Monireh; Hadidi, Saba

    2015-01-01

    The interaction of hepatitis B drug, adefovir dipivoxil with human serum albumin (HSA) was studied by using UV–vis, fluorometric, circular dichroism (CD) and molecular docking techniques. The results indicated that the binding of the drug to HSA caused fluorescence quenching through static quenching mechanism with binding constant of 1.3×103 M −1 . The thermodynamic parameters indicated that the hydrophobic force contacts are the major forces in the stability of protein-drug complex (ΔH>0 and ΔS>0). The displacement experiments using the site probes viz., warfarin and ibuprofen showed that adefovir dipivoxil could bind to the site III of HSA. The results of CD and UV–vis spectroscopy indicated that the binding of the drug induced some conformational changes in HSA. Furthermore, the study of molecular docking also confirmed binding of adefovir dipivoxil to the site III of HSA by hydrophobic interaction. - Highlights: • The interaction of adefovir dipivoxil, drug for the treatment of HIV and HBV with human serum albumin (HSA) is investigated. • The drug bound to HSA by hydrophobic force and induced some conformational changes in HSA. • The study of molecular docking showed that adefovir dipivoxil could bind to the site III of HSA mainly

  5. 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 (76T), while 68% had mutant pfmdr-1 genotype (86Y). 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 (51I/59R/108N/164L) 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/pyrimethamine in

  6. Recent progress, challenges and trends in trace determination of drug analysis using molecularly imprinted solid-phase microextraction technology.

    Science.gov (United States)

    Ansari, Saeedeh; Karimi, Majid

    2017-03-01

    The quantification of drugs in biological samples is a significant task for determination of the physiological efficiency in evaluated drugs in the drug discovery. To analysis of the chemical compounds at the trace and ultratrace levels, adequate analytical procedures should be applied. Therefore, sample preparation method undoubtedly is the most important stage in the trace determination process. In spite of the great growth of analytical instrumentation during the recent years, sample preparation is still nowadays considered the impasse of the all analytical procedure, especially in drugs analysis. Because of the low concentration level of drugs in blood, plasma, and the diversity of the metabolites, the chosen extraction technique should be almost perfect. Solid-phase microextraction (SPME) is a powerful, simple, fast and an equilibrium-based sample preparation method that permits integration of sampling, sample clean-up, and pre-concentration in a single solvent-free step for chemical analysis. Molecularly imprinted polymers (MIPs) that provided by the presence of a template during their synthesis are the stable polymers with molecular recognition abilities and excellent materials which provide selectivity to sample preparation. Because of its characteristics such as easy preparation, high selectivity, and chemical stability, MIP is widely utilized in many analytical fields. Accordingly, the molecular imprinting and SPME methods combination would prepare a strong analytical instrumentation which comprises simplicity, flexibility, and the selectivity characteristics of both methods. This review focuses on the application of solid-phase microextraction method coupled with molecularly imprinted polymers, namely molecularly imprinted solid-phase microextraction (MISPME), for trace determination in drug analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Evaluation of the use of Cocos nucifera as antimalarial remedy in Malaysian folk medicine.

    Science.gov (United States)

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

    2011-04-12

    White flesh extract of Cocos nucifera (coconut) was studied to ascertain the ethnopharmacological standing of its antimalarial usage in Malaysian folk medicine. The crude methanol extract was investigated for phytochemical constituents and acute oral toxicity. Antimalarial activity of different extract doses of 50, 100, 200 and 400mg/kg were investigated in vivo against Plasmodium berghei (NK65) infections in mice during early, established and residual infections. Chloroquine (20mg/kg) and pyrimethamine (1.2mg/kg) were used as reference drugs. The results revealed that the extract contained some phytochemical constituents and is toxicologically safe by oral administration. The extract significantly reduced the parasitaemia by the 200 and 400mg/kg doses in the all three in vivo assessment assays. However, the extract did not significantly increase the survival time of the infected mice. The observed pharmacological activities suggest that the Malaysian folkloric medicinal application of Cocos nucifera has a pharmacological basis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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

    Science.gov (United States)

    Bamunuarachchi, Gayan S; Ratnasooriya, Wanigasekara D; Premakumara, Sirimal; Udagama, Preethi V

    2013-12-01

    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. 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. 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. 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.

  9. Imatinib (Gleevec@) conformations observed in single crystals, protein-Imatinib co-crystals and molecular dynamics: Implications for drug selectivity

    Science.gov (United States)

    Golzarroshan, B.; Siddegowda, M. S.; Li, Hong qi; Yathirajan, H. S.; Narayana, B.; Rathore, R. S.

    2012-06-01

    Structure and dynamics of the Leukemia drug, Imatinib, were examined using X-ray crystallography and molecular dynamics studies. Comparison of conformations observed in single crystals with several reported co-crystals of protein-drug complexes suggests existence of two conserved conformations of Imatinib, extended and compact (or folded), corresponding to two binding modes of interaction with the receptor. Furthermore, these conformations are conserved throughout a dynamics simulation. The present study attempts to draw a parallel on conformations and binding patterns of interactions, obtained from small-molecule single-crystal and macromolecule co-crystal studies, and provides structural insights for understanding the high selectivity of this drug molecule.

  10. Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

    DEFF Research Database (Denmark)

    Kopec, Wojciech; Khandelia, Himanshu

    2014-01-01

    mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations...... for the negatively charged bilayer. We show that the origin of such changes is the drug induced decrease of the interfacial tension, which ultimately leads to the significant membrane expansion. Our findings support the hypothesis that the phenothiazines therapeutic activity may arise from the drug...

  11. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Daria Van Tyne

    2011-04-01

    Full Text Available The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb, and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS, searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.