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Sample records for antimalarial drug quality

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

    PubMed

    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.

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

    PubMed Central

    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

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

    PubMed

    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.

  4. Herbicidal properties of antimalarial drugs

    PubMed Central

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

    2017-01-01

    The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true; many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules. PMID:28361906

  5. Antimalarial drug quality in the most severely malarious parts of Africa - a six country study.

    PubMed

    Bate, Roger; Coticelli, Philip; Tren, Richard; Attaran, Amir

    2008-05-07

    A range of antimalarial drugs were procured from private pharmacies in urban and peri-urban areas in the major cities of six African countries, situated in the part of that continent and the world that is most highly endemic for malaria. Semi-quantitative thin-layer chromatography (TLC) and dissolution testing were used to measure active pharmaceutical ingredient content against internationally acceptable standards. 35% of all samples tested failed either or both tests, and were substandard. Further, 33% of treatments collected were artemisinin monotherapies, most of which (78%) were manufactured in disobservance of an appeal by the World Health Organisation (WHO) to withdraw these clinically inappropriate medicines from the market. The high persistence of substandard drugs and clinically inappropriate artemisinin monotherapies in the private sector risks patient safety and, through drug resistance, places the future of malaria treatment at risk globally.

  6. Substandard Antimalarials Available in Afghanistan: A Case for Assessing the Quality of Drugs in Resource Poor Settings

    PubMed Central

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

    2015-01-01

    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. PMID:25897070

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

    PubMed

    Lalani, Mirza; Kaur, Harparkash; Mohammed, Nader; Mailk, Naiela; van Wyk, Albert; 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.

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

    PubMed Central

    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

  9. Rational quality assessment procedure for less-investigated herbal medicines: Case of a Congolese antimalarial drug with an analytical report.

    PubMed

    Tshitenge, Dieudonné Tshitenge; Ioset, Karine Ndjoko; Lami, José Nzunzu; Ndelo-di-Phanzu, Josaphat; Mufusama, Jean-Pierre Koy Sita; Bringmann, Gerhard

    2016-04-01

    Herbal medicines are the most globally used type of medical drugs. Their high cultural acceptability is due to the experienced safety and efficiency over centuries of use. Many of them are still phytochemically less-investigated, and are used without standardization or quality control. Choosing SIROP KILMA, an authorized Congolese antimalarial phytomedicine, as a model case, our study describes an interdisciplinary approach for a rational quality assessment of herbal drugs in general. It combines an authentication step of the herbal remedy prior to any fingerprinting, the isolation of the major constituents, the development and validation of an HPLC-DAD analytical method with internal markers, and the application of the method to several batches of the herbal medicine (here KILMA) thus permitting the establishment of a quantitative fingerprint. From the constitutive plants of KILMA, acteoside, isoacteoside, stachannin A, and pectolinarigenin-7-O-glucoside were isolated, and acteoside was used as the prime marker for the validation of an analytical method. This study contributes to the efforts of the WHO for the establishment of standards enabling the analytical evaluation of herbal materials. Moreover, the paper describes the first phytochemical and analytical report on a marketed Congolese phytomedicine.

  10. New tissue schizontocidal antimalarial drugs

    PubMed Central

    Davidson, David E.; Ager, Arba L.; Brown, John L.; Chapple, Frank E.; Whitmire, Richard E.; Rossan, Richard N.

    1981-01-01

    Over 700 causal prophylactic and radical curative antimalarial drugs have been discovered during the screening of approximately 4000 chemical compounds in rodent and simian malaria models. Causal prophylactic activity in the Plasmodium berghei—rodent model was demonstrated by 10 distinct groups of chemicals: 1) tetrahydrofolate dehydrogenase inhibitors, 2) naphthoquinones, 3) dihydroacridinediones, 4) tetrahydrofurans, 5) guanylhydrazones, 6) analogues of clopidol, 7) quinoline esters, 8) dibenzyltetrahydro-pyrimidines, 9) 6-aminoquinolines, 10) 8-aminoquinolines. Of the causal prophylactic compounds, only the 6- and 8-aminoquinolines were capable of curing persistent exoerythrocytic infections of P. cynomolgi in rhesus monkeys. The 6-aminoquinolines were substantially less active than primaquine. This report describes a series of 4-methyl-5-phenoxy-6-methoxy-8-aminoquinolines, which are potent blood schizontocides and radical curative drugs. The most active member of this series, 4-methyl-5-(3-trifluoromethylphenoxy)-6-methoxy-8-[(4-amino-1-methylbutyl)| amino]quinoline succinate (WR 225448), was 5 times more active than primaquine in curing persistent exoerythrocytic infections of P. cynomolgi in rhesus monkeys. As a blood schizontocide, WR 225448 was effective in animal models against P. berghei, P. cynomolgi, P. vivax, and both drug-sensitive and drug-resistant strains of P. falciparum. WR 225448 was also more toxic than primaquine in rats on subacute (28-day) administration. PMID:6976854

  11. The Tragedy Caused by Fake Antimalarial Drugs

    PubMed Central

    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. PMID:22708042

  12. Trends in antimalarial drug use in Africa.

    PubMed

    Flegg, Jennifer A; Metcalf, Charlotte J E; Gharbi, Myriam; Venkatesan, Meera; Shewchuk, Tanya; Hopkins Sibley, Carol; Guerin, Philippe J

    2013-11-01

    Resistance to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) led the World Health Organization (WHO) to recommend changes in national drug policies. The time between policy changes and their implementation profoundly affects program impact. We developed a model based on data on antimalarial treatments, extracted from household surveys and national antimalarial policy information from the literature. Drug use in each country during the time period 1999-2011 and the trend in reduction of CQ use after policy change were estimated. The SP use estimates were correlated with the prevalence of a molecular marker associated with SP resistance. There was no spatial pattern in the country-level rate of reduction of CQ use, after policy change. In East Africa SP drug use was strongly correlated to resistance. If artemisinin resistance spreads to, or emerges in, Africa this methodology will be a valuable tool to estimate actual drug use and its impact on changes in drug efficacy.

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

    PubMed

    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.

  14. Counterfeit and Substandard Antimalarial Drugs

    MedlinePlus

    ... products, because some manufacturers try to avoid costly quality control and good manufacturing practices. The quality of commercially ... vary due to lack of regulations and poor quality control practices in many of these countries. Some pills ...

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

    PubMed Central

    Grimberg, Brian T.; Mehlotra, Rajeev K.

    2011-01-01

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

  16. Hemozoin Formation as a Target for Antimalarial Drug Design

    DTIC Science & Technology

    2005-02-01

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

  17. Development of mefloquine as an antimalarial drug*

    PubMed Central

    1983-01-01

    The spread of multiresistant strains of Plasmodium falciparum in south-east Asia and South America and the appearance of chloroquine resistance in Africa indicates the urgent need for alternative drugs against these parasites. Mefloquine, a 4-quinoline methanol, is the only new drug that is currently at an advanced stage of development. Studies in animal models and in the clinic have shown that it is highly active as a blood schizontocide against strains that are resistant to many established antimalarials, e.g., chloroquine and pyrimethamine. It is not, however, effective as a causal prophylactic agent. Preclinical toxicological, teratological, and carcinogenicity studies do not indicate any major contraindications to its use. Intensive clinical studies have been carried out in Africa, North and South America, south-east Asia, and Europe. These studies have indicated that the compound is generally well tolerated, safe, and effective in the treatment of malaria, particularly infections with chloroquine-resistant parasites. In order to protect this new and promising drug against the development of resistance to it in endemic areas, it is important that its introduction should be accomplished in a rational and deliberate manner. Appropriate precautionary measures include the development of mefloquine combinations (a combination of mefloquine with pyrimethamine—sulfadoxine is presently under investigation), its use with primaquine as a gametocytocidal drug to prevent transmission, and its deployment primarily for treatment, being used for prophylaxis only in special risk groups. PMID:6407767

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

    PubMed

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

    2017-01-14

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

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

    PubMed Central

    Mukherjee, Avinaba; Sadhukhan, Gobinda Chandra

    2016-01-01

    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 resistance. PMID

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

    PubMed Central

    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

  1. Using evidence to change antimalarial drug policy in Kenya.

    PubMed

    Shretta, R; Omumbo, J; Rapuoda, B; Snow, R W

    2000-11-01

    Chloroquine resistance was first detected in Kenya in 1978 and escalated during the 1980s. Chloroquine remained the treatment of choice for uncomplicated malaria infections until revised guidelines were launched in 1998 despite a plethora of scientific evidence on failure. This review analyses the range and quality of the evidence base that was used to change the drug policy in Kenya from chloroquine to SP and examines the process of consensus building and decision making. Our review illustrates the difficulties in translating sensitivity data with gross geographical, temporal and methodological variations into national treatment policy. The process was complicated by limited options, unknown adverse effects of replacement therapies, cost, as well as limited guidance on factors pertinent to changing the drug policy for malaria. Although > 50% of the studies showed parasitological failures by 1995, there was a general lack of consensus on the principles for assessing drug failures, the inclusion criteria for the study subjects and the relative benefits of parasitological and clinical assessments. A change in international recommendations for assessment of drug efficacy in 1996 from parasitological to clinical response further perplexed the decisions. There is an urgent need for international standards and evidence-based guidelines to provide a framework to assist the process by which decision-makers in malaria-endemic countries can make rational choices for antimalarial drug policy change.

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

    PubMed

    Hromadkova, L; Soukup, T; Vlcek, J

    2012-08-01

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

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

    PubMed

    Ridley, Robert G

    2002-02-07

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

  4. Solution structures of antimalarial drug-heme complexes.

    PubMed

    Leed, Alison; DuBay, Kateri; Ursos, Lyann M B; Sears, Devin; De Dios, Angel C; Roepe, Paul D

    2002-08-13

    Paramagnetic metal centers [such as Fe(III) found within ferriprotoporphyrin IX heme (FPIX)] exert through space effects on the relaxation rate of nearby proton spins that depend critically on the metal-proton distance. We have measured these effects for all protons of several antimalarial drugs that bind to FPIX by systematically varying the drug:heme molar ratio in high field NMR experiments. These measurements allow us to determine precise FPIX Fe-drug H distances for the solution structures of noncovalent complexes formed between FPIX mu-oxo dimers and the antimalarial drugs chloroquine (CQ), quinine (QN), and quinidine (QD). Using these distances, we then performed distance restraint calculations to determine the lowest-energy solution structures of these complexes. Structures were solved for neutral, monoprotic (+1), and diprotic (+2) forms of the drugs. Analysis of these structures allows us to visualize for the first time the stereospecific differences between QN and QD binding to FPIX and the differences in populations of QN and QD solution structures upon changes in digestive vacuolar pH for drug resistant malarial parasites [Dzekunov, S. M., et al. (2000) Mol. Biochem. Parasitol. 110, 107-124]. The data indicate a previously unrecognized key role for the CQ aliphatic chain in stabilizing FPIX-CQ complexes, and suggest how lengthening or shortening the chain might perturb stability. We also define FPIX:drug stoichiometries of 2:1 for the complexes formed at physiological FPIX concentrations, in contrast to the 4:1 and 5:1 stoichiometries previously determined at higher FPIX concentrations [Dorn, A., et al. (1998) Biochem. Pharmacol. 55, 727-736]. These atomic resolution antimalarial drug-heme structures should help elucidate how these drugs inhibit formation of hemozoin during metabolism of heme within the malarial parasite Plasmodium falciparum and assist ongoing development of strategies for circumventing antimalarial drug resistance.

  5. Miniaturized Cultivation of Microbiota for Antimalarial Drug Discovery.

    PubMed

    Waterman, Carrie; Calcul, Laurent; Beau, Jeremy; Ma, Wai Sheung; Lebar, Matthew D; von Salm, Jacqueline L; Harter, Charles; Mutka, Tina; Morton, Lindsay C; Maignan, Patrick; Barisic, Betty; van Olphen, Alberto; Kyle, Dennis E; Vrijmoed, Lilian; Pang, Ka-Lai; Pearce, Cedric J; Baker, Bill J

    2016-01-01

    The ongoing search for effective antiplasmodial agents remains essential in the fight against malaria worldwide. Emerging parasitic drug resistance places an urgent need to explore chemotherapies with novel structures and mechanisms of action. Natural products have historically provided effective antimalarial drug scaffolds. In an effort to search nature's chemical potential for antiplasmodial agents, unconventionally sourced organisms coupled with innovative cultivation techniques were utilized. Approximately 60,000 niche microbes from various habitats (slow-growing terrestrial fungi, Antarctic microbes, and mangrove endophytes) were cultivated on a small-scale, extracted, and used in high-throughput screening to determine antimalarial activity. About 1% of crude extracts were considered active and 6% partially active (≥ 67% inhibition at 5 and 50 μg/mL, respectively). Active extracts (685) were cultivated on a large-scale, fractionated, and screened for both antimalarial activity and cytotoxicity. High interest fractions (397) with an IC50 < 1.11 μg/mL were identified and subjected to chromatographic separation for compound characterization and dereplication. Identifying active compounds with nanomolar antimalarial activity coupled with a selectivity index tenfold higher was accomplished with two of the 52 compounds isolated. This microscale, high-throughput screening project for antiplasmodial agents is discussed in the context of current natural product drug discovery efforts.

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

    PubMed

    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.

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

    PubMed Central

    Vale, Nuno; Aguiar, Luísa; Gomes, Paula

    2014-01-01

    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. PMID:25566072

  8. PfCRT and its role in antimalarial drug resistance

    PubMed Central

    Ecker, Andrea; Lehane, Adele M.; Clain, Jérôme; Fidock, David A.

    2012-01-01

    Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the ‘Chloroquine Resistance Transporter’ (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes. PMID:23020971

  9. Quantifying the pharmacology of antimalarial drug combination therapy

    PubMed Central

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

    2016-01-01

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

  10. Heme Aggregation inhibitors: antimalarial drugs targeting an essential biomineralization process.

    PubMed

    Ziegler, J; Linck, R; Wright, D W

    2001-02-01

    Malaria, resulting from the parasites of the genus Plasmodium, places an untold burden on the global population. As recently as 40 years ago, only 10% of the world's population was at risk from malaria. Today, over 40% of the world's population is at risk. Due to increased parasite resistance to traditional drugs and vector resistance to insecticides, malaria is once again resurgent. An emergent theme from current strategies for the development of new antimalarials is that metal homeostasis within the parasite represents an important drug target. During the intra-erythrocytic phase of its life cycle, the malaria parasite can degrade up to 75% of an infected cell's hemoglobin. While hemoglobin proteolysis yields requisite amino acids, it also releases toxic free heme (Fe(III)PPIX). To balance the metabolic requirements for amino acids against the toxic effects of heme, malaria parasites have evolved a detoxification mechanism which involves the formation of a crystalline heme aggregate known as hemozoin. An overview of the biochemistry of the critical detoxification process will place it in the appropriate context with regards to drug targeting and design. Quinoline-ring antimalarial drugs are effective against the intraerythrocytic stages of pigment-producing parasites. Recent work on the mechanism of these compounds suggests that they prevent the formation of hemozoin. Evidence for such a mechanism is reviewed, especially in the context of the newly reported crystal structure of hemozoin. Additionally, novel drugs, such as the hydroxyxanthones, which have many of the characteristics of the quinolines are currently being investigated. Recent work has also highlighted two classes of inorganic complexes that have interesting antimalarial activity: (1) metal-N(4)O(2) Schiff base complexes and (2) porphyrins. The mechanism of action for these complexes is discussed. The use of these complexes as probes for the elucidation of structure-activity relationships in heme

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

    PubMed Central

    2011-01-01

    Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems. PMID:22152094

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

    PubMed Central

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

    2015-01-01

    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 Ca2+, and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. PMID:26195527

  13. Long term effectiveness of antimalarial drugs in rheumatic diseases

    PubMed Central

    Avina-Zubieta, J; Galindo-Rodriguez, G.; Newman, S.; Suarez-Almazor, M.; Russell, A.

    1998-01-01

    OBJECTIVE—The purpose of this study was to compare the long term effectiveness between chloroquine (CQ) and hydroxychloroquine (HCQ).
METHODS—Medical charts of all patients seen by eight rheumatologists practising in two tertiary care centres and starting antimalarial treatment between January 1985 and December 1993 were reviewed. Patient characteristics, disease, and treatment information were collected. The main outcome measures were the cause of and the time to the discontinuation of antimalarial drugs resulting from all causes, principally toxicity or inefficacy, or both. Bivariate analysis including t tests and χ2 tests were used to assess differences between means and proportions respectively. Survival curves were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox regression) was used to adjust for potential confounders.
RESULTS—After all medical records were reviewed, 1042 eligible cases were identified. From these, 940 (90%) had usable information and they represent the cohort. Five hundred and fifty eight had rheumatoid arthritis, 178 had systemic lupus erythematosus, 127 had palindromic arthritis, and 77 had other diagnoses. Fifty seven per cent of the patients received CQ and 43% HCQ. The proportion of patients with side effects taking HCQ and CQ was 15% and 28% respectively (p=0.001). Using Cox regression model to adjust for age at the onset of antimalarial treatment, physician differences, sex, disease type, disease duration before treatment, and rank selection, there were no differences in the hazard ratio (HR) for overall discontinuations between CQ and HCQ. While the HR for discontinuations because of toxicity was lower for HCQ (HR= 0.6, 95% CI 0.4, 0.9), the HR for discontinuations because of inefficacy was significantly higher for HCQ (HR= 1.4, 95% CI 1.1, 1.9).
CONCLUSIONS—After adjusting for time and several confounders HCQ was less toxic but less effective than CQ. Only one case of probable

  14. Potential P-glycoprotein-mediated drug-drug interactions of antimalarial agents in Caco-2 cells.

    PubMed

    Oga, Enoche F; Sekine, Shuichi; Shitara, Yoshihisa; Horie, Toshiharu

    2012-07-01

    Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 μM) and quinidine (1 μM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-to-apical (B-A) P-gp-mediated DIG transport at concentrations of 100 μM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general.

  15. Paper Test Cards for Presumptive Testing of Very Low Quality Antimalarial Medications

    PubMed Central

    Weaver, Abigail A.; Lieberman, Marya

    2015-01-01

    Carrying out chemical analysis of antimalarials to detect low-quality medications before they reach a patient is a costly venture. Here, we show that a library of chemical color tests embedded on a paper card can presumptively identify formulations corresponding to very low quality antimalarial drugs. The presence or absence of chloroquine (CQ), doxycycline (DOX), quinine, sulfadoxine, pyrimethamine, and primaquine antimalarial medications, in addition to fillers used in low-quality pharmaceuticals, are indicated by patterns of colors that are generated on the test cards. Test card sensitivity for detection of these pure components ranges from 90% to 100% with no false positives in the absence of pharmaceutical. The color intensities from reactions characteristic of CQ or DOX allowed visual detection of formulations of these medications cut with 60% or 100% filler, although samples cut with 30% filler could not be reliably detected colorimetrically. However, the addition of unexpected fillers, even in 30% quantities, or substitute pharmaceuticals, could sometimes be detected by other color reactions on the test cards. Tests are simple and inexpensive enough to be carried out in clinics, pharmacies, and ports of entry and could provide a screening method to presumptively indicate very low quality medicines throughout the supply chain. PMID:25897064

  16. Assessment of urinary excretion of antimalarial drugs in large-scale chemotherapeutic eradication projects

    PubMed Central

    Bruce-Chwatt, L. J.

    1959-01-01

    Assessment of the urinary excretion of an antimalarial drug is a useful means of checking the amount of drug administered and the regularity of intake. The author describes the various methods available for the qualitative and quantitative estimation of antimalarial drugs in urine and discusses their relative merits, with special reference to their suitability for use in the field. He points out the difficulties involved in estimating the urinary excretion of antimalarials in large-scale chemotherapeutic eradication projects and stress the importance of simplifying testing techniques as far as possible. PMID:13805135

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

    PubMed Central

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

    2015-01-01

    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. PMID:26259943

  18. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    PubMed

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

    2016-01-01

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

  19. [The proper use of antimalarial drugs currently available].

    PubMed

    Bourgeade, A; Delmont, J

    1998-01-01

    French medical practitioners have at their disposal several antimalarial drugs for giving chemoprophylaxis to people travelling to a malaria endemic country or treating an imported malaria case in a patient. The choice depends on the contre-indications and indications of each drug, essentially subordinated to the presence and level of Plasmodium falciparum chemosensitivity in the visited area. For prevention, chloroquine alone can be taken in the areas where P. falciparum is absent or not chloroquine resistant; elsewhere, the choice between chloroquine/proguanil or mefloquine depends on knowing the prevalence and level of falciparum chloroquine resistance in these areas. For treatment, the only indications of chloroquine are imported malaria cases either due to P. vivax, P. ovale or P. malariae, or caused by P. falciparum contracted in one of the rare countries where the species is still sensitive to chloroquine. For uncomplicated falciparum malaria cases acquired in a chemoresistance area, mefloquine, halofantrine, sulfadoxine-pyrimethamine or oral quinine is selected, depending on the observed chemoprophylaxis, the contra-indications and the suspicion of chemoresistance type. Whatever the provenance area, P. falciparum in a patient with one or several serious symptoms or possibly profuse vomiting is treated by intravenous quinine, associated with tetracycline if the patient comes from an area known for a low quinine sensitivity of this species. The spectrum of falciparum malaria treatment has recently broadened to include new drugs such as artemisinin, artemether or atovaquone/proguanil, the latter being as yet unauthorized in France.

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

    PubMed

    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) < 85% or > 115% (including one counterfeit). Of the 95 antimalarials, 30 (32%) had %API < 85 > 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 < 85% API (with one counterfeit containing additional amoxicillin). Of 34 oral artesunate samples, 7 (21%) contained %API out of the 85-115% range. Coordinated and synergistic partnership adopted by the participating countries, International Criminal Police Organization (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.

  1. Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

    PubMed Central

    Matthews, Holly; Deakin, Jon; Rajab, May; Idris-Usman, Maryam

    2017-01-01

    The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26–32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product. PMID:28257497

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

    PubMed

    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.

  3. Role of US military research programs in the development of US Food and Drug Administration--approved antimalarial drugs.

    PubMed

    Kitchen, Lynn W; Vaughn, David W; Skillman, Donald R

    2006-07-01

    US military physicians and researchers helped identify the optimum treatment dose of the naturally occurring compound quinine and collaborated with the pharmaceutical industry in the development and eventual US Food and Drug Administration approval of the synthetic antimalarial drugs chloroquine, primaquine, chloroquine-primaquine, sulfadoxine-pyrimethamine, mefloquine, doxycycline, halofantrine, and atovaquone-proguanil. Because malaria parasites develop drug resistance, the US military must continue to support the creation and testing of new drugs to prevent and treat malaria until an effective malaria vaccine is developed. New antimalarial drugs also benefit civilians residing in and traveling to malarious areas.

  4. Inclusion of gametocyte parameters in anti-malarial drug efficacy studies: filling a neglected gap needed for malaria elimination.

    PubMed

    Abdul-Ghani, Rashad; Basco, Leonardo K; Beier, John C; Mahdy, Mohammed A K

    2015-10-19

    Standard anti-malarial drug efficacy and drug resistance assessments neglect the gametocyte parameters in their protocols. With the spread of drug resistance and the absence of clinically proven vaccines, the use of gametocytocidal drugs or drug combinations with transmission-blocking activity is a high priority for malaria control and elimination. However, the limited repertoire of gametocytocidal drugs and induction of gametocytogenesis after treatment with certain anti-malarial drugs necessitate both regular monitoring of gametocytocidal activities of anti-malarial drugs in clinical use and the effectiveness of candidate gametocytocidal agents. Therefore, updating current protocols of anti-malarial drug efficacy is needed to reflect the effects of anti-malarial drugs or drug combinations on gametocyte carriage and gametocyte density along with asexual parasite density. Developing protocols of anti-malarial drug efficacy that include gametocyte parameters related to both microscopic and submicroscopic gametocytaemias is important if drugs or drug combinations are to be strategically used in transmission-blocking interventions in the context of malaria elimination. The present piece of opinion highlights the challenges in gametocyte detection and follow-up and discuss the need for including the gametocyte parameter in anti-malarial efficacy studies.

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

    PubMed

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

    2016-06-17

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

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

    PubMed

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

    2015-01-01

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

  7. Considerations about the structure—activity relationships of 8-aminoquinoline antimalarial drugs

    PubMed Central

    McChesney, James D.

    1981-01-01

    A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinolines. It is emphasized that the mechanism of action of 8-aminoquinoline agents has not yet been established and thus any analysis of SAR must be speculative. PMID:6976853

  8. Potentiation of antimalarial drug action by chlorpheniramine against multidrug-resistant Plasmodium falciparum in vitro.

    PubMed

    Nakornchai, Sunan; Konthiang, Phattanapong

    2006-09-01

    Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the 3H-hypoxanthine incorporation. Chlorphenirame inhibited P. falciparum K1 and T9/94 growth with IC50 values of 136.0+/-40.2 microM and 102.0+/-22.6 microM respectively. A combination of antimalarial drug and chlorpheniramine was tested against resistant P. falciparum in vitro. Isobologram analysis showed that chlorpheniramine exerts marked synergistic action on chloroquine against P. falciparum K1 and T9/94. Chlorpheniramine also potentiated antimalarial action of mefloquine, quinine or pyronaridine against both of the resistant strains of P. falciparum. However, chlorpheniramine antagonism with artesunate was obtained in both P. falciparum K1 and T9/94. The results in this study indicate that antihistaminic drugs may be promising candidates for potentiating antimalarial drug action against drug resistant malarial parasites.

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

    PubMed

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

    2015-11-10

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

  10. Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

    PubMed Central

    Niknahad, Hossein; Heidari, Reza; Firuzi, Roya; Abazari, Farzaneh; Ramezani, Maral; Azarpira, Negar; Hosseinzadeh, Massood; Najibi, Asma; Saeedi, Arastoo

    2016-01-01

    Purpose: Accumulating evidence suggests that drug exposure during a modest inflammation induced by bacterial lipopolysaccharide (LPS) might increase the risk of drug-induced liver injury. The current investigation was designed to test if antimalarial drugs hepatotoxicity is augmented in LPS‑treated animals. Methods: Rats were pre-treated with LPS (100 µg/kg, i.p). Afterward, non-hepatotoxic doses of amodiaquine (25, 50 and 100 mg/kg, oral) and chloroquine (25, 50 and 100 mg/kg, oral) were administered. Results: Interestingly, liver injury was evident only in animals treated with both drug and LPS as estimated by pathological changes in serum biochemistry (ALT, AST, LDH, and TNF-α), and liver tissue (severe hepatitis, endotheliitis, and sinusoidal congestion). An increase in liver myeloperoxidase enzyme activity, lipid peroxidation, and protein carbonylation, along with tissue glutathione depletion were also detected in LPS and drug co-treated animals. Conclusion: Antimalarial drugs rendered hepatotoxic in animals undergoing a modest inflammation. These results indicate a synergistic liver injury from co-exposure to antimalarial drugs and inflammation. PMID:28101469

  11. Irrational use of antimalarial drugs in rural areas of eastern Pakistan: a random field study

    PubMed Central

    2012-01-01

    Background Prescription of antimalarial drugs in the absence of malarial disease is a common practice in countries where malaria is endemic. However, unwarranted use of such drugs can cause side effects in some people and is a financial drain on local economies. In this study, we surveyed the prevalence of malaria parasites in humans, and the prevalence of the malaria transmitting mosquito vectors in the study area. We also investigated the use of antimalarial drugs in the local people. We focused on randomly selected rural areas of eastern Pakistan where no malaria cases had been reported since May 2004. Methods Mass blood surveys, active case detection, passive case detection, and vector density surveys were carried out in selected areas of Sargodha district from September 2008 to August 2009. Data pertaining to the quantities and types of antimalarial drugs used in these areas were collected from health centers, pharmacies, and the district CDC program of the Health Department of the Government of the Punjab. Results Seven hundred and forty four blood samples were examined, resulting in a Blood Examination Rate (BER) of 3.18; microscopic analysis of blood smears showed that none of the samples were positive for malaria parasites. Investigation of the mosquito vector density in 43 living rooms (bedrooms or rooms used for sleeping), 23 stores, and 32 animal sheds, revealed no vectors capable of transmitting malaria in these locations. In contrast, the density of Culex mosquitoes was high. Substantial consumption of a variety of antimalarial tablets, syrups, capsules and injections costing around 1000 US$, was documented for the region. Conclusion Use of antimalarial drugs in the absence of malarial infection or the vectors that transmit the disease was common in the study area. Continuous use of such drugs, not only in Pakistan, but in other parts of the world, may lead to drug-induced side effects amongst users. Better training of health care professionals is

  12. A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

    PubMed Central

    Jiménez-Díaz, María Belén; Viera, Sara; Ibáñez, Javier; Mulet, Teresa; Magán-Marchal, Noemí; Garuti, Helen; Gómez, Vanessa; Cortés-Gil, Lorena; Martínez, Antonio; Ferrer, Santiago; Fraile, María Teresa; Calderón, Félix; Fernández, Esther; Shultz, Leonard D.; Leroy, Didier; Wilson, David M.; García-Bustos, José Francisco; Gamo, Francisco Javier; Angulo-Barturen, Iñigo

    2013-01-01

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

  13. Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine

    PubMed Central

    Olafson, Katy N.; Ketchum, Megan A.; Rimer, Jeffrey D.; Vekilov, Peter G.

    2015-01-01

    Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-μM concentration of chloroquine fully arrests layer generation and step advancement, which is ∼104× less than hematin’s physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials. PMID:25831526

  14. Impact of prepackaging antimalarial drugs on cost to patients and compliance with treatment.

    PubMed Central

    Yeboah-Antwi, K.; Gyapong, J. O.; Asare, I. K.; Barnish, G.; Evans, D. B.; Adjei, S.

    2001-01-01

    OBJECTIVE: To examine the extent to which district health teams could reduce the burden of malaria, a continuing major cause of mortality and morbidity, in a situation where severe resource constraints existed and integrated care was provided. METHODS: Antimalarial drugs were prepackaged into unit doses in an attempt to improve compliance with full courses of chemotherapy. FINDINGS: Compliance improved by approximately 20% in both adults and children. There were 50% reductions in cost to patients, waiting time at dispensaries and drug wastage at facilities. The intervention, which tended to improve both case and drug management at facilities, was well accepted by health staff and did not involve them in additional working time. CONCLUSION: The prepackaging of antimalarials at the district level offers the prospect of improved compliance and a reduction in the spread of resistance. PMID:11417034

  15. A nuclear magnetic resonance study of the interactions of antimalarial drugs with porphyrins.

    PubMed

    Moreau, S; Perly, B; Chachaty, C; Deleuze, C

    1985-05-29

    Haematins (hydroxyferriprotoporphyrin IX) constitute a possible receptor for antimalarial drugs such as chloroquine or quinine. This paper reports the study of the interactions of these two molecules with two tetrapyrrole (haematin and uroporphyrin I) by 1H-NMR spectroscopy. This method provided us with the geometry of the interactions in aqueous medium. The interaction consists of a close stacking of the porphyrin ring and the quinoleine moiety of the drugs. Using a porphyrin ring current model it was possible to reach the spatial relationships of the interacting species. It was concluded that hydrophobic forces play a key role in the interaction. The porphyrin plane can accommodate wide structural variations of the interacting species, leading to a weak specificity. The consequences on the mode of action of antimalarial drugs are discussed.

  16. Mind the gaps - the epidemiology of poor-quality anti-malarials in the malarious world - analysis of the WorldWide Antimalarial Resistance Network database

    PubMed Central

    2014-01-01

    Background Poor quality medicines threaten the lives of millions of patients and are alarmingly common in many parts of the world. Nevertheless, the global extent of the problem remains unknown. Accurate estimates of the epidemiology of poor quality medicines are sparse and are influenced by sampling methodology and diverse chemical analysis techniques. In order to understand the existing data, the Antimalarial Quality Scientific Group at WWARN built a comprehensive, open-access, global database and linked Antimalarial Quality Surveyor, an online visualization tool. Analysis of the database is described here, the limitations of the studies and data reported, and their public health implications discussed. Methods The database collates customized summaries of 251 published anti-malarial quality reports in English, French and Spanish by time and location since 1946. It also includes information on assays to determine quality, sampling and medicine regulation. Results No publicly available reports for 60.6% (63) of the 104 malaria-endemic countries were found. Out of 9,348 anti-malarials sampled, 30.1% (2,813) failed chemical/packaging quality tests with 39.3% classified as falsified, 2.3% as substandard and 58.3% as poor quality without evidence available to categorize them as either substandard or falsified. Only 32.3% of the reports explicitly described their definitions of medicine quality and just 9.1% (855) of the samples collected in 4.6% (six) surveys were conducted using random sampling techniques. Packaging analysis was only described in 21.5% of publications and up to twenty wrong active ingredients were found in falsified anti-malarials. Conclusions There are severe neglected problems with anti-malarial quality but there are important caveats to accurately estimate the prevalence and distribution of poor quality anti-malarials. The lack of reports in many malaria-endemic areas, inadequate sampling techniques and inadequate chemical analytical methods and

  17. Reliability of antimalarial sensitivity tests depends on drug mechanisms of action.

    PubMed

    Wein, Sharon; Maynadier, Marjorie; Tran Van Ba, Christophe; Cerdan, Rachel; Peyrottes, Suzanne; Fraisse, Laurent; Vial, Henri

    2010-05-01

    In vitro antimalarial activity tests play a pivotal role in malaria drug research or for monitoring drug resistance in field isolates. We applied two isotopic tests, two enzyme-linked immunosorbent assays (ELISA) and the SYBR green I fluorescence-based assay, to test artesunate and chloroquine, the metabolic inhibitors atovaquone and pyrimethamine, our fast-acting choline analog T3/SAR97276, and doxycycline, which has a delayed death profile. Isotopic tests based on hypoxanthine and ethanolamine incorporation are the most reliable tests provided when they are applied after one full 48-h parasite cycle. The SYBR green assay, which measures the DNA content, usually requires 72 h of incubation to obtain reliable results. When delayed death is suspected, specific protocols are required with increasing incubation times up to 96 h. In contrast, both ELISA tests used (pLDH and HRP2) appear to be problematic, leading to disappointing and even erroneous results for molecules that do not share an artesunatelike profile. The reliability of these tests is linked to the mode of action of the drug, and the conditions required to get informative results are hard to predict. Our results suggest some minimal conditions to apply these tests that should give rise to a standard 50% inhibitory concentration, regardless of the mechanism of action of the compounds, and highlight that the most commonly used in vitro antimalarial activity tests do not have the same potential. Some of them might not detect the antimalarial potential of new classes of compounds with innovative modes of action, which subsequently could become promising new antimalarial drugs.

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

    PubMed Central

    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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Marya; Khan, Haroon; Ahmad, Izhar

    2017-01-15

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

  1. Production of the antimalarial drug precursor artemisinic acid in engineered yeast.

    PubMed

    Ro, Dae-Kyun; Paradise, Eric M; Ouellet, Mario; Fisher, Karl J; Newman, Karyn L; Ndungu, John M; Ho, Kimberly A; Eachus, Rachel A; Ham, Timothy S; Kirby, James; Chang, Michelle C Y; Withers, Sydnor T; Shiba, Yoichiro; Sarpong, Richmond; Keasling, Jay D

    2006-04-13

    Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

  2. Altering Antimalarial Drug Regimens May Dramatically Enhance and Restore Drug Effectiveness

    PubMed Central

    Hastings, Ian M.

    2015-01-01

    There is considerable concern that malaria parasites are starting to evolve resistance to the current generation of antimalarial drugs, the artemisinin-based combination therapies (ACTs). We use pharmacological modeling to investigate changes in ACT effectiveness likely to occur if current regimens are extended from 3 to 5 days or, alternatively, given twice daily over 3 days. We show that the pharmacology of artemisinins allows both regimen changes to substantially increase the artemisinin killing rate. Malaria patients rarely contain more than 1012 parasites, while the standard dosing regimens allow approximately 1 in 1010 parasites to survive artemisinin treatment. Parasite survival falls dramatically, to around 1 in 1017 parasites if the dose is extended or split; theoretically, this increase in drug killing appears to be more than sufficient to restore failing ACT efficacy. One of the most widely used dosing regimens, artemether-lumefantrine, already successfully employs a twice-daily dosing regimen, and we argue that twice-daily dosing should be incorporated into all ACT regimen design considerations as a simple and effective way of ensuring the continued long-term effectiveness of ACTs. PMID:26239993

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

    PubMed

    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.

  4. Computer-assisted design of pro-drugs for antimalarial atovaquone.

    PubMed

    Karaman, Rafik; Hallak, Hussein

    2010-10-01

    Density Functional Theory (DFT) and ab initio calculation results for the proton transfer reaction in Kirby's enzyme models 1-6 reveal that the reaction rate is largely dependent on the existence of a hydrogen bonding net in the reactants and the corresponding transition states. Further, the distance between the two reacting centers and the angle of the hydrogen bonding formed along the reaction path has profound effects on the rate. Hence, the study on the systems reported herein could provide a good basis for designing antimalarial (atovaquone) pro-drug systems that can be used to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for pro-drug 1Pro may be predicted to be about 10¹¹ times faster than that for a pro-drug 4Pro and about 10⁴ times faster than pro-drug 2Pro: rate (1Pro) > rate (2Pro > rate (4Pro). Thus, the rate by which the pro-drug releases the antimalarial drug can be determined according to the nature of the linker (Kirby's enzyme model 1-6).

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

    PubMed Central

    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.

    2016-01-01

    Malaria is an infectious disease caused by parasites of the genus Plasmodium that inflicts 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 (NMT), which catalyzes N-myristoylation of protein substrates. 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 NMT inhibitors. We demonstrate that NMT 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 development of new antimalarials targeting NMT. PMID:24451586

  6. Chemical and genetic validation of thiamine utilization as an antimalarial drug target.

    PubMed

    Chan, Xie Wah Audrey; Wrenger, Carsten; Stahl, Katharina; Bergmann, Bärbel; Winterberg, Markus; Müller, Ingrid B; Saliba, Kevin J

    2013-01-01

    Thiamine is metabolized into an essential cofactor for several enzymes. Here we show that oxythiamine, a thiamine analog, inhibits proliferation of the malaria parasite Plasmodium falciparum in vitro via a thiamine-related pathway and significantly reduces parasite growth in a mouse malaria model. Overexpression of thiamine pyrophosphokinase (the enzyme that converts thiamine into its active form, thiamine pyrophosphate) hypersensitizes parasites to oxythiamine by up to 1,700-fold, consistent with oxythiamine being a substrate for thiamine pyrophosphokinase and its conversion into an antimetabolite. We show that parasites overexpressing the thiamine pyrophosphate-dependent enzymes oxoglutarate dehydrogenase and pyruvate dehydrogenase are up to 15-fold more resistant to oxythiamine, consistent with the antimetabolite inactivating thiamine pyrophosphate-dependent enzymes. Our studies therefore validate thiamine utilization as an antimalarial drug target and demonstrate that a single antimalarial can simultaneously target several enzymes located within distinct organelles.

  7. [WHO program for prequalification of antiretroviral, antimalarial and antituberculosis drugs].

    PubMed

    Gross, O

    2006-12-01

    Partnered with UNICEF, UNAIDS and the UN Population Fund, and receiving support from the World Bank, the WHO Prequalification Programme provides a solid, scientific assessment of the quality of both generic and patented medicines, based on internationally harmonized standards for evaluating information on product quality and bioequivalence, inspecting manufacturing sites, and undertaking quality control of pharmaceutical production. Agencies and organizations who procure medicines can be assured that products prequalified by WHO are of proven quality and that they do not themselves have to test these products. The WHO list of prequalified products also means that agencies procuring medicines can choose between several manufacturers offering the same quality product, which offers scope for negotiating lower prices. As a result of this Programme, capacity to manufacture generic products of assured quality is increasing, as is capacity to monitor that quality. Initially focusing on medicines for HIV/AIDS, TB and malaria, the Programme is now being expanded to also cover medicines for reproductive health.

  8. Voltammetric behaviour of antimalarial drug artesunate in solubilized systems.

    PubMed

    Jain, Rajeev; Vikas

    2011-12-01

    The voltammetric behaviour of artesunate is studied at glassy carbon electrode in different buffer systems using square wave, differential pulse and cyclic voltammetric techniques. The peak current is linear with the drug concentration in the range 4.0-40 μg mL(-1) for serum, plasma and urine. The mean percentage recoveries of the drug, urine, plasma and serum samples are 98.6-100.2%. No electroactive interferences from the excipients and endogenous substance could be observed in the pharmaceutical dosage forms and in biological samples.

  9. Antimalarial Drug Discovery: Approaches and Progress towards New Medicines

    PubMed Central

    Flannery, Erika L.; Chatterjee, Arnab K.; Winzeler, Elizabeth A.

    2014-01-01

    Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next generation medicines, public-private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of the parasite lifecycle. Here, we review the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing. PMID:24217412

  10. Clinical status and implications of antimalarial drug resistance.

    PubMed

    Winstanley, Peter A; Ward, Steven A; Snow, Robert W

    2002-02-01

    Africa carries the greatest burden of disease caused by Plasmodium falciparum, and we can expect this burden to rise in the near future, mainly because of drug resistance. Although effective drugs are available (such as artemether-lumefantrine, mefloquine, atovaquone-proguanil and halofantrine) they are uniformly too expensive for routine use. Affordable options include chloroquine plus sulfadoxine-pyrimethamine (SP), amodiaquine (alone or in combination with SP) and chlorproguanil-dapsone. Artemisinin combination therapy may offer considerable advantages over alternative therapies, but its introduction faces considerable logistic difficulty.

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

    NASA Astrophysics Data System (ADS)

    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

  12. Genotoxic evaluation of the antimalarial drug, fansidar, in cultured human lymphocytes.

    PubMed

    Abou-Eisha, A; Afifi, M

    2004-09-01

    Fansidar (pyrimethamine-sulfadoxine) has been used extensively worldwide for the treatment of chloroquine resistant Plasmodium falciparum malaria, toxoplasmosis and Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Because of the wide usage of pyrimethamine-sulfadoxine in developing countries and the lake of information from open literature and reports from manufacturers about the genotoxicity of such antimalarial drug, the present work was suggested. The possible genetic toxicity of fansidar has been evaluated in human peripheral blood lymphocyte cultures. The frequencies of sister-chromatid exchanges (SCE) and micronuclei (MN) were scored as genetic endpoints. Both tests covering a wide range of induced genetic damage as primary DNA damage, clastogenicity and aneugenicity. Cultures were set up by using blood samples from two healthy donors and the treatment was done using different fansidar concentrations ranging from 1:20 to 10:200 microg/ml. From our results, it appears that this drug is able to induce moderate genotoxic effects, as revealed by the increases found in SCE and MN frequencies in cultures from the two donors at the two highest concentrations tested (5:100 and 10:200 microg/ml). In addition, cyotoxic/cytostatic effects of fansidar were revealed by a decrease in the proliferative rate index (PRI) and in the cytokinesis block proliferation index (CBPI). Our findings suggest that the use of this drug should be restricted to situations where other antimalarial drugs cannot be used. The drug should never be given to pregnant women.

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

    PubMed Central

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

    2016-01-01

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

  14. Comparative efficacy and safety of chloroquine and alternative antimalarial drugs: a meta-analysis from six African countries.

    PubMed

    Mengesha, T; Makonnen, E

    1999-06-01

    A meta-analysis study evaluating the efficacy and safety of chloroquine and alternative antimalarial drugs used in six African countries including Ethiopia, Kenya, Uganda, Cote D'Ivoire, Gambia and Nigeria is presented. Findings from the six countries showed a higher efficacy of amodiaquine and quinine (over 90%) in malaria treatment compared to chloroquine, which was found to be 70% or more effective. The efficacy of amodiaquine can also be compared to other antimalarial drugs such as mefloquine and halofantrine. Data showed that fever clearance time of these drugs was less than 2 days, but parasite clearance time ranged from 2.5 days to 1 week. Recrudescence rate also varied among the different drugs. This is a very important indicator in determining which drug can be used for prophylactic or suppressive treatment of malaria. Pharmacokinetic profile demonstrates that all these drugs have similar therapeutic effects, but differ in their adverse reactions, contraindications, and half-life. A significant difference was also noted in the cost of these antimalarial drugs; chloroquine was the cheapest, while halofantrine was the most expensive among the drugs. Based on these results, the study recommends that different aspects of antimalarial drugs have to be considered before deciding which drug is the best alternative treatment.

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

    PubMed Central

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

    2013-01-01

    Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital) and Rawalpindi (twin city). Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors' analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs. PMID:24223321

  16. Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread

    PubMed Central

    Klein, E.Y.

    2013-01-01

    The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread. PMID:23394809

  17. Effect of membrane filtration of antimalarial drug solutions on in vitro activity against Plasmodium falciparum*

    PubMed Central

    Baird, J. K.; Lambros, C.

    1984-01-01

    Antimalarial activities of chloroquine, mefloquine, amodiaquine, and quinine in vitro against Plasmodium falciparum were diminished as a consequence of membrane filtration. Filtered drug solutions gave ID50 values up to 25-fold greater than those of non-filtered (ethanol-sterilized) drug solutions. Loss of activity by filtration was overcome by increasing the drug concentration prior to filtration. Water solutions filtered through Millex-GS filter units consistently showed an absorbance maximum at 277 nm, accompanied by a lesser peak at 225 nm. Water filtrates from Nucleopore and Millex-GV filters showed no absorbance at 277 nm and only slight absorbance was evident for the Gelman filter unit. Activity losses were attributed to extractable contaminating moieties in the membrane filters and/or drug binding to the membrane filters. PMID:6380786

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

    PubMed Central

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

    2015-01-01

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

  19. Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector--Results from a Nationally Representative Outlet Survey.

    PubMed

    2015-06-01

    Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85-115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential.

  20. Purine import into malaria parasites as a target for antimalarial drug development.

    PubMed

    Frame, I J; Deniskin, Roman; Arora, Avish; Akabas, Myles H

    2015-04-01

    Infection with Plasmodium species parasites causes malaria. Plasmodium parasites are purine auxotrophs. In all life cycle stages, they require purines for RNA and DNA synthesis and other cellular metabolic processes. Purines are imported from the host erythrocyte by equilibrative nucleoside transporters (ENTs). They are processed via purine salvage pathway enzymes to form the required purine nucleotides. The Plasmodium falciparum genome encodes four putative ENTs (PfENT1-4). Genetic, biochemical, and physiologic evidence suggest that PfENT1 is the primary purine transporter supplying the purine salvage pathway. Protein mass spectrometry shows that PfENT1 is expressed in all parasite stages. PfENT1 knockout parasites are not viable in culture at purine concentrations found in human blood (<10 μM). Thus, PfENT1 is a potential target for novel antimalarial drugs, but no PfENT1 inhibitors have been identified to test the hypothesis. Identifying inhibitors of PfENT1 is an essential step to validate PfENT1 as a potential antimalarial drug target.

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

    PubMed

    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.

  2. CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives.

    PubMed

    Boulton, Ian C; Nwaka, Solomon; Bathurst, Ian; Lanzer, Michael; Taramelli, Donatella; Vial, Henri; Doerig, Christian; Chibale, Kelly; Ward, Steve A

    2010-07-13

    Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change). It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted.The CRIMALDDI Consortium (a European Union funded initiative) has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.

  3. Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production

    PubMed Central

    Pulice, Giuseppe; Pelaz, Soraya; Matías-Hernández, Luis

    2016-01-01

    Malaria is a parasite infection affecting millions of people worldwide. Even though progress has been made in prevention and treatment of the disease; an estimated 214 million cases of malaria occurred in 2015, resulting in 438,000 estimated deaths; most of them occurring in Africa among children under the age of five. This article aims to review the epidemiology, future risk factors and current treatments of malaria, with particular focus on the promising potential of molecular farming that uses metabolic engineering in plants as an effective anti-malarial solution. Malaria represents an example of how a health problem may, on one hand, influence the proper development of a country, due to its burden of the disease. On the other hand, it constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is proposed here as a sustainable, promising, alternative for the production, not only of natural herbal repellents for malaria prevention but also for the production of sustainable anti-malarial drugs, like artemisinin (AN), used for primary parasite infection treatments. AN, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua. However, the low concentration of AN in the plant makes this molecule relatively expensive and difficult to produce in order to meet the current worldwide demand of Artemisinin Combination Therapies (ACTs), especially for economically disadvantaged people in developing countries. The biosynthetic pathway of AN, a process that takes place only in glandular secretory trichomes of A. annua, is relatively well elucidated. Significant efforts have been made using plant genetic engineering to increase production of this compound. These include diverse genetic manipulation approaches, such as studies on diverse transcription factors which have been shown to regulate the AN genetic pathway and other biological processes. Results look promising; however, further

  4. Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname

    PubMed Central

    2012-01-01

    Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to significant problems with

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

    PubMed Central

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

    2016-01-01

    The malaria SYBR green assay, which is used to profile in vitro drug susceptibility of Plasmodium falciparum, is a reliable drug screening and surveillance tool. Malaria field surveillance efforts provide isolates with various low levels of parasitemia. To be advantageous, malaria drug sensitivity assays should perform reproducibly among various starting parasitemia levels rather than at one fixed initial value. We examined the SYBR green assay standardized procedure developed by the Worldwide Antimalarial Resistance Network (WWARN) for its sensitivity and ability to accurately determine the drug concentration that inhibits parasite growth by 50% (IC50) in samples with a range of initial parasitemia levels. The initial sensitivity determination of the WWARN procedure yielded a detection limit of 0.019% parasitemia. P. falciparum laboratory strains and field isolates with various levels of initial parasitemia were then subjected to a range of doses of common antimalarials. The IC50s were comparable for laboratory strains with between 0.0375% and 0.6% parasitemia and for field isolates with between 0.075% and 0.6% parasitemia for all drugs tested. Furthermore, assay quality (Z′) analysis indicated that the WWARN procedure displays high robustness, allowing for drug testing of malaria field samples within the derived range of initial parasitemia. The use of the WWARN procedure should allow for the inclusion of more malaria field samples in malaria drug sensitivity screens that would have otherwise been excluded due to low initial parasitemia levels. PMID:26856829

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

    PubMed

    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.

  7. Holographic analysis on deformation and restoration of malaria-infected red blood cells by antimalarial drug

    NASA Astrophysics Data System (ADS)

    Byeon, Hyeokjun; Ha, Young-Ran; Lee, Sang Joon

    2015-11-01

    Malaria parasites induce morphological, biochemical, and mechanical changes in red blood cells (RBCs). Mechanical variations are closely related to the deformability of individual RBCs. The deformation of various RBCs, including healthy and malaria-infected RBCs (iRBCs), can be directly observed through quantitative phase imaging (QPI). The effects of chloroquine treatment on the mechanical property variation of iRBCs were investigated using time-resolved holographic QPI of single live cells on a millisecond time scale. The deformabilities of healthy RBCs, iRBCs, and drug-treated iRBCs were compared, and the effect of chloroquine on iRBC restoration was experimentally examined. The present results are beneficial to elucidate the dynamic characteristics of iRBCs and the effect of the antimalarial drug on iRBCs.

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

    PubMed

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

    NASA Astrophysics Data System (ADS)

    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.

  10. The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles.

    PubMed

    Marrelli, Mauro Toledo; Brotto, Marco

    2016-11-02

    Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.

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

    PubMed

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

    2016-04-01

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

  12. Studies on genotoxicity and carcinogenicity of antibacterial, antiviral, antimalarial and antifungal drugs.

    PubMed

    Brambilla, Giovanni; Mattioli, Francesca; Robbiano, Luigi; Martelli, Antonietta

    2012-07-01

    This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity studies performed of antibacterial, antiviral, antimalarial and antifungal drugs of long-term or intermittent frequent use. Of the 48 drugs considered, 9 (18.75%) do not have retrievable data, whereas the other 39 (81.25%) have at least one genotoxicity or carcinogenicity tests result. Of these 39 drugs, 24 tested positive in at least one genotoxicity assay and 19 in at least one carcinogenicity assay; 14 of them gave a positive response in both at least one genotoxicity assay and at least one carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the results of long-term carcinogenesis assays, of 23 drugs with both genotoxicity and carcinogenicity data: 2 (8.7%) were neither genotoxic nor carcinogenic, 2 (8.7%) tested positive in at least one genotoxicity assay but were non-carcinogenic, 4 (17.4%) tested negative in genotoxicity assays but were carcinogenic, and 15 (65.2%) gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 18 (37.5%) of the 48 drugs examined had all data required by present guidelines for testing of pharmaceuticals, but a fraction of them (49%) were developed and marketed prior to the present regulatory climate. In the absence of compelling indications, the prescription of the 19 drugs that are animal carcinogens should be avoided.

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

    NASA Astrophysics Data System (ADS)

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

    2011-08-01

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

  14. Sentinel network for monitoring in vitro susceptibility of Plasmodium falciparum to antimalarial drugs in Colombia: a proof of concept.

    PubMed

    Aponte, Samanda L; Díaz, Gustavo; Pava, Zuleima; Echeverry, Diego F; Ibarguen, Darío; Rios, Melissa; Murcia, Luz M; Quelal, Claudia; Murillo, Claribel; Gil, Pedro; Björkman, Anders; Osorio, Lyda

    2011-08-01

    Drug resistance is one of the principal obstacles blocking worldwide malaria control. In Colombia, malaria remains a major public health concern and drug-resistant parasites have been reported. In vitro drug susceptibility assays are a useful tool for monitoring the emergence and spread of drug-resistant Plasmodium falciparum. The present study was conducted as a proof of concept for an antimalarial drug resistance surveillance network based on in vitro susceptibility testing in Colombia. Sentinel laboratories were set up in three malaria endemic areas. The enzyme linked immunosorbent assay-histidine rich protein 2 and schizont maturation methods were used to assess the susceptibility of fresh P. falciparum isolates to six antimalarial drugs. This study demonstrates that an antimalarial drug resistance surveillance network based on in vitro methods is feasible in the field with the participation of a research institute, local health institutions and universities. It could also serve as a model for a regional surveillance network. Preliminary susceptibility results showed widespread chloroquine resistance, which was consistent with previous reports for the Pacific region. However, high susceptibility to dihydroartemisinin and lumefantrine compounds, currently used for treatment in the country, was also reported. The implementation process identified critical points and opportunities for the improvement of network sustainability strategies.

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

    PubMed

    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.

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

    PubMed

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

    2013-01-01

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

  17. Alteration of redox status by commonly used antimalarial drugs in the north-western region of Nigeria.

    PubMed

    Muhammad, A; Ibrahim, M A; Mohammed, H A; Erukainure, O L; Malami, I; Suleiman, A; Mansir, A; Godwin, A; Khalil, H A

    2017-02-01

    This study was designed to investigate the alteration of redox status by commonly used antimalarials in Nigeria. Drugs used were artemisinin, artesunate, chloroquine, coartem and quinine at the final concentrations of 0.5-8.0 mg/mL. Blood samples were collected from malarial patients and apparently healthy humans for comparison. Reduced glutathione, catalase, superoxide dismutase (SOD) activities, protein content and lipid peroxidation were determined. All drugs significantly ( p < 0.05) increases the protein level relative to control in normal blood, whereas in the infected, a significant ( p < 0.05) reduction was observed. In normal blood, the antimalarials dose dependently decreased ( p < 0.05) SOD and catalase activities with significant ( p < 0.05) increase in the infected. The level of glutathione in normal blood significantly ( p < 0.05) increases as compared with control, whereas in the infected, similar observation was made except that the levels were less, relative to control sample. Malondialdehyde level significantly ( p < 0.05) increases with increase in drugs concentration even though less than the level in the control with few exceptions. These effects were dose dependent and more pronounced in non-malarial conditions. Commonly used antimalarials might alter the redox status in both healthy and non-healthy subjects thereby inducing oxidative stress.

  18. Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

    PubMed Central

    D'Alessandro, Sarah; Corbett, Yolanda; Ilboudo, Denise P.; Misiano, Paola; Dahiya, Nisha; Abay, Solomon M.; Habluetzel, Annette; Grande, Romualdo; Gismondo, Maria R.; Dechering, Koen J.; Koolen, Karin M. J.; Sauerwein, Robert W.; Taramelli, Donatella; Parapini, Silvia

    2015-01-01

    The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads. PMID:26055362

  19. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

    SciTech Connect

    Paeshuyse, Jan; Coelmont, Lotte; Vliegen, Inge; Hemel, Johan van; Vandenkerckhove, Jan; Peys, Eric; Sas, Benedikt; Clercq, Erik De; Neyts, Johan . E-mail: johan.neyts@rega.kuleuven.be

    2006-09-15

    We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC{sub 5}) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 {+-} 21 {mu}M. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 {mu}M) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin.

  20. Repurposing the anti-malarial drug, quinacrine: new anti-colitis properties

    PubMed Central

    Chumanevich, Alexander A.; Witalison, Erin E.; Chaparala, Anusha; Chumanevich, Anastasiya; Nagarkatti, Prakash; Nagarkatti, Mitzi; Hofseth, Lorne J.

    2016-01-01

    Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with an increased risk of colorectal cancer in 8-10 years after disease onset. Current colitis treatment strategies do not offer a cure for the disease, but only treat the symptoms with limited success and dangerous side-effects. Also, there is no preventive treatment for either UC or colorectal cancer. Quinacrine is an anti-malarial drug with versatile use in the treatment of diseases involving inflammatory response such as rheumatoid arthritis and lupus erythematosus. It also has putative anti-cancer effect. Quinacrine's anti-inflammatory, anti-oxidant properties, and anti-tumorigenic properties make it a potential small molecule preventive agent for both UC and associated colorectal cancer. Results There were obvious changes in the CDI, histology, and inflammatory load in quinacrine-treated groups in a dose and time dependent manner in both models of UC, induced by chemical or haptenating agent. Methods We tested quinacrine at two different doses as a colitis treatment agent in two mouse models of UC - the dextran sulfate sodium and oxazolone. The clinical disease index (CDI), histological changes of the colon, levels of inflammatory markers (Cox-2, iNOS, p53) and overall health vitals were evaluated. Conclusions We demonstrate that quinacrine successfully suppresses colitis without any indication of toxicity or side-effects in two mouse models of UC. PMID:27447967

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

    PubMed

    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.

  2. Effects of quinoline-containing antimalarials on the erythrocyte membrane and their significance to drug action on Plasmodium falciparum.

    PubMed

    Ginsburg, H; Krugliak, M

    1988-05-15

    Quinoline-containing antimalarials are cationic amphiphiles which accumulate to high levels in lysosomes and are known to interact with membrane phospholipids. It was therefore hypothesized that they could exert their antimalarial effect by compromising the integrity of the parasite's acidic organelles. To test this hypothesis, the effects of chloroquine (CQ), quinine (Q) and mefloquine (MQ) on the osmotic stability of human red blood cells exposed to hypotonic solutions have been investigated. With CQ and Q stabilization was observed at pH 7.8 and destabilization at pH 5, indicating that destabilization is caused by the protonated forms of the drugs. With MQ the pH dependence was reversed, i.e. it destabilized at pH 7.8 and stabilized at pH 5, suggesting that destabilization is caused by the unprotonated drug. MQ caused cell lysis at the tenth millimolar range by a detergent effect. The possible destabilizing effect of drugs on the membranes of Plasmodium falciparum acidic organelles was investigated in metabolically-labelled parasites. We expected an increase in degradation of parasite proteins if drugs did indeed cause the release of acid hydrolases from destabilized organelles to the cytoplasm. No effect of drugs on parasite protein degradation could be observed, but protein synthesis was inhibited at therapeutic drug concentrations. These results imply that quinoline-containing antimalarials do not compromise the integrity of parasite acidic organelles, and that inhibition of protein synthesis results from a limited supply of essential amino acid(s) due to the demonstrable drug-mediated suppression of parasite digestion of host cell cytosol.

  3. Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity.

    PubMed

    Ginsburg, H; Nissani, E; Krugliak, M

    1989-08-15

    Quinoline-containing antimalarial drugs accumulate inside the acid food vacuole of the parasite where they inhibit the digestion of ingested host cell cytosol, and consequently, parasite growth. In order to verify whether this inhibition is caused by drug-induced alkalinization of the food vacuole, we investigated the accumulation of acridine orange (AO) as a vacuolar pH probe in intact Plasmodium falciparum-infected human erythrocytes as affected by the drugs chloroquine (CQ), 7H-quinoleine (7HQ), quinine (Q) and mefloquine (MQ). It was established by various criteria that AO accumulates primarily in the acid compartment(s) of the parasite as a function of the pH difference between it and the extracellular medium. This pH gradient was dissipated by the drugs in the rank order MQ greater than CQ greater than Q greater than 7HQ. The kinetics of vacuolar alkalinization and the concentration ranges at which it was observed imply that the monoprotic drugs MQ and Q exerted their effect mostly by translocating protons across the vacuolar membrane, i.e. they could cross the membrane as a protonated species, while the diprotic drugs CQ and 7HQ raised the vacuolar pH mostly by proton trapping. Similarly, hydrophobic alkylamines raised the vacuolar pH by proton translocation, while their relatively more polar congeners and ammonia did so by proton titration. However, the alkalinizing effect of each drug was observed at a concentration which was 1-2 orders of magnitude larger than the IC50 of its antimalarial effect. These results mean that vacuolar alkalinization is not the primary effect of antiparasitic action of quinoline antimalarials.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26130467

  5. Initial evaluation of low-dose phenobarbital as an indicator of compliance with antimalarial drug treatment.

    PubMed Central

    Karbwang, J.; Fungladda, W.; Pickard, C. E.; Shires, S.; Hay, A.; Feely, M.

    1998-01-01

    Since poor compliance with antimalarial therapy is often suspected but difficult to prove, this study attempted to establish a model for predicting the plasma concentration of phenobarbital (given in low doses in conjunction with the drug) as an indicator of compliance. Phenobarbital was chosen because its value had been demonstrated as a marker of compliance in long-course therapies, any significant departure from steady-state concentrations (achieved with full compliance) indicating one or more missed doses. Therapy for uncomplicated malaria varies from 5 days with artesunate to 7 days with quinine + tetracycline. Volunteers with confirmed falciparum malaria were randomized into 5 groups and given malaria therapy as well as phenobarbital daily for 3-7 days. Plasma samples for determination of phenobarbital concentrations were taken just prior to the daily dose of phenobarbital. Although there was a clear and predictable individual pattern of blood concentrations following each dose of phenobarbital, inter-individual variation in blood levels was significant and reduced their predictive value beyond the second day's dose. The cause of the variations is not clear; it could be attributable to different sources of the drug, previous intake of phenobarbital by the patient, or differences in drug absorption and disposition in malaria patients. Results for the 5-day artesunate regimen suggest that phenobarbital may be useful as a marker of compliance if the patient stops medication after 3 days; clear differences were evident at the end of the course of treatment between plasma phenobarbital concentrations in individuals completing the 5-day course and those who stopped after 3 days. For the quinine-tetracycline regimen, results suggest that it may be possible to discriminate between subjects where there is a 3-day difference in treatment. Phenobarbital is a better discriminant when dosing is every 24 hours as with artesunate, rather than the 8-hourly regimen for

  6. A New Set of Chemical Starting Points with Plasmodium falciparum Transmission-Blocking Potential for Antimalarial Drug Discovery

    PubMed Central

    Almela, Maria Jesus; Lozano, Sonia; Lelièvre, Joël; Colmenarejo, Gonzalo; Coterón, José Miguel; Rodrigues, Janneth; Gonzalez, Carolina; Herreros, Esperanza

    2015-01-01

    The discovery of new antimalarials with transmission blocking activity remains a key issue in efforts to control malaria and eventually eradicate the disease. Recently, high-throughput screening (HTS) assays have been successfully applied to Plasmodium falciparum asexual stages to screen millions of compounds, with the identification of thousands of new active molecules, some of which are already in clinical phases. The same approach has now been applied to identify compounds that are active against P. falciparum gametocytes, the parasite stage responsible for transmission. This study reports screening results for the Tres Cantos Antimalarial Set (TCAMS), of approximately 13,533 molecules, against P. falciparum stage V gametocytes. Secondary confirmation and cytotoxicity assays led to the identification of 98 selective molecules with dual activity against gametocytes and asexual stages. Hit compounds were chemically clustered and analyzed for appropriate physicochemical properties. The TCAMS chemical space around the prioritized hits was also studied. A selection of hit compounds was assessed ex vivo in the standard membrane feeding assay and demonstrated complete block in transmission. As a result of this effort, new chemical structures not connected to previously described antimalarials have been identified. This new set of compounds may serve as starting points for future drug discovery programs as well as tool compounds for identifying new modes of action involved in malaria transmission. PMID:26317851

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

    PubMed

    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.

  8. The antimalarial drug primaquine targets Fe-S cluster proteins and yeast respiratory growth.

    PubMed

    Lalève, Anaïs; Vallières, Cindy; Golinelli-Cohen, Marie-Pierre; Bouton, Cécile; Song, Zehua; Pawlik, Grzegorz; Tindall, Sarah M; Avery, Simon V; Clain, Jérôme; Meunier, Brigitte

    2016-04-01

    Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Δsod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe-S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe-S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe-S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe-S cluster - and of other ROS-sensitive enzymes - could inhibit parasite development.

  9. The antimalarial drug primaquine targets Fe–S cluster proteins and yeast respiratory growth

    PubMed Central

    Lalève, Anaïs; Vallières, Cindy; Golinelli-Cohen, Marie-Pierre; Bouton, Cécile; Song, Zehua; Pawlik, Grzegorz; Tindall, Sarah M.; Avery, Simon V.; Clain, Jérôme; Meunier, Brigitte

    2015-01-01

    Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Δsod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe–S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe–S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe–S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe–S cluster – and of other ROS-sensitive enzymes – could inhibit parasite development. PMID:26629948

  10. Blocking Plasmodium falciparum Malaria Transmission with Drugs: The Gametocytocidal and Sporontocidal Properties of Current and Prospective Antimalarials

    PubMed Central

    Kiszewski, Anthony E.

    2011-01-01

    Drugs that kill or inhibit the sexual stages of Plasmodium could potentially amplify or synergize the impact of other interventions by blocking transmission to mosquitoes. Primaquine and other 8-aminoquinolines have long offered such potential, but safety and other concerns have limited their use. Although transmission-blocking properties are not often a priority of drug discovery efforts, a number of interesting gametocytocidal and/or sporontocidal drug candidates have emerged in recent years. Some still bear significant technical and safety concerns, while others have passed clinical trials and are on the verge of entering the antimalarial armamentarium. Recent advances in our knowledge of gametocyte differentiation, gametogenesis and sporogony have also led to the identification of a large array of potential new targets for drugs that might interfere with malaria transmission. This review examines the properties of existing and prospective drugs, mechanisms of action, counter-indications and their potential role in regional malaria elimination efforts.

  11. Incorporating Stage-Specific Drug Action into Pharmacological Modeling of Antimalarial Drug Treatment

    PubMed Central

    2016-01-01

    Pharmacological modeling of antiparasitic treatment based on a drug's pharmacokinetic and pharmacodynamic properties plays an increasingly important role in identifying optimal drug dosing regimens and predicting their potential impact on control and elimination programs. Conventional modeling of treatment relies on methods that do not distinguish between parasites at different developmental stages. This is problematic for malaria parasites, as their sensitivity to drugs varies substantially during their 48-h developmental cycle. We investigated four drug types (short or long half-lives with or without stage-specific killing) to quantify the accuracy of the standard methodology. The treatment dynamics of three drug types were well characterized with standard modeling. The exception were short-half-life drugs with stage-specific killing (i.e., artemisinins) because, depending on time of treatment, parasites might be in highly drug-sensitive stages or in much less sensitive stages. We describe how to bring such drugs into pharmacological modeling by including additional variation into the drug's maximal killing rate. Finally, we show that artemisinin kill rates may have been substantially overestimated in previous modeling studies because (i) the parasite reduction ratio (PRR) (generally estimated to be 104) is based on observed changes in circulating parasite numbers, which generally overestimate the “true” PRR, which should include both circulating and sequestered parasites, and (ii) the third dose of artemisinin at 48 h targets exactly those stages initially hit at time zero, so it is incorrect to extrapolate the PRR measured over 48 h to predict the impact of doses at 48 h and later. PMID:26902760

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

    PubMed

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2016-08-01

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

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

    PubMed Central

    Neto, Zoraima; Machado, Marta; Lindeza, Ana; do Rosário, Virgílio; Gazarini, Marcos L.; Lopes, Dinora

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs). Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group's 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest. PMID:23691276

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

    PubMed

    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

    2016-08-21

    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.

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

    PubMed Central

    2011-01-01

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

  17. Natural polyhydroxyalkanoate-gold nanocomposite based biosensor for detection of antimalarial drug artemisinin.

    PubMed

    Phukon, Pinkee; Radhapyari, Keisham; Konwar, Bolin Kumar; Khan, Raju

    2014-04-01

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate-gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate-gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01-0.08μg mL(-1)) with sensitivity of 0.26μAμg mL(-1). The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035μg mL(-1) and 0.0036μg mL(-1) in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis.

  18. Erythrophagocytosis Enhances Heme-Dependent Cytotoxicity of Antimalarial Drugs in Canine Histiocytic Sarcoma Cell Line DH82

    PubMed Central

    CHIKAZAWA, Seishiro; KITAHARA, Yasunori; ANDO, Erika; HORI, Yasutomo; HOSHI, Fumio; KANAI, Kazutaka; ITO, Naoyuki; HIGUCHI, Seiichi

    2013-01-01

    ABSTRACT Antimalarial drugs, dihydroartemisinin (DHA) and artesunate (ATS), exhibit iron-dependent cytotoxicity in tumor cells. We hypothesized that erythrophagocytic uptake of heme-iron enhances the cytotoxicity of DHA and ATS. Erythrophagocytic (EP) treatment of the canine histiocytic sarcoma cell line DH82 markedly increased the cytotoxicity of DHA and ATS compared to controls. Succinyl acetone, an inhibitor of intracellular heme synthesis, decreased the cytotoxicity of DHA and ATS in normal cells, but this change was not observed in EP cells. These results suggest that exogenous heme derived from erythrocytes can enhance the cytotoxicity of DHA and ATS. Furthermore, our study suggests that heme could be a novel component of tumor treatment in veterinary medicine. PMID:24065080

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

    PubMed Central

    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. PMID:27788228

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

    PubMed

    Schmuck, G; Haynes, R K

    2000-01-01

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

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

    PubMed Central

    2016-01-01

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

  2. Resistance of Plamodium falciparum to antimalarial drugs in Zaragoza (Antioquia, Colombia), 1998.

    PubMed

    Blair-Trujillo, Silvia; Lacharme-Lora, Leidy; Carmona-Fonseca, Jaime

    2002-04-01

    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.

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

    PubMed

    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

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

    PubMed

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

    2011-04-01

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

  5. Prescribing Pattern of Anti-malarial Drugs with Particular Reference to the use of Artesunate in Complicated Plasmodium Vivax Cases

    PubMed Central

    Singh, Ashutosh Kumar; Khan, Mohd Sajid

    2014-01-01

    Background: In developing countries, Malaria has been found to be one of the most common cause of fever and morbidity, particularly among infants and young children. Therefore, its drug utilization studies should be carried out to know the rationality of treatment. Aim: To evaluate the use of antimalarial agents in children with a diagnosis of Malaria and visited to OPD & IPD Paediatric department of a tertiary care teaching hospital. Materials and Methods: This was a prospective six months study based on a Medication Utilization Form, which has been designed in consultation with the paediatrician. One hundred eighty three children <12 y of age were selected on the basis of inclusion and exclusion criteria. Results: Out of 183 patients, 110 were infected with Plasmodium falciparum (60.10%) and 73 with Plasmodium vivax (39.89%). Most of the patients were male, 56.83% and 43.16% were female patients. Most of the complicated cases were found from Plasmodium falciparum (n = 110) than Plasmodium vivax (n=15). In prescriptions with monotherapy, Artesunate (n=101) was found to be the most commonly prescribed drug and in prescriptions containing more than one drug, Artesunate – lumefantrine (n=125) combinations were frequently used. Most of the drugs were prescribed by oral route (n=285), than the parenteral route (n=140). The average number of drugs per encounter was 2.32 and only 4.50% drugs were prescribed by generic name. Average drug cost per prescription in complicated cases was found to be higher (185.5 INR) than uncomplicated cases (115 INR). Conclusion: Artemisinin were used as first line drugs irrespective of the causative agent for malaria, which is not recommended, however has been found to be effective in complicated cases of Plasmodium vivax also. The cost of the prescription was higher. Interventions to rectify over prescription of injectables necessary to further improve rational drug use in our facility. Also, there should be an awareness program

  6. Antimalarials for children: indications, toxicities, and guidelines.

    PubMed

    Ziering, C L; Rabinowitz, L G; Esterly, N B

    1993-05-01

    The use of antimalarial drugs in children has been discussed extensively in the rheumatology literature, but there is scant information in the dermatology literature. We discuss indications, dosing, administration, and side effects of antimalarial drugs in children as well as skin diseases in children who have been treated with chloroquine or hydroxychloroquine.

  7. Selection of Parasites with Diminished Drug Sensitivity by Amodiaquine-Containing Antimalarial Regimens in Uganda

    PubMed Central

    Nawaz, Fatima; Nsobya, Samuel L.; Kiggundu, Moses; Joloba, Moses; Rosenthal, Philip J.

    2009-01-01

    Background Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy. Methods We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized to treatment with AQ/SP, AS/AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro sensitivity to monodesethylamodiaquine (MDAQ) was measured with a histidine rich protein-2-based ELISA, and potential resistance-mediating polymorphisms pfmdr-1were evaluated. Results Parasites from subjects previously treated with AQ/SP or AS/AQ within 12 weeks were less sensitive to MDAQ (n=18; mean IC50 62.9 nM; range 12.7–158.3 nM) than parasites from those not treated within 12 weeks (n=43; mean IC50 37.5 nM; range 6.3–184.7 nM; p=0.0085) or only those in the treatment arm that did not contain AQ (n=20; mean IC50 28.8 nM; range 6.3–121.8 nM; p=0.0042). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr-1 86Y and 1246Y) increased after prior AQ therapy, although differences were not significant. Conclusions Prior therapy selected for diminished response to MDAQ, suggesting that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr-1. PMID:19905933

  8. The antimalarial drug proguanil is an antagonist at 5-HT3 receptors.

    PubMed

    Lochner, Martin; Thompson, Andrew J

    2014-12-01

    Proguanil is an antimalarial prodrug that is metabolized to 4-chlorophenyl-1-biguanide (CPB) and the active metabolite cycloguanil (CG). These compounds are structurally related to meta-chlorophenyl biguanide (mCPBG), a 5-hydroxytryptamine 3 (5-HT3) receptor agonist. Here we examine the effects of proguanil and its metabolites on the electrophysiology and ligand-binding properties of human 5-HT3A receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. 5-HT3 receptor responses were reversibly inhibited by proguanil, with an IC50 of 1.81 μM. Competitive antagonism was shown by a lack of voltage-dependence, Schild plot (Kb = 1.70 μM), and radioligand competition (Ki = 2.61 μM) with the 5-HT3 receptor antagonist [(3)H]granisetron. Kinetic measurements (kon = 4.0 × 10(4) M(-1) s(-1) ; koff = 0.23 s(-1)) were consistent with a simple bimolecular reaction scheme with a Kb of 4.35 μM. The metabolites CG and CPB similarly inhibited 5-HT3 receptors as assessed by IC50 (1.48 and 4.36 μM, respectively), Schild plot (Kb = 2.97 and 11.4 μM), and radioligand competition (Ki = 4.89 and 0.41 μM). At higher concentrations, CPB was a partial agonist (EC50 = 14.1 μM; I/Imax = 0.013). These results demonstrate that proguanil competitively inhibits 5-HT3 receptors, with an IC50 that exceeds whole-blood concentrations following its oral administration. They may therefore be responsible for the occasional gastrointestinal side effects, nausea, and vomiting reported following its use. Clinical development of related compounds should therefore consider effects at 5-HT3 receptors as an early indication of possible unwanted gastrointestinal side effects.

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

    PubMed Central

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

    2012-01-01

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

  10. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.

    PubMed

    Meister, Stephan; Plouffe, David M; Kuhen, Kelli L; Bonamy, Ghislain M C; Wu, Tao; Barnes, S Whitney; Bopp, Selina E; Borboa, Rachel; Bright, A Taylor; Che, Jianwei; Cohen, Steve; Dharia, Neekesh V; Gagaring, Kerstin; Gettayacamin, Montip; Gordon, Perry; Groessl, Todd; Kato, Nobutaka; Lee, Marcus C S; McNamara, Case W; Fidock, David A; Nagle, Advait; Nam, Tae-gyu; Richmond, Wendy; Roland, Jason; Rottmann, Matthias; Zhou, Bin; Froissard, Patrick; Glynne, Richard J; Mazier, Dominique; Sattabongkot, Jetsumon; Schultz, Peter G; Tuntland, Tove; Walker, John R; Zhou, Yingyao; Chatterjee, Arnab; Diagana, Thierry T; Winzeler, Elizabeth A

    2011-12-09

    Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

  11. Factors relating to neurotoxicity of artemisinin antimalarial drugs "listening to arteether".

    PubMed

    Brewer, T G; Genovese, R F; Newman, D B; Li, Q

    1998-01-01

    The discovery of the occult brainstem neurotoxicity subsequent to widespread deployment of artemisinin derivatives has created particular problems. That is, the clinical setting for artemisinin use is problematic for accomplishing what ordinarily would be addressed in phase I-II clinical trials. Nevertheless, it is clear that an urgent and vital need exists for the deployment and widespread availability of artemisinins. The work done to date has already yielded a substantial body of evidence that, while incomplete, provides guidelines for artemisinin use to minimize the risk of these drugs while preserving their much-needed efficacy. The evidence thus far shows that route of administration, oil/water solubility and concentration-duration of drug level, are critical determinants of toxicity and can be given appropriate consideration in the clinical decisions regarding route, choice of drug used, and drug regimens. In this regard, an oral, water-soluble drug with moderately rapid clearance may be the most attractive choice in the absence of significant differences in efficacy. The same body of evidence clearly shows that toxicity can, and does, develop with no obvious or useful clinical marker. Therefore, the development and validation of a test that can reliably detect the onset of injury, at a reversible stage, is a critical path task for any future development in this class. More complete understanding of mechanisms, kinetics, and molecular targets of neurotoxicity, will certainly be forthcoming. A continuing, more generalized use of these drugs, however, cannot be fully endorsed without a useful, practical clinical test of toxicity. The requirement is especially critical in light of the reality that those patients receiving artemisinin derivatives live in high risk environments and are likely to receive repeated courses of therapy with little likelihood of close, post marketing surveillance.

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

    PubMed

    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.

  13. How can we identify parasite genes that underlie antimalarial drug resistance?

    PubMed Central

    Anderson, Tim; Nkhoma, Standwell; Ecker, Andrea; Fidock, David

    2011-01-01

    This article outlines genome-scale approaches that can be used to identify mutations in malaria (Plasmodium) parasites that underlie drug resistance and contribute to treatment failure. These approaches include genetic mapping by linkage or genome-wide association studies, drug selection and characterization of resistant mutants, and the identification of genome regions under strong recent selection. While these genomic approaches can identify candidate resistance loci, genetic manipulation is needed to demonstrate causality. We therefore also describe the growing arsenal of available transfection approaches for direct incrimination of mutations suspected to play a role in resistance. Our intention is both to review past progress and highlight promising approaches for future investigations. PMID:21174623

  14. Comparative Study of Antimalarial and Other Drugs on G6PD Deficient Red Cells.

    DTIC Science & Technology

    the WR compounds previously studied. The suggested use of xylitol as a protective agent against hemolytic drugs (Wang et al) had raised considerable...expectation. Unfortunately, xylitol at the dosages of 20 and 30 g./day was unable, in our experimental set up (transfusion of 51 Cr tagged G6PD

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

    PubMed

    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.

  16. Ascertainment of risk of serious adverse reactions associated with chemoprophylactic antimalarial drugs.

    PubMed Central

    Phillips-Howard, P. A.; Bjorkman, A. B.

    1990-01-01

    Serious adverse reactions during malaria chemoprophylaxis are reviewed. Three drugs considered to have caused serious reactions in recent years are pyrimethamine/sulfadoxine (Fansidar), pyrimethamine/dapsone (Maloprim) and amodiaquine. These reactions are principally independent of dose and cannot be determined during screening for optimal doses. However, host factors may precipitate dose-dependent reactions, some of which could be avoided with improvements in drug licensing. Since serious and life-threatening reactions are relatively rare (between 1:1000 and 1:20,000), Phase I to III trials cannot identify them. Reliance must therefore be placed on Phase IV post-marketing studies, including ongoing reviews of national registers, and specially tailored studies to identify the risk using prescription-event monitoring in high-risk populations. Occasionally, medical-record linkage, case-control and cohort studies may provide supportive data. Although large numbers of travellers must, of necessity, be exposed to a drug before relatively rare reactions are identified, the ascertainment of risk using post-marketing surveillance was prevented by the following five deficiencies: lack of awareness of early alerts, inadequate use of national registers, poor attention to epidemiological and statistical rigour, inadequate verification of denominators, and inadequacy of data records. Recommendations are given for minimizing such errors in the future. PMID:2208562

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

    NASA Astrophysics Data System (ADS)

    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

  18. Malaria Related Perceptions, Care Seeking after Onset of Fever and Anti-Malarial Drug Use in Malaria Endemic Settings of Southwest Ethiopia

    PubMed Central

    Birhanu, Zewdie; Abebe, Lakew; Sudhakar, Morankar; Dissanayake, Gunawardena; Yihdego, Yemane Ye-ebiyo; Alemayehu, Guda; Yewhalaw, Delenasaw

    2016-01-01

    Background Prompt care seeking and appropriate use of anti-malarial drugs are critical components of malaria prevention and control. This study assessed malaria related perceptions, care seeking behavior and anti-malarial drug use in malaria endemic settings of Ethiopia. Methods Data were generated from a community based cross-sectional study conducted among 798 households during January 2014 as part of a larger household behavioral study in three malaria endemic districts of Jimma Zone, Southwest Ethiopia. Both quantitative and qualitative data were collected and analyzed using SPSS 17.0 and STATA 12.0. Results In this study, only 76.1% of the respondents associated malaria to mosquito bite, and incorrect beliefs and perceptions were noted. Despite moderate level of knowledge (estimated mean = 62.2, Std Err = 0.7, 95% CI: 60.6–63.8%), quite high favorable attitude (overall estimated mean = 91.5, Std Err = 0.6, 95% CI: 90.1–92.9%) were recorded towards malaria preventive measures. The mean attitude score for prompt care seeking, appropriate use of anti-malarial drugs, LLIN use and Indoor Residual Spray acceptance was 98.5 (Std Err = 0.4, 95% CI:97.5–99.4), 92.7 (Std Err = 0.6 95% CI:91.5–93.9), 88.8 (Std Err = 0.5, 95% CI:85.5–92.1) and 86.5 (Std Err = 1.2, 95% CI: 83.9–89.1), respectively. The prevalence of fever was 2.9% (116/4107) and of the study participants with fever, 71.9% (95% CI: 65.5–78.3%) sought care and all of them consulted formal health care system. However, only 17 (19.8%) sought care within 24 hours after onset of fever. The frequency of care seeking was higher (77.8%, n = 21/27) and more prompt (28.6%, 6/21) for children under five as compared to old age groups despite it was not statistically significant (p > 0.05). However, higher median time of seeking first care was observed among Muslims and people who did not attend school (p < 0.05). Of those who used anti-malarial drugs, 9.1% indicated that they used it inappropriately

  19. 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

    PubMed Central

    Suswardany, Dwi Linna; Sibbritt, David W.; Supardi, Sudibyo; Pardosi, Jerico F.; Chang, Sungwon; Adams, Jon

    2017-01-01

    Background The level of traditional medicine use, particularly Jamu use, in Indonesia is substantial. Indonesians do not always seek timely treatment for malaria and may seek self-medication via traditional medicine. This paper reports findings from the first focused analyses of traditional medicine use for malaria in Indonesia and the first such analyses worldwide to draw upon a large sample of respondents across high-risk malaria endemic areas. Methods A sub-study of the Indonesia Basic Health Research/Riskesdas Study 2010 focused on 12,226 adults aged 15 years and above residing in high-risk malaria-endemic provinces. Logistic regression was undertaken to determine the significant associations for traditional medicine use for malaria symptoms. Findings Approximately one in five respondents use traditional medicine for malaria symptoms and the vast majority experiencing multiple episodes of malaria use traditional medicine alongside free antimalarial drug treatments. Respondents consuming traditional medicine for general health/common illness purposes every day (odds ratio: 3.75, 95% Confidence Interval: 2.93 4.79), those without a hospital in local vicinity (odds ratio: 1.31, 95% Confidence Interval: 1.10 1.57), and those living in poorer quality housing, were more likely to use traditional medicine for malaria symptoms. Conclusion A substantial percentage of those with malaria symptoms utilize traditional medicine for treating their malaria symptoms. In order to promote safe and effective malaria treatment, all providing malaria care in Indonesia need to enquire with their patients about possible traditional medicine use. PMID:28329019

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

    PubMed

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

    2017-02-10

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

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

    PubMed

    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 E2 (PGE2), 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, PGE2/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 activated

  2. Effects of the antimalarial drugs ferroquine and artesunate on Plasmodium yoelii yoelii gametocytegenesis and vectorial transmission.

    PubMed

    Mustfa, Kamla; Landau, Irène; Chabaud, Alain-Gabriel; Chavatte, Jean-Marc; Chandenier, Jacques; Duong, Thanh Hai; Richard-Lenoble, Dominique

    2011-01-01

    Chemistry still has a role in the management of malaria, alongside the mosquito netting soaked in insecticide that is used increasingly, as we continue to await the long anticipated vaccine. During its cycle, the hematozoon parasite develops through three major periods. The first, malarial infection, corresponds to the intrahepatic development of infective forms from the mosquito vector; this period is not sensitive to treatment and is often asymptomatic. The period of erythrocytic schizogony is the most urgent, and treatment activity is primordial. Finally, the phase of sexual reproduction, when gametocytes develop within the erythrocytes ensures the perpetuation of the species when these reach the blood-feeding female anopheles mosquitoes. The aim of our work was to study the effect on gametocytes of drugs known to be effective on the asexual blood forms of the protozoan and thus the potential repercussions on malaria transmission. This experimental study was conducted with an animal model whose parasite cycle and modes of transmission are close to those of human malaria: Plasmodium yoelii, maintained on Swiss mice, with the Anopheles stephensi vector (maintained in an animal facility at the National Museum of Natural History in Paris). Two drugs were tested: ferroquine (a chloroquine derivative with a ferrocene molecule at the lateral carbon chain that restores its efficacy against chloroquine-resistant strains) and artesunate (a derivative of artemisinin, from ginghao, a Chinese plant also known as artemisia annua, or sweet wormwood), a treatment of choice in the combined therapies recommended by WHO. The efficacy of these drugs, prescribed at doses subcurative for the asexual forms, were tested against gametocyte production, quantitatively by counting them in the blood and qualitatively by counting the quantity of oocysts developed on the mosquito's midgut, which are indicators of gametocyte activity. The mice that were parasite-infected and then treated

  3. Plasmodial sugar transporters as anti-malarial drug targets and comparisons with other protozoa

    PubMed Central

    2011-01-01

    Glucose is the primary source of energy and a key substrate for most cells. Inhibition of cellular glucose uptake (the first step in its utilization) has, therefore, received attention as a potential therapeutic strategy to treat various unrelated diseases including malaria and cancers. For malaria, blood forms of parasites rely almost entirely on glycolysis for energy production and, without energy stores, they are dependent on the constant uptake of glucose. Plasmodium falciparum is the most dangerous human malarial parasite and its hexose transporter has been identified as being the major glucose transporter. In this review, recent progress regarding the validation and development of the P. falciparum hexose transporter as a drug target is described, highlighting the importance of robust target validation through both chemical and genetic methods. Therapeutic targeting potential of hexose transporters of other protozoan pathogens is also reviewed and discussed. PMID:21676209

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

    PubMed

    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.

  5. Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?

    PubMed

    Sutherland, Colin J; Babiker, Hamza; Mackinnon, Margaret J; Ranford-Cartwright, Lisa; El Sayed, Badria Babiker

    2011-10-01

    Artemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the 'premier' combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.

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

    PubMed Central

    Souares, Aurélia; Lalou, Richard; Sene, Ibra; Sow, Diarietou; Le Hesran, Jean-Yves

    2009-01-01

    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. PMID:19497103

  7. The quality of antimalarial medicines in western Cambodia: a case study along the Thai-Cambodian border.

    PubMed

    Phanouvong, Souly; Raymond, Christopher; Krech, Laura; Dijiba, Yanga; Mam, Boravann; Lukulay, Patrick; Socheat, Duong; Sovannarith, Tey; Sokhan, Chroeng

    2013-05-01

    The prevalence, availability, and use of antimalarial medicines (AMLs) were studied in six Cambodian provinces along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in Pursat, Pailin, Battambang, Bantey Meanchey, Oddar Meanchey, and Preah Vihear and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for confirmatory testing. For the second part of the study, face-to-face interviews were conducted using standardized surveys with members of randomly selected households and staff of health facilities in the villages with highest malaria incidence to find out where they acquired their AMLs and which were most frequently used. The results showed an overall failure rate of 12.3% (n = 46 of 374 total AML samples). The causes of medication sample failure were low active pharmaceutical ingredient (API) content, failed dissolution properties, and unacceptably high levels of impurities. A total of 86.2% of survey respondents (n = 1,648 of 1,912) reported a member of their household having malaria in the previous year. The most commonly used medicines were paracetamol (67.1% of respondents), Malarine (A+M co-blistered, 28.6%), artesunate + mefloquine co-blistered (public sector product, 17.3%), quinine (16.7%), and artesunate monotherapy (11.9%). Health staff typically prescribed co-blistered artesunate plus mefloquine in the public sector (67.8%), the artesunate plus mefloquine "social marketing" product from Population Services International (PSI), Malarine (50.3%) in the private sector, artemether (49.7%), chloroquine (39%) and paracetamol (72.9%) to reduce fever.

  8. Research in Experimental Antimalarial Chemotherapy.

    DTIC Science & Technology

    1995-01-01

    and reversal of chloroquine resistance with promethazine (WRBL 50601), chlorpheniramine , diphenhydramine and pyrilamine were identified and published...in 1991 and 1992. The findings on reversal of chloroquine resistance with promethazine and chlorpheniramine represent the first demonstration of the...pharmacokinetics and clinical efficacy of potential combinations of chlorpheniramine with antimalarial drugs in human volunteers and animal models

  9. Microbial transformation of antimalarial terpenoids.

    PubMed

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

    2012-01-01

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

  10. Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid

    PubMed Central

    Ro, Dae-Kyun; Ouellet, Mario; Paradise, Eric M; Burd, Helcio; Eng, Diana; Paddon, Chris J; Newman, Jack D; Keasling, Jay D

    2008-01-01

    Background Due to the global occurrence of multi-drug-resistant malarial parasites (Plasmodium falciparum), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (Artemisia annua). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from A. annua. In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required. Results Three plant genes coding for amorphadiene synthase, amorphadiene oxidase (AMO or CYP71AV1), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 μg mL-1 in shake-flask cultures and 1 g L-1 in bio-reactors with the use of Leu2d selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance (PDR) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by

  11. New Antimalarial Hits from Dacryodes edulis (Burseraceae) - Part I: Isolation, In Vitro Activity, In Silico “drug-likeness” and Pharmacokinetic Profiles

    PubMed Central

    Zofou, Denis; Tematio, Esther Laure; Ntie-Kang, Fidele; Tene, Mathieu; Ngemenya, Moses N.; Tane, Pierre; Titanji, Vincent P. K.

    2013-01-01

    The aims of the present study were to identify the compounds responsible for the anti-malarial activity of Dacryoedes edulis (Burseraceae) and to investigate their suitability as leads for the treatment of drug resistant malaria. Five compounds were isolated from ethyl acetate and hexane extracts of D. edulis stem bark and tested against 3D7 (chloroquine-susceptible) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum, using the parasite lactate dehydrogenase method. Cytotoxicity studies were carried out on LLC-MK2 monkey kidney epithelial cell-line. In silico analysis was conducted by calculating molecular descriptors using the MOE software running on a Linux workstation. The “drug-likeness” of the isolated compounds was assessed using Lipinski criteria, from computed molecular properties of the geometry optimized structures. Computed descriptors often used to predict absorption, distribution, metabolism, elimination and toxicity (ADMET) were used to assess the pharmacokinetic profiles of the isolated compounds. Antiplasmodial activity was demonstrated for the first time in five major natural products previously identified in D. edulis, but not tested against malaria parasites. The most active compound identified was termed DES4. It had IC50 values of 0.37 and 0.55 µg/mL, against 3D7 and Dd2 respectively. In addition, this compound was shown to act in synergy with quinine, satisfied all criteria of “Drug-likeness” and showed considerable probability of providing an antimalarial lead. The remaining four compounds also showed antiplasmodial activity, but were less effective than DES4. None of the tested compounds was cytotoxicity against LLC-MK2 cells, suggesting their selective activities on malaria parasites. Based on the high in vitro activity, low toxicity and predicted “Drug-likeness” DES4 merits further investigation as a possible drug lead for the treatment of malaria. PMID:24282507

  12. [Synthetic antimalarials].

    PubMed

    Fardet, L; Revuz, J

    2005-01-01

    The antimalarials, mainly chloroquine and hydroxychloroquine, derive from the quinoleine core of quinine. Their initial therapeutic indication was the treatment of malaria attacks but, because of anti-inflammatory and immuno-modulatory activities, they have been since used to treat many other pathologies, in particular dermatological ones. For some of these pathologies, lupus or porphyria cutanea tarda for example, the use of these molecules is based on obvious scientific evidence. For other pathologies (cutaneous sarcoidosis, polymyositis, polymorphous light eruption...), the data on the medical literature corroborating the daily clinical practice are extremely poor. Their toxicity is limited. Their most common toxic effects are gastrointestinal (mild nausea or diarrhea) or mucocutaneous (reversible skin or mucosal pigmentation). Their most serious and dreaded side effect, retinopathy, can be largely prevented by using amounts of APS adapted to the weight of the patients. The recommended "safe" daily dose for hydroxychloroquine is 6.5 mg per kilogramme of body weight and for chloroquine 4 mg per kilogramme of body weight. However, at 6- to 12 months intervals, follow-up eye examinations should be performed.

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

    PubMed Central

    Kabongo Kamitalu, Ramsès; Aloni, Michel Ntetani

    2016-01-01

    Aim. To assess the self-medication against malaria infection in population of Congolese students in Kinshasa, Democratic Republic of Congo (DRC). Methods. A cross-sectional study was carried out in University of Kinshasa, Kinshasa, Democratic Republic of Congo. Medical records of all students with malaria admitted to Centre de Santé Universitaire of University of Kinshasa from January 1, 2008, to April 30, 2008, were reviewed retrospectively. Results. The median age of the patients was 25.4 years (range: from 18 to 36 years). The majority of them were male (67.9%). Artemisinin-based combination treatments (ACTs) was the most used self-prescribed antimalarial drugs. However, self-medication was associated with the ingestion of quinine in 19.9% of cases. No case of ingestion of artesunate/artemether in monotherapy was found. All the medicines taken were registered in DRC. In this series, self-prescribed antimalarial was very irrational in terms of dose and duration of treatment. Conclusion. This paper highlights self-medication by a group who should be aware of malaria treatment protocols. The level of self-prescribing quinine is relatively high among students and is disturbing for a molecule reserved for severe disease in Congolese health care policy in management of malaria. PMID:27340411

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

    PubMed

    Kabongo Kamitalu, Ramsès; Aloni, Michel Ntetani

    2016-01-01

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

  15. Use of the atmospheric generators for capnophilic bacteria Genbag-CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti-malarial drugs

    PubMed Central

    2011-01-01

    Background The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. Methods The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine) by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2® system and compared to controlled incubator conditions (5% CO2 and 10% O2). Results The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2 and 10% O2) were significantly higher than those of Genbag® conditions (2738 cpm vs 2282 cpm, p < 0.0001). The geometric mean IC50 estimated under the incubator atmospheric conditions was significantly lower for atovaquone (1.2 vs 2.1 nM, p = 0.0011) and higher for the quinolines: chloroquine (127 vs 94 nM, p < 0.0001), quinine (580 vs 439 nM, p < 0.0001), monodesethylamodiaquine (41.4 vs 31.8 nM, p < 0.0001), mefloquine (57.5 vs 49.7 nM, p = 0.0011) and lumefantrine (23.8 vs 21.2 nM, p = 0.0044). There was no significant difference of IC50 between the 2 conditions for dihydroartemisinin, doxycycline and pyrimethamine. To reduce this difference in term of anti-malarial susceptibility, a specific cut-off was estimated for each drug under Genbag® conditions by regression. The cut-off was estimated at 77 nM for chloroquine (vs 100 nM in 10% O2), 611 nM for quinine (vs 800 nM), 30 nM for mefloquine (vs 30 nM), 61 nM for monodesethylamodiaquine (vs 80 nM) and 1729 nM for pyrimethamine (vs 2000 nM). Conclusions The atmospheric

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

    PubMed Central

    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

  17. Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase.

    PubMed

    Talawanich, Yuwadee; Kamchonwongpaisan, Sumalee; Sirawaraporn, Worachart; Yuthavong, Yongyuth

    2015-09-01

    Interaction between antimalarial drugs is important in determining the outcome of chemotherapy using drug combinations. Inhibitors of dihydrofolate reductase (DHFR) such as pyrimethamine and of dihydropteroate synthase (DHPS) such as sulfa drugs are known to have synergistic interactions. However, studies of the synergism are complicated by the fact that the malaria parasite can also salvage exogenous folates, and the salvage may also be affected by the drugs. It is desirable to have a convenient system to study interaction of DHFR and DHPS inhibitors without such complications. Here, we describe the use of Escherichia coli transformed with malarial DHFR and DHPS, while its own corresponding genes have been inactivated by optimal concentration of trimethoprim and genetic knockout, respectively, to study the interaction of the inhibitors. Marked synergistic effects are observed for all combinations of pyrimethamine and sulfa inhibitors in the presence of trimethoprim. At 0.05μM trimethoprim, sum of fractional inhibitory concentrations, ΣFIC of pyrimethamine with sulfadoxine, pyrimethamine with sulfathiazole, pyrimethamine with sulfamethoxazole, and pyrimethamine with dapsone are in the range of 0.24-0.41. These results show synergism between inhibitors of the two enzymes even in the absence of folate transport and uptake. This bacterial surrogate system should be useful as a tool for assessing the interactions of drug combinations between the DHFR and DHPS inhibitors.

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

    PubMed

    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.

  19. Optimization of propafenone analogues as antimalarial leads.

    PubMed

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

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

    PubMed

    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 (<8 %) were found in just two of the countries, whilst 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.

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

    PubMed

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

    2014-08-30

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

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

    PubMed Central

    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. PMID:9763718

  3. Assessment of the efficacy of antimalarial drugs recommended by the National Malaria Control Programme in Madagascar: Up-dated baseline data from randomized and multi-site clinical trials

    PubMed Central

    Ménard, Didier; Ratsimbasoa, Arsène; Randrianarivelojosia, Milijaona; Rabarijaona, Léon-Paul; Raharimalala, Lucie; Domarle, Olivier; Randrianasolo, Laurence; Randriamanantena, Arthur; Jahevitra, Martial; Andriantsoanirina, Valérie; Rason, Marie-Ange; Raherinjafy, Rogelin; Rakotomalala, Emma; Tuseo, Luciano; Raveloson, Andrianirina

    2008-01-01

    Background In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP). Methods Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events. Results A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period. Conclusion These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria. PMID:18394169

  4. Genotoxic effects of the antimalarial drug lumefantrine in human lymphocytes in vitro and computational prediction of the mechanism associated with its interaction with DNA.

    PubMed

    de Lucca, Renato M R; Batista Júnior, João; Fontes, Cor J Fernandes; Bahia, Marcelo de Oliveira; Bassi-Branco, Carmen L

    2015-07-01

    Lumefantrine (LF) is an aryl-amino alcohol antimalarial drug used in artemisinin-based combination therapies against malaria worldwide. In this study, we investigated the genotoxic effects of LF in human lymphocytes in vitro, and the potential noncovalent interaction of LF with DNA using a 3D DNA-docking model. The number of DNA breaks and the frequency of nuclear buds (NBUDS) was significantly increased (P < 0.01 and P < 0. 05, respectively) at LF concentrations of 60, 80, and 100 µg/mL (LF60, LF80, and LF100, respectively). Frequency (‰) of micronuclei (MN) formation also increased after LF treatments. However, this was only significant for LF100 (P = 0.01) and LF80 (P = 0.001). LF did not affect the frequency of nucleoplasmic bridges (NPBs) (P = 0.12) or the nuclear division index (NDI) (P = 0.32). Computational analysis suggests that LF may interact noncovalently with DNA via the DNA minor groove surface with a predicted binding affinity energy of -7.2 kcal/mol and showing a favorable shape complementary to this groove. Our results suggest that LF has clastogenic effects in human lymphocytes in vitro due to noncovalent interaction with the minor groove of DNA.

  5. Repurposing the anti-malarial drug dihydroartemisinin suppresses metastasis of non-small-cell lung cancer via inhibiting NF-κB/GLUT1 axis

    PubMed Central

    Jiang, Jie; Geng, Guojun; Yu, Xiuyi; Liu, Hongming; Gao, Jing; An, Hanxiang; Cai, Chengfu; Li, Ning; Shen, Dongyan; Wu, Xiaoqiang; Zheng, Lisheng; Mi, Yanjun; Yang, Shuyu

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is an aggressive malignancy and long-term survival remains unsatisfactory for patients with metastatic and recurrent disease. Repurposing the anti-malarial drug dihydroartemisinin (DHA) has been proved to possess potent antitumor effect on various cancers. However, the effects of DHA in preventing the invasion of NSCLC cells have not been studied. In the present study, we determined the inhibitory effects of DHA on invasion and migration and the possible mechanisms involved using A549 and H1975 cells. DHA inhibited in vitro migration and invasion of NSCLC cells even in low concentration with little cytotoxicity. Additionally, low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA. Our results suggested that DHA can inhibit metastasis of NSCLC by targeting glucose metabolism via inhibiting NF-κB signaling pathway and DHA may deserve further investigation in NSCLC treatment. PMID:27895313

  6. [Animal drugs quality status and reason analysis].

    PubMed

    Ding, Qing; Qiu, Ya-jing; Fang, Ke-hui; Hu, Hao-bin; Wu, Yue

    2015-11-01

    In order to reaction the quality present situation, problems on the current quality of animal sources of drugs are summed up by using test data analysis, literature search and marketing research. This paper can also help the improvement of the quality management, the revision of the relevant department policy system and the improvement of standards.

  7. Antimalarial Activity of Cupredoxins

    PubMed Central

    Cruz-Gallardo, Isabel; Díaz-Moreno, Irene; Díaz-Quintana, Antonio; Donaire, Antonio; Velázquez-Campoy, Adrián; Curd, Rachel D.; Rangachari, Kaveri; Birdsall, Berry; Ramos, Andres; Holder, Anthony A.; De la Rosa, Miguel A.

    2013-01-01

    The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design. PMID:23749994

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

    PubMed

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

    2017-04-03

    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.

  9. Slowing down glioblastoma progression in mice by running or the anti-malarial drug dihydroartemisinin? Induction of oxidative stress in murine glioblastoma therapy

    PubMed Central

    Lemke, Dieter; Pledl, Hans-Werner; Zorn, Markus; Jugold, Manfred; Green, Ed; Blaes, Jonas; Löw, Sarah; Hertenstein, Anne; Ott, Martina; Sahm, Felix; Steffen, Ann-Catherine; Weiler, Markus; Winkler, Frank; Platten, Michael

    2016-01-01

    Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer. Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy. PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species. PMID:27447560

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

    PubMed

    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.

  11. Molecular epidemiology of malaria in Cameroon. XXIV. Trends of in vitro antimalarial drug responses in Yaounde, Cameroon.

    PubMed

    Basco, Leonardo K; Ringwald, Pascal

    2007-01-01

    In vitro response to chloroquine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin was assessed by the radioisotopic microtest in Yaoundé, Cameroon, during 2000-2004 and compared with our previous data obtained during 1996-1999. Based on the cut-off value of 100 nmol/L, 36.3% of isolates were chloroquine-susceptible (N = 175; geometric mean IC(50), 40.3 nmol/L) and 63.7% were chloroquine-resistant (N = 307; geometric mean IC(50), 211 nmol/L). There was no significant difference (P > 0.05) in the mean IC(50)s from 1996 to 2004, but a significant linear trend (P < 0.05) toward an increased proportion of chloroquine-resistant isolates was observed from 1996 (49%) to 2004 (69%). All chloroquine-susceptible isolates and most chloroquine-resistant isolates were susceptible to monodesethylamodiaquine (i.e., IC(50) < 60 nmol/L). Despite the positive correlation between chloroquine and monodesethylamodiaquine (r = 0.739, P < 0.05), the IC(50)s for monodesethylamodiaquine remained stable during 1997-2004, with no increase in the proportion of monodesethylamodiaquine-resistant isolates. Mefloquine, lumefantrine, and dihydroartemisinin were equally active against the chloroquine-susceptible and chloroquine-resistant parasites. The responses to these three drugs were positively correlated, and a significant decrease (P < 0.05) in the mean IC(50)s was observed during the study period compared with our earlier data in 1997-1999, probably because of their inverse relationship with chloroquine response. The in vitro results were in general agreement with the in vivo response to chloroquine and amodiaquine. In vitro drug susceptibility assay is a useful, complementary laboratory tool for determining the trend of response to drugs for which there is still no established molecular marker and may serve as an early warning system for emerging drug resistance.

  12. Sensitivity in vitro of Plasmodium falciparum to three currently used antimalarial drugs on the western border of Thailand.

    PubMed

    Fèvre, E M; Barnish, G; Yamokgul, P; Rooney, W

    1999-01-01

    The sensitivity in vitro of Plasmodium falciparum to mefloquine, quinine and artemisinin was assessed in an area of multi-drug resistance on the Thai-Myanmar border, using the World Health Organization's microtest, based on schizont maturation inhibition. Participating individuals were exclusively those who had contracted their infections within Myanmar. A total of 34 successful tests were carried out for mefloquine and quinine, showing a marked decrease in sensitivity compared to previously published results. Ten artemisinin tests were successful, with many failures due to the poor storage stability of the test plates. The implications of the shelf-life of the artemisinin plates is discussed. These results contribute to setting a base line of sensitivity to artemisinin in vitro.

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

    PubMed

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

    2008-08-01

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

  14. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs.

    PubMed

    Spillman, Natalie Jane; Kirk, Kiaran

    2015-12-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na(+) concentration and the plasma membrane P-type cation translocating ATPase 'PfATP4' has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's 'Malaria Box'. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na(+). Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field.

  15. A combined within-host and between-hosts modelling framework for the evolution of resistance to antimalarial drugs.

    PubMed

    Legros, Mathieu; Bonhoeffer, Sebastian

    2016-04-01

    The spread of drug resistance represents a significant challenge to many disease control efforts. The evolution of resistance is a complex process influenced by transmission dynamics between hosts as well as infection dynamics within these hosts. This study aims to investigate how these two processes combine to impact the evolution of resistance in malaria parasites. We introduce a stochastic modelling framework combining an epidemiological model of Plasmodium transmission and an explicit within-human infection model for two competing strains. Immunity, treatment and resistance costs are included in the within-host model. We show that the spread of resistance is generally less likely in areas of intense transmission, and therefore of increased competition between strains, an effect exacerbated when costs of resistance are higher. We also illustrate how treatment influences the spread of resistance, with a trade-off between slowing resistance and curbing disease incidence. We show that treatment coverage has a stronger impact on disease prevalence, whereas treatment efficacy primarily affects resistance spread, suggesting that coverage should constitute the primary focus of control efforts. Finally, we illustrate the importance of feedbacks between modelling scales. Overall, our results underline the importance of concomitantly modelling the evolution of resistance within and between hosts.

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

    PubMed

    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 < 0.05) in the concentrations of serum albumin, urea, creatinine, cholesterol and triglyceride of rabbits administered SP, A and SPA for 4 weeks, except in serum total protein. No significant differences existed in the activities of AST, ALT and ALP, except in creatine kinase which was elevated in the control. The brain serotonin 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.

  17. Use of antimalarials in dermatology.

    PubMed

    Ochsendorf, Falk R

    2010-10-01

    The antimalarials chloroquine and hydroxychloroquine have been used for the treatment of inflammatory diseases for more than 60 years. Even today new indications evolve due to the complex mode of action of these compounds. Due to the fear of side effects, especially irreversible retinopathy, their use is often limited. These side-effects, however, are a consequence of excessive daily dosages. An effective, safe therapy needs correct dosing, i. e. adherence to maximal daily dosages of 3.5(-4) mg chloroquine or 6(-6.5) mg hydroxychloroquine per kilogram ideal body weight. If the actual body weight is lower than the ideal body weight, this actual weight is used for the calculation of the dosage. Observing these limits allows a rather safe therapy of the diseases like lupus erythematosus, REM syndrome, porphyria cutanea tarda (2 × 125 mg chloroquine/week), cutaneous sarcoidosis and dermatomyositis. If standard therapies fail, then antimalarials can be tried to treat Sjögren syndrome, granuloma annulare or erosive lichen planus. If therapy fails, either can be combined with quinacrine to increase their effectiveness. Chloroquine and hydroxychloroquine are indispensable and well-tolerated essential drugs in dermatology and especially suited as part of a combination scheme, for example with corticosteroids, as they act synergistically and reduce side-effects.

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

    PubMed

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

    2016-06-29

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

  19. Design, Synthesis and Testing of Novel Antimalarial

    DTIC Science & Technology

    2006-05-05

    malaria can be caused by four species of protozoan parasites: Plasmodium (P.) falciparum, P. vivax, P. ovale, and P. malariae. The most serious...conditions arise from infection by P. falciparum and may include heart, lung, kidney and brain problems or death. Resistance to many currently used anti...more active than quinine in mice, even against Plasmodium strains resistant to pyrimethamine and other antimalarial drugs. In monkeys, the results

  20. Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana

    PubMed Central

    Koski, Alissa; Cofie, Patience; Mirzabagi, Ellie; Grady, Breanne L; Brooke, Steve

    2012-01-01

    Objectives Given use of uterotonics for postpartum haemorrhage and other obstetric indications, the importance of potent uterotonics is indisputable. This study evaluated access to and potency of injectable uterotonics in Ghana. Design Study design involved research assistants simulating clients to purchase oxytocin and ergometrine from different sources. Drug potency was measured via chemical assay by the Ghana Food and Drugs Board. Setting The study was conducted in three contrasting districts in Ghana. Outcome measure The per cent of active pharmaceutical ingredient was measured to assess the quality of oxytocin and ergometrine. Results 69 formal points of sale were visited, from which 55 ergometrine ampoules and 46 oxytocin ampoules were purchased. None of the ergometrine ampoules were within British Pharmacopoeia specification for active ingredient, none were expired and one showed 0% active ingredient, suggestive of a counterfeit drug. Among oxytocin ampoules purchased, only 11 (26%) were within British Pharmacopoeia specification for active ingredient and two (4%) were expired. The median percentages of active ingredients were 64% and 50% for oxytocin and ergometrine, respectively. Conclusions The quality of injectable uterotonics in three contrasting districts in Ghana is a serious problem. Restrictions regarding the sale of unregistered drugs, and of registered drugs from unlicensed shops, are inadequately enforced. These problems likely exist elsewhere but are not assessed, as postmarketing drug quality surveillance is generally restricted to well-funded disease-specific programmes relying on antiretroviral, antimalarial and antibiotic drugs. Maternal health programmes must adopt and fund the same approach to drug quality as is standard in programmes addressing infectious disease. PMID:22556159

  1. Antimalarial properties of imipramine and amitriptyline

    SciTech Connect

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

    1986-03-01

    This laboratory has previously demonstrated that imipramine (IM) and amitriptyline (AM), inhibit the conversion of riboflavin to its coenzymic derivatives. Several other laboratories have shown that dietary riboflavin deficiency is protective against malarial infection. In the present investigation, the authors determined whether IM and AM exert antimalarial effects similar to that of riboflavin deficiency, as they have hypothesized. In addition, they evaluated whether these drugs, like other antimalarial agents, increase the hemolytic response to ferriprotoporphyrin IX (FP). The growth of P. falciparum (FCR3) in the absence or presence of these drugs (80 ..mu..M) was measured by incubating parasitized erythrocytes for 48 h in RPMI 1640 medium. Parasitemia was determined by counting erythrocyte smears and monitoring (/sup 3/H)hypoxanthine uptake. With no drug, parasitemia was 20.3 +/- 5.3%, whereas in the presence of IM and AM, parasitemia was reduced to 7.3 +/- 0.8% and 13.6 +/- 2.8%, respectively. The uptake of (/sup 3/H)hypoxanthine was reduced to 47 +/- 3.6% and 54 +/- 2.9% of control by IM and AM, respectively. Assays of hemolysis were conducted by incubating 0.5% RBC suspension in NaCl-Tris buffer for 3 h at 37/sup 0/C with variable concentrations of drugs and/or FP (1-7 ..mu..M). Both drugs at 10 to 100 ..mu..M significantly enhanced hemolysis induced by FP. No hemolysis by these drugs was detected in the absence of FP. It is concluded that the tricyclic antidepressants, IM and AM, possess substantial antimalarial properties, thereby supporting the hypothesis that drugs which interfere with riboflavin metabolism should also provide protection against malaria.

  2. Antimalarial pharmacology and therapeutics of atovaquone.

    PubMed

    Nixon, Gemma L; Moss, Darren M; Shone, Alison E; Lalloo, David G; Fisher, Nicholas; O'Neill, Paul M; Ward, Stephen A; Biagini, Giancarlo A

    2013-05-01

    Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.

  3. [The evolution over time of the in-vitro resistance of Plasmodium falciparum to antimalarial drugs in 2 areas of the Brazilian Amazonia with distinct socioeconomic and geographic characteristics].

    PubMed

    Couto, A A; Calvosa, V S; Santos, M A; de Souza, J M

    1995-01-01

    We evaluated the temporal progression of in vitro P. falciparum resistance to chloroquine, amodiaquine, quinine and mefloquine in two areas with distinct socioeconomical and geographical characteristics: Lourenço, in Amapá state and Paragominas, in Pará state. The former region is essentially an "open" gold mining camp, whereas the latter is one currently undergoing a colonization settlement process, in addition to expanding economical activities which mainly include cattle raising and wood exploitation. Our results show high resistance rates to chloroquine in the two study areas: 79.8% and 68.4% in Lourenço and Paragominas, respectively. Variations in the response of P. falciparum to both amodiaquine and quinine were recorded throughout the study period. On the other hand, no mefloquine P. falciparum resistant strains could be identified, despite the tact we had noted a decrease in sensitivity to this antimalarial drug throughout the study period.

  4. Knowledge and perceptions of drug quality among drug sellers and consumers in Lao PDR.

    PubMed

    Syhakhang, Lamphone; Freudenthal, Solveig; Tomson, Göran; Wahlström, Rolf

    2004-11-01

    In most developing countries, including the Lao People's Democratic Republic (PDR), high prevalence of low quality drugs has been reported. The aim of this study was to explore knowledge and perceptions regarding drug quality among drug sellers and consumers, in Savannakhet province, Lao PDR. Quantitative and qualitative methods were used. Fifty-nine drug sellers and 278 exit customers were interviewed. Eight focus group discussions with drug sellers and community members were conducted. There was inadequate scientific drug knowledge among drug sellers. Only a few customers were aware of the existence of low quality drugs. Only one drug seller knew what constitutes a good quality drug according to the given criteria, and only two drug sellers knew the correct temperature for drug storage. Forty-four per cent had correct knowledge on drug labelling and 73% could read the expiry date. Fifty-eight per cent stated that they bought some drugs from unauthorized sources. Both drug sellers and consumers also elaborated on a local definition of drug quality. They determined drug quality by its perceived efficacy in the sense that a drug is good if it takes the disease away. They also trusted the responsible authorities not to provide them with low quality drugs. A majority of the consumers (73%) did not worry about the quality of the drugs, their greatest problem being financial constraints. People living in urban districts had significantly more knowledge on aspects of drug quality than those living in rural and remote areas. The limitations in scientific knowledge among drug sellers and the low awareness among consumers may contribute to the continued existence of low quality drugs. Government interventions through training of drug sellers and drug information for lay people are suggested.

  5. In silico and in vivo anti-malarial studies of 18β glycyrrhetinic acid from Glycyrrhiza glabra.

    PubMed

    Kalani, Komal; Agarwal, Jyoti; Alam, Sarfaraz; Khan, Feroz; Pal, Anirban; Srivastava, Santosh Kumar

    2013-01-01

    Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA) as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69 µg/ml) anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock) score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68-100% at doses of 62.5-250 mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.

  6. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

    PubMed

    Kato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M; Bittker, Joshua A; Corey, Victoria; Clarke, David; Derbyshire, Emily R; Dornan, Gillian L; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A; Koolen, Karin M J; Lewis, Timothy A; Lui, Ping S; Lukens, Amanda K; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C; McPhail, Jacob A; Mitasev, Branko; Moss, Eli L; Sayes, Morgane; Van Gessel, Yvonne; Wawer, Mathias J; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M; Bhatia, Sangeeta N; Burke, John E; Catteruccia, Flaminia; Clardy, Jon C; Clemons, Paul A; Dechering, Koen J; Duvall, Jeremy R; Foley, Michael A; Gusovsky, Fabian; Kocken, Clemens H M; Marti, Matthias; Morningstar, Marshall L; Munoz, Benito; Neafsey, Daniel E; Sharma, Amit; Winzeler, Elizabeth A; Wirth, Dyann F; Scherer, Christina A; Schreiber, Stuart L

    2016-10-20

    Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

  7. Antimalarial properties of SAABMAL®: an ethnomedicinal polyherbal formulation for the treatment of uncomplicated malaria infection in the tropics

    PubMed Central

    Obidike, I.C.; Amodu, B.; Emeje, M.O.

    2015-01-01

    Background & objectives: Malaria is a serious problem in the countries of the developing world. As the malaria parasite has become resistant to most of the antimalaria drugs available currently, there is a need to search for newer drugs. This study reports the pharmaceutical quality and in vivo antimalarial activities of a polyherbal formulation (SAABMAL®) used as malarial remedy in Nigeria. Methods: The antiplasmodial activity of SAABMAL® was determined by using the 4-day suppressive test in Plasmodium berghei-infected mice. The formulation was tried on three different experimental animal models for in vivo antimalarial activities, which are prophylactic, suppressive and curative in mice. Chloroquine and pyrimethamine were used as standard drugs for comparison. Results: The suppressive study showed that, SAABMAL® (200 and 400 mg/kg/bw) significantly (P<0.01) produced a suppression (29.39 - 100%) of parasitaemia in a dose-dependent manner, while the curative study showed that SAABMAL® at 400 mg significantly (P<0.01) reduced (95.80%) parasitaemia compared with controls. The mean survival time of SAABMAL®-treated groups (100 and 200 mg/kg) was higher than that of the chloroquine-treated group. Histopathologically, no changes were found in the spleen of both untreated and treated groups. SAABMAL® capsules were of good mechanical properties with low weight variation and high degree of content mass uniformity. Interpretation & conclusions: The results obtained in this study showed the efficacy of SAABMAL®, a herbal antimalarial formulation against chloroquine sensitive malaria and its potential use in the treatment of uncomplicated malaria infection. Further studies need to be done in humans to test its efficacy and safety for its potential use as an antimalarial drug. PMID:25900958

  8. Reliable low-cost capillary electrophoresis device for drug quality control and counterfeit medicines.

    PubMed

    Marini, R D; Rozet, E; Montes, M L A; Rohrbasser, C; Roht, S; Rhème, D; Bonnabry, P; Schappler, J; Veuthey, J-L; Hubert, Ph; Rudaz, S

    2010-12-15

    The proportion of counterfeit medicines is dramatically increasing these last few years. According to numerous official sources, in some pharmaceutical wholesalers in African countries, the proportion has reached 80%. Unfortunately, this situation is far to be improved due to lack of suitable analytical equipment allowing rapid actions of the Regulatory Agencies based on scientific consideration, at affordable cost and all over the drug supply chain. For that purpose, a network group considered that mater by building a low-cost original capillary electrophoresis (CE) equipment equipped with a new deep UV detector based on LED technology. The generic conditions for analysis were investigated: capillary zone electrophoresis (CZE) performed at acidic pH for basic drug molecules (i.e., quinine, highly used as the last antimalarial rampart), basic pH for compounds such as furosemide (a common diuretic drug) and at neutral pH for a well known antibiotic combination, trimethoprim/sulfamethoxazol. To evaluate the ability of the CE equipment for quantification, a full validation and a method comparison study were carried out for the CZE method dedicated to quinine determination. The validation involved the use of accuracy profile and total error concept to monitor the adequacy of the results obtained by the new prototype. The method comparison was based on the Bland and Altman approach by comparing results obtained by the low-cost CE and a conventional set-up. Subsequent validation studies were realized with neutral and acidic drug molecules, each focusing on a single concentration level calibration curve in order to maintain as low as possible the expenses due to reagents and thus the cost of analysis, as important advantages of CE for drug quality control.

  9. Assessment of hand-held Raman instrumentation for in situ screening for potentially counterfeit artesunate antimalarial tablets by FT-Raman spectroscopy and direct ionization mass spectrometry.

    PubMed

    Ricci, Camilla; Nyadong, Leonard; Yang, Felicia; Fernandez, Facundo M; Brown, Christopher D; Newton, Paul N; Kazarian, Sergei G

    2008-08-15

    Pharmaceutical counterfeiting has become a significant public health problem worldwide and new, rapid, user-friendly, reliable and inexpensive methods for drug quality screening are needed. This work illustrates the chemical characterization of genuine and fake artesunate antimalarial tablets by portable Raman spectroscopy and validation by FT-Raman spectroscopy and ambient mass spectrometry. The applicability of a compact and robust portable Raman spectrometer (TruScan) for the in situ chemical identification of counterfeit tablets is reported.

  10. Rapid and Specific Drug Quality Testing Assay for Artemisinin and Its Derivatives Using a Luminescent Reaction and Novel Microfluidic Technology

    PubMed Central

    Ho, Nga T.; Desai, Darash; Zaman, Muhammad H.

    2015-01-01

    Globally, it is estimated that about 10–30% of pharmaceuticals are of poor quality. Poor-quality drugs lead to long-term drug resistance, create morbidity, and strain the financial structure of the health system. The current technologies for substandard drug detection either are too expensive for low-resource regions or only provide qualitative results. To address the current limitations with point-of-care technologies, we have developed an affordable and robust assay to quantify the amount of active pharmaceutical ingredients (APIs) to test product quality. Our novel assay consists of two parts: detection reagent (probe) and a microfluidic testing platform. As antimalarials are of high importance in the global fight against malaria and are often substandard, they are chosen as the model to validate our assay. As a proof-of-concept, we have tested the assay with artesunate pure and substandard samples (Arsuamoon tablets) from Africa and compared with the conventional 96-well plate with spectrophotometer to demonstrate the quantitative efficacy and performance of our system. PMID:25897061

  11. On the molecular basis of the activity of the antimalarial drug chloroquine: EXAFS-assisted DFT evidence of a direct Fe-N bond with free heme in solution

    NASA Astrophysics Data System (ADS)

    Macetti, Giovanni; Rizzato, Silvia; Beghi, Fabio; Silvestrini, Lucia; Lo Presti, Leonardo

    2016-02-01

    4-aminoquinoline antiplasmodials interfere with the biocrystallization of the malaria pigment, a key step of the malaria parasite metabolism. It is commonly believed that these drugs set stacking π···π interactions with the Fe-protoporphyrin scaffold of the free heme, even though the details of the heme:drug recognition process remain elusive. In this work, the local coordination of Fe(III) ions in acidic solutions of hematin at room temperature was investigated by extended x-ray absorption fine structure (EXAFS) spectroscopy in the 4.0-5.5 pH range, both in the presence and in the absence of the antimalarial drug chloroquine. EXAFS results were complemented by DFT simulations in polarizable continuum media to model solvent effects. We found evidence that a complex where the drug quinoline nitrogen is coordinated with the iron center might coexist with formerly proposed adduct geometries, based on stacking interactions. Charge-assisted hydrogen bonds among lateral chains of the two molecules play a crucial role in stabilizing this complex, whose formation is favored by the presence of lipid micelles. The direct Fe-N bond could reversibly block the axial position in the Fe 1st coordination shell in free heme, acting as an inhibitor for the crystallization of the malaria pigment without permanently hampering the catalytic activity of the redox center. These findings are discussed in the light of possible implications on the engineering of drugs able to thwart the adaptability of the malaria parasite against classical aminoquinoline-based therapies.

  12. A search for sources of drug resistance by the 4D-QSAR analysis of a set of antimalarial dihydrofolate reductase inhibitors

    NASA Astrophysics Data System (ADS)

    Santos-Filho, Osvaldo Andrade; Hopfinger, Anton J.

    2001-01-01

    A set of 18 structurally diverse antifolates including pyrimethamine, cycloguanil, methotrexate, aminopterin and trimethoprim, and 13 pyrrolo[2,3-d]pyrimidines were studied using four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis. The corresponding biological activities of these compounds include IC50 inhibition constants for both the wild type, and a specific mutant type of Plasmodium falciparum dihydrofolate reductase (DHFR). Two thousand conformations of each analog were sampled to generate a conformational ensemble profile (CEP) from a molecular dynamics simulation (MDS) of 100,000 conformer trajectory states. Each sampled conformation was placed in a 1 Å cubic grid cell lattice for each of five trial alignments. The frequency of occupation of each grid cell was computed for each of six types of pharmacophore groups of atoms of each compound. These grid cell occupancy descriptors (GCODs) were then used as a descriptor pool to construct 4D-QSAR models. Models for inhibition of both the `wild' type and the mutant enzyme were generated which provide detailed spatial pharmacophore requirements for inhibition in terms of atom types and their corresponding relative locations in space. The 4D-QSAR models indicate some structural features perhaps relevant to the mechanism of resistance of the Plasmodium falciparum DHFR to current antimalarials. One feature identified is a slightly different binding alignment of the ligands to the mutant form of the enzyme as compared to the wild type.

  13. Detecting Counterfeit Antimalarial Tablets by Near-Infrared Spectroscopy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Counterfeit antimalarial drugs are found in many developing countries, but it is challenging to differentiate between genuine and fakes due to their increasing sophistication. Near-infrared spectroscopy (NIRS) is a powerful tool in pharmaceutical forensics, and we tested this technique for discrim...

  14. Antimalarial hybrid molecules: a close reality or a distant dream?

    PubMed

    Agarwal, Drishti; Gupta, Rinkoo D; Awasthi, Satish K

    2017-03-13

    Emergence of drug resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected towards finding alternate chemotherapeutic agents that are capable of combating multi-drug resistant parasite strains. In the above light, scientists have come up with the concept of hybridisation of two or more active pharmacophores into a single chemical entity, resulting in 'antimalarial hybrids.' The approach has been applied widely for lead generation against deadly diseases such as cancer and AIDS, with proven potential to be used as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on design and synthesis of hybrids for treating malaria, and may be regarded as proof of their potential advantages over Artemisinin based Combination Therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics and easier formulation, have yet to be realised. A number of questions left unaddressed at present need to be answered before this approach can progress in to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light over the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

  15. Synthesis of a potent new antimalarial through natural products conjugation

    PubMed Central

    Bruno, Michela; Trucchi, Beatrice; Monti, Diego; Romeo, Sergio; Kaiser, Marcel; Verotta, Luisella

    2013-01-01

    Three natural products have been assembled to obtain a new antimalarial hit. (+)-Usnic acid was used as scaffold to design and synthesize new products, that were tested on asexual development for P. falciparum and P. berghei. Among them, the ester of (+)-usnic acid-4-aminobutyric acid 14 with dihydroartemisinin shows considerable in vivo antimalarial activity against P. berghei in mice, similar to the synthetic drug artesunate. Compound 14 behaves as a delivery system for dihydroartemisinin and combine the effects of the endoperoxide with the redox properties of the phenolic portions of (+)-usnic acid. PMID:23307699

  16. In Vitro Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

    PubMed Central

    Sullivan, Margery; McCutchan, Thomas F.

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation. PMID:25779576

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

    PubMed Central

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

    2015-01-01

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

  18. Antimalarial activity of methanolic leaf extract of Piper betle L.

    PubMed

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

    2010-12-28

    The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against Plasmodium berghei (NK65) during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P < 0.05) schizonticidal activity in all three antimalarial evaluation models. Phytochemical screening showed that the leaf extract contains some vital antiplasmodial chemical constituents. The extract also exhibited a potent ability to scavenge the free radicals. The results of acute toxicity showed that the methanol extract of Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

  19. Artemisinin Antimalarials: Preserving the “Magic Bullet”

    PubMed Central

    Maude, Richard J; Woodrow, Charles J; White, Lisa J

    2010-01-01

    The artemisinins are the most effective antimalarial drugs known. They possess a remarkably wide therapeutic index. These agents have been used in traditional Chinese herbal medicine for more than 2,000 years but were not subjected to scientific scrutiny until the 1970s. The first formal clinical trials of the artemisinins, and the development of methods for their industrial scale production, followed rapidly. A decade later, Chinese scientists shared their findings with the rest of the world; since then, a significant body of international trial evidence has confirmed these drugs to be far superior to any available alternatives. In particular, they have the ability to rapidly kill a broad range of asexual parasite stages at safe concentrations that are consistently achievable via standard dosing regimens. As their half-life is very short, there was also thought to be a low risk of resistance. These discoveries coincided with the appearance and spread of resistance to all the other major classes of antimalarials. As a result, the artemisinins now form an essential element of recommended first-line antimalarial treatment regimens worldwide. To minimize the risk of artemisinin resistance, they are recommended to be used to treat uncomplicated malaria in combination with other antimalarials as artemisinin combination therapies (ACTs). Their rollout has resulted in documented reductions in malaria prevalence in a number of African and Asian countries. Unfortunately, there are already worrisome early signs of artemisinin resistance appearing in western Cambodia. If this resistance were to spread, it would be disastrous for malaria control efforts worldwide. The enormous challenge for the international community is how to avert this catastrophe and preserve the effectiveness of this antimalarial “magic bullet”. Drug Dev Res 71: 12–19, 2010. © 2009 Wiley-Liss, Inc. PMID:21399699

  20. Screening of Thai medicinal plant extracts and their active constituents for in vitro antimalarial activity.

    PubMed

    Ichino, C; Soonthornchareonnon, N; Chuakul, W; Kiyohara, H; Ishiyama, A; Sekiguchi, H; Namatame, M; Otoguro, K; Omura, S; Yamada, H

    2006-04-01

    To discover antimalarial substances from plants cultivated in Thailand 80%-EtOH extracts from selected plants were screened for in vitro antimalarial activity against the drug resistant K1 strain of Plasmodium falciparum. In total, 86 Thai medicinal plant samples representing 48 species from 35 genera in 16 families were screened and two species (Polyalthia viridis and Goniothalamus marcanii) were found to show notable antimalarial activity (IC50: 10.0 and 6.3 microg/mL). Marcanine A and 16-hydroxycleroda-3,13(14)Z-dien-15,16-olide were identified as the respective major active constituents in P. viridis and G. marcanii, respectively.

  1. Crystal and molecular structure of the antimalarial agent enpiroline.

    PubMed Central

    Karle, J M; Karle, I L

    1989-01-01

    To identify common spatial and structural features of amino alcohol antimalarial agents with the eventual goal of designing more effective drugs and a better understanding of the mechanism of action of this class of antimalarial agents, the three-dimensional crystal and molecular structure of enpiroline, a new antimalarial agent active against chloroquine-resistant Plasmodium falciparum, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids and of the new antimalarial agent WR 194,965. The aromatic rings of the phenyl-pyridine ring system of enpiroline are twisted from each other by approximately 18 degrees. The intramolecular aliphatic N-O distance in enpiroline was 2.80 A (1 A = 0.1 nm), which is close to the N-O distance found in the antimalarial cinchona alkaloids. Enpiroline contains both an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms and an intermolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms of two neighboring molecules. One enantiomer of enpiroline superimposed best with quinine, and the other enantiomer of enpiroline superimposed best with quinidine, suggesting that both enantiomers of enpiroline possess antimalarial activity. Since a common feature of the crystal structures of the amino alcohol antimalarial agents is the formation of intermolecular hydrogen bonds, the common spatial direction of hydrogen bond formation indicates the potential ability of these antimalarial agents to bind to a common receptor site. The crystallographic parameters were as follows: C19H18F6N5O; Mr = 404.3; symmetry of unit cell, monoclinic; space group, P2(1)/a; parameters of unit cell---a = 9.454 +/- 0.004 A, b = 18.908 +/- 0.008 A, c = 10.300 +/- 0.004 A, and beta = 96.55 +/- 0.03 degrees: V (volume of unit cell) = 1829.2 A3; Z (number of molecules per unit cell) = 4; Dchi (calculated density) = 1.46 g cm-3; source of radiation, CuK alpha (lambda = 1.54178 A); mu

  2. Novel molecular targets for antimalarial chemotherapy.

    PubMed

    Jana, Snehasis; Paliwal, Jyoti

    2007-07-01

    The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Malaria control has relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the last quarter of the 20th century. An alarming increase in drug-resistant strains of the malaria parasite poses a significant problem for effective control. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of parasite metabolism and organelle function could be attractive targets. It is expected that the application of functional genomic tools in combination with modern approaches such as structure-based drug design and combinatorial chemistry will lead to the development of effective new drugs against drug-resistant malaria strains. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.

  3. Antimalarial activity of WR 243251, a Dihydroacridinedione.

    PubMed Central

    Berman, J; Brown, L; Miller, R; Andersen, S L; McGreevy, P; Schuster, B G; Ellis, W; Ager, A; Rossan, R

    1994-01-01

    WR 243251 is a dihydroacridinedione that was evaluated for antimalarial blood schizonticidal activity in vitro and in vivo. The in vitro doses calculated to kill 50% of organisms were 11 nM for a chloroquine-susceptible, mefloquine-resistant standard strain and 25 nM for a chloroquine- and pyrimethamine-resistant standard strain. The total dose needed to cure 100% of mice infected with a drug-susceptible strain of Plasmodium berghei was 12 to 20 mg/kg of body weight for both oral and subcutaneous administration. The regimen needed to cure 100% of Aotus monkeys infected with Plasmodium falciparum was 8 mg/kg/day for 3 days (chloroquine-susceptible strain) and 16 mg/kg/day for 3 days (chloroquine-resistant strain). The 100% curative doses for Aotus monkeys did not increase for parasites previously exposed to subcurative doses. The absolute value of the curative doses of WR 243251 was comparable to or lower than the values for clinical antimalarial agents. The high absolute activity, comparability of activities against susceptible and resistant parasites, and inability to induce resistance by exposure to subcurative doses suggest that WR 243251 has strong potential as a blood schizonticidal agent. PMID:7986005

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

    PubMed

    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.

  5. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement.

    PubMed

    Shen, Shuo; Liu, Shu-Zhi; Zhang, Yu-Shi; Du, Mao-Bo; Liang, Ai-Hua; Song, Li-Hua; Ye, Zu-Guang

    2015-01-01

    Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem-ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic.

  6. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

    PubMed Central

    Shen, Shuo; Liu, Shu-Zhi; Zhang, Yu-Shi; Du, Mao-Bo; Liang, Ai-Hua; Song, Li-Hua; Ye, Zu-Guang

    2015-01-01

    Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic. PMID:26170661

  7. Potent Antimalarial Activity of Acriflavine In Vitro and In Vivo

    PubMed Central

    2015-01-01

    Malaria continues to be a major health problem globally. There is an urgent need to find new antimalarials. Acriflavine (ACF) is known as an antibacterial agent and more recently as an anticancer agent. Here, we report that ACF inhibits the growth of asexual stages of both chloroquine (CQ) sensitive and resistant strains of human malarial parasite, Plasmodium falciparum in vitro at nanomolar concentration. ACF clears the malaria infection in vivo from the bloodstreams of mice infected with Plasmodium berghei. Interestingly, ACF is accumulated only in the parasitized red blood cells (RBCs) and parasite specific transporters may have role in this specific drug accumulation. We further show that ACF impairs DNA replication foci formation in the parasites and affects the enzymatic activities of apicoplast specific Gyrase protein. We thus establish ACF as a potential antimalarial amidst the widespread incidences of drug resistant Plasmodium strains. PMID:25089658

  8. Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

    PubMed Central

    Rudrapal, Mithun; Chetia, Dipak

    2016-01-01

    Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains of Plasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistant P. falciparum malaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system lacking the lactone ring that constitutes the most important endoperoxide structural scaffold is believed to be the key pharmacophoric moiety and is primarily responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. Due to this reason, research into endoperoxide, particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based scaffolds, has gained significant interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive effort has been made to review the development of endoperoxide antimalarials from traditional antimalarial leads (natural/semisynthetic) and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based structural scaffolds, including their chimeric (hybrid) molecules, which are newer and potent antimalarial agents. PMID:27843298

  9. From Local Quality Improvement to National Drug Recall

    PubMed Central

    Herzer, Kurt R.; Lim, Christine; Li, Matthew; Xie, Yanjun; Doyle, Peter A.; Cover, Renee; Mark, Lynette J.

    2014-01-01

    Medication errors due to look-alike drugs put patients at risk and can be fatal. Neuromuscular blocking agents, such as vecuronium, can cause awake-paralysis in patients if administered as a single agent. Recent literature reported six cases in which vecuronium was inadvertently administered instead of the antibiotic drug cefazolin. This article describes a standardized quality improvement process used at The Johns Hopkins Hospital that was locally implemented following an adverse drug event and culminated in a nationwide FDA-mandated drug recall of vecuronium. PMID:23508529

  10. Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy.

    PubMed

    Milner, Erin; Sousa, Jason; Pybus, Brandon; Auschwitz, Jennifer; Caridha, Diana; Gardner, Sean; Grauer, Kristina; Harris, Erin; Hickman, Mark; Kozar, Michael P; Lee, Patricia; Leed, Susan; Li, Qigui; Melendez, Victor; Moon, Jay; Ngundam, Franklyn; O'Neil, Michael; Parriott, Sandi; Potter, Brittney; Sciotti, Rick; Tangteung, Anchalee; Dow, Geoffrey S

    2012-03-01

    Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

  11. Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.

    PubMed

    Gilson, Paul R; Tan, Cyrus; Jarman, Kate E; Lowes, Kym N; Curtis, Joan M; Nguyen, William; Di Rago, Adrian E; Bullen, Hayley E; Prinz, Boris; Duffy, Sandra; Baell, Jonathan B; Hutton, Craig A; Jousset Subroux, Helene; Crabb, Brendan S; Avery, Vicky M; Cowman, Alan F; Sleebs, Brad E

    2017-02-09

    Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

  12. Potential antimalarials from African natural products: A reviw

    PubMed Central

    Lawal, Bashir; Shittu, Oluwatosin Kudirat; Kabiru, Adamu Yusuf; Jigam, Ali Audu; Umar, Maimuna Bello; Berinyuy, Eustace Bonghan; Alozieuwa, Blessing Uchenna

    2015-01-01

    Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health, and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in vivo or in vitro against malaria parasite. Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, and Science domain) that report on antiplasmodial activity of natural products from differernts Africa region. A total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%), Fababceae (8.128%), Euphorbiaceae (5.52%), Rubiaceas (5.52%), and Apocyanaceae (5.214%), have received more scientific validation than others. African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against Plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products are of paramount importance. PMID:26649238

  13. Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

    PubMed Central

    Shafiq, N.; Rajagopalan, S.; Kushwaha, H. N.; Mittal, N.; Chandurkar, N.; Bhalla, A.; Kaur, S.; Pandhi, P.; Puri, G. D.; Achuthan, S.; Pareek, A.; Singh, S. K.; Srivastava, J. S.; Gaur, S. P. S.; Malhotra, S.

    2014-01-01

    Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T1/2, MRT, and AUC0−∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials. PMID:24800100

  14. Adverse Drug Reactions and quality deviations monitored by spontaneous reports

    PubMed Central

    Visacri, Marília Berlofa; de Souza, Cinthia Madeira; Sato, Catarina Miyako Shibata; Granja, Silvia; de Marialva, Mécia; Mazzola, Priscila Gava; Moriel, Patricia

    2014-01-01

    Objectives The aim of this study was to determine the frequency and profile of spontaneous reports of Adverse Drug Reactions (ADRs) and quality deviations in a Brazilian teaching hospital and propose a consistent classification to study quality deviations. Methods This is a descriptive and retrospective study involving the analysis of spontaneous reports of ADRs and quality deviations in 2010. ADRs were classified according to the reaction mechanism, severity, and causality. The drugs were classified according to their therapeutic classes and symptoms according to the affected organ. The quality deviations were classified according to the type of deviation and type of medicine available in the Brazilian market. Results A total of 68 forms were examined; ADRs accounted for 39.7% of the notifications, while quality deviations accounted for 60.3%. ADRs occurred more frequently in men (51.9%) and adults (63.0%). The skin (28.0%) was the most affected organ, while anti-infectives (40.7%) were the therapeutic class that caused the most ADRs. The most common ADRs were type B (74.0%), moderates (37.0%), and probables (55.6%). In relation to quality deviations, the most frequent notifications were breaks, splits and leaks (20.9%) and related to generic drugs (43.9%). Conclusion The classification system to study quality deviations was clear and consistent. This study demonstrated that practices and public policies related to more effective pharmacovigilance need to be implemented so that the number of spontaneous reports increases. PMID:25972731

  15. Data quality of the Drug Abuse Warning Network.

    PubMed

    Roberts, C D

    1996-08-01

    The purpose of this article was to assess the quality of data collected by the Drug Abuse Warning Network (DAWN), which reports drug abuse emergency department visits. The results of quality assurance studies at 36 sites were reviewed and interpreted. Data collection procedures are not consistent among hospitals and, along with personnel, regularly change within a hospital. Trained investigators reabstracted DAWN report forms at 24 sites and determined that only 57.4% of the cases that met DAWN case definition criteria had been reported; one of five cases had been reported at one site. The technique used in 11 (47.8%) of 23 hospitals to screen for potential DAWN cases detected only 36% of the cases found when all medical charts are examined. The investigators found discrepancies between reported and actual cases in 81.3% of the report forms reabstracted, with an average of 2.3 errors per form. Information as to the drug(s) involved was incorrect in 36.3% of the forms. Due to underreporting of drug abuse emergency department visits and poor quality data in DAWN report forms, DAWN estimates of drug activity must be viewed with caution. Furthermore, estimation of trends is risky, due to differences between emergency departments as to reporting systems and changes over time.

  16. Access to orphan drugs despite poor quality of clinical evidence

    PubMed Central

    Dupont, Alain G; Van Wilder, Philippe B

    2011-01-01

    AIM We analysed the Belgian reimbursement decisions of orphan drugs as compared with those of innovative drugs for more common but equally severe diseases, with special emphasis on the quality of clinical evidence. METHODS Using the National Health Insurance Agency administrative database, we evaluated all submitted orphan drug files between 2002 and 2007. A quality analysis of the clinical evidence in the orphan reimbursement files was performed. The evaluation reports of the French ‘Haute Autorité de Santé’, including the five-point scale parameter ‘Service Médical Rendu (SMR), were examined to compare disease severity. Chi-squared tests (at P < 0.05 significance level) were used to compare the outcome of the reimbursement decisions between orphan and non-orphan innovative medicines. RESULTS Twenty-five files of orphan drugs and 117 files of non-orphan drugs were evaluated. Twenty-two of 25 (88%) submissions of orphan drugs were granted reimbursement as opposed to 74 of the 117 (63%) non-orphan innovative medicines (P = 0.02). Only 52% of the 25 orphan drug files included a randomized controlled trial as opposed to 84% in a random control sample of 25 non-orphan innovative submissions (P < 0.01). The duration of drug exposure was in most cases far too short in relation to the natural history of the disease. CONCLUSIONS Orphan drug designation predicts reimbursement despite poor quality of clinical evidence. The evidence gap at market authorization should be reduced by post-marketing programmes, in which the centralized regulatory and the local reimbursement authorities collaborate in an efficient way across the European Union member states. PMID:21395641

  17. Detecting counterfeit antimalarial tablets by near-infrared spectroscopy.

    PubMed

    Dowell, Floyd E; Maghirang, Elizabeth B; Fernandez, Facundo M; Newton, Paul N; Green, Michael D

    2008-11-04

    Counterfeit antimalarial drugs are found in many developing countries, but it is challenging to differentiate between genuine and fakes due to their increasing sophistication. Near-infrared spectroscopy (NIRS) is a powerful tool in pharmaceutical forensics, and we tested this technique for discriminating between counterfeit and genuine artesunate antimalarial tablets. Using NIRS, we found that artesunate tablets could be identified as genuine or counterfeit with high accuracy. Multivariate classification models indicated that this discriminatory ability was based, at least partly, on the presence or absence of spectral signatures related to artesunate. This technique can be field-portable and requires little training after calibrations are developed, thus showing great promise for rapid and accurate fake detection.

  18. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... DRUGS (Eff. 12-12-2011) Quality Assurance § 212.20 What activities must I perform to ensure drug...

  19. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

    PubMed Central

    Parhizgar, Arezoo Rafiee; Tahghighi, Azar

    2017-01-01

    Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold. PMID:28360437

  20. Assessing Website Pharmacy Drug Quality: Safer Than You Think?

    PubMed Central

    Bate, Roger; Hess, Kimberly

    2010-01-01

    Background Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality. Methods and Findings This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17) websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from “approved”, “legally compliant” or “not recommended” websites (0 out of 86), whereas 8.6% (3 out of 35) failed from “highly not recommended” and unidentifiable websites. Conclusions Of those drugs that could be assessed, all except Viagra® passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by

  1. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action.

    PubMed

    Sanz, Laura M; Crespo, Benigno; De-Cózar, Cristina; Ding, Xavier C; Llergo, Jose L; Burrows, Jeremy N; García-Bustos, Jose F; Gamo, Francisco-Javier

    2012-01-01

    Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately determine the parasite killing rate in response to treatment. Commonly used techniques essentially measure metabolic activity as a proxy for parasite viability. However, these approaches are susceptible to artefacts, as viability and metabolism are two parameters that are coupled during the parasite life cycle but can be differentially affected in response to drug actions. Moreover, traditional techniques do not allow to measure the speed-of-action of compounds on parasite viability, which is an essential efficacy determinant. We present here a comprehensive methodology to measure in vitro the direct effect of antimalarial compounds over the parasite viability, which is based on limiting serial dilution of treated parasites and re-growth monitoring. This methodology allows to precisely determine the killing rate of antimalarial compounds, which can be quantified by the parasite reduction ratio and parasite clearance time, which are key mode-of-action parameters. Importantly, we demonstrate that this technique readily permits to determine compound killing activities that might be otherwise missed by traditional, metabolism-based techniques. The analysis of a large set of antimalarial drugs reveals that this viability-based assay allows to discriminate compounds based on their antimalarial mode-of-action. This approach has been adapted to perform medium throughput screening, facilitating the identification of fast-acting antimalarial compounds, which are crucially needed for the control and possibly the eradication of malaria.

  2. Antimalarial activity of fractions of aqueous extract of Acacia nilotica root

    PubMed Central

    Alli, Lukman Adewale; Adesokan, Abdulfatai Ayoade; Salawu, Adeola Oluwakanyinsola

    2016-01-01

    Background: The problem of resistance of malarial parasites to available antimalarial drugs makes the development of new drugs imperative, with natural plant products providing an alternative source for discovering new drugs. Aim: To evaluate the antimalarial activity of eluted fractions of Acacia nilotica root extract and determine the phytochemicals responsible for its antimalarial activity. Materials and Methods: The extract was eluted successively in gradients of solvent mixture (hexane, ethyl acetate, and methanol) in multiples of 100 ml, and each fraction was collected separately. Eluates that showed similar thin layer chromatographic profiles and Rf values were combined to produce 4 main fractions (F-1, F-2, F-3, and F-4), which were tested separately for antimalarial activity using the curative test. Changes in body weight, temperature, and packed cell volume (PCV) were also recorded. Results: Fraction F-1 of A. nilotica at 50 and 100 mg/kg b/w produced significant and dose-dependent reduction in parasite count in Plasmodium berghei infected mice compared to the control, and also significantly increased the survival time of the mice compared to the control group. This fraction also ameliorated the malaria-induced anemia by improving PCV in treated mice. Conclusion: Antimalarial activity of extract of A. nilotica root is probably localized in the F-1 fraction of the extract, which was found to be rich in alkaloids and phenolics. Further study will provide information on the chemical properties of the active metabolites in this fraction. PMID:27104040

  3. X-ray Spectroscopy for Quality Control of Chemotherapy Drugs

    SciTech Connect

    Greaves, E. D.; Barros, H.; Bermudez, J.; Sajo-Bohus, L.; Angeli-Greaves, M.

    2007-10-26

    We develop a method, employing Compton peak standardization and the use of matrix-matched spiked samples with Total Reflection X-ray Fluorescence (TXRF), for the determination of platinum plasma concentrations of patients undergoing chemotherapy with Pt-bearing drugs. Direct blood plasma analysis attains Pt detection limits of 70 ng/ml. Measurement results of prescribed drug doses are compared to achieved blood Pt concentrations indicating a lack of expected correlations. Direct analysis of Pt-containing infused drugs from a variety of suppliers indicates cases of abnormal concentrations which raises quality control issues. We demonstrate the potential usefulness of the method for pharmacokinetic studies or for routine optimization and quality control of Pt chemotherapy treatments.

  4. From a cytotoxic agent to the discovery of a novel antimalarial agent.

    PubMed

    Singh, Ravi S P; Das, Umashankar; Auschwitz, Jennifer M; Leed, Susan E; Hickman, Mark R; Dimmock, Jonathan R; Alcorn, Jane

    2013-01-15

    A novel cytotoxin 3,5-bis(4-chlorobenzylidene)-1-[4-{2-(4-morpholinyl)ethoxy}phenyl-carbonyl]-4-piperidone hydrochloride 2 demonstrated potent antimalarial properties with IC(50) values of 0.60 and 1.97 μM against the drug sensitive D6 strain and the C235 drug-resistant strain of Plasmodium falciparum. This compound concentrates in red blood cells, lowers glutathione concentrations in erythrocytes and permeates across CACO-2 cells. These data reveal 2 to be a promising lead compound in the quest for novel antimalarial agents.

  5. Synthesis and Screening of New Antimalarial Drugs

    DTIC Science & Technology

    1987-10-30

    monkeys free froliny blood parasites are transferred to experimental wing and kept in mosquito free rooms. They are supplied standard pellet diet, seasonal...on 5% multivitamin solution. b) Infection of mosquitoes s In order to infect the Anopheles stephensi mosquitoes , the daily course of parasitaemia...observed 5-8 day 0fwes later. Mosquito infectivity studies at CDRI during the last 5 years have shown that ideal infection rate is obtained when mosquitoes

  6. Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

    PubMed Central

    Sarkar, Souvik; Siddiqui, Asim A.; Saha, Shubhra J.; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S.; Nag, Shiladitya; Adhikari, Susanta

    2016-01-01

    We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [3H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. PMID:27139466

  7. [Ophthalmological monitoring protocol for patients treated with long-term antimalarials or vigabatrin].

    PubMed

    Ingster-Moati, I; Orssaud, C

    2009-01-01

    Treatment with the antimalarials chloroquine or hydroxychloroquine rarely causes retinopathy. Chloroquine and hydroxychloroquine toxicity are untreatable and can progress to legal blindness. Since 1957, there has been a consensus on the need to monitor patients on long-term chloroquine or hydroxychloroquine therapy. Currently, the procedure for follow-up includes collection of patient information, complete ophthalmological exam with automated central perimetry, and retinal electrophysiology. Screening should take place before treatment or no more than 6 months after initiation of antimalarial therapy. During treatment, monitoring relative to the baseline should be at a frequency determined by whether there are risk factors for development of toxicity, such as a cumulative dose greater than 1.8 kg, a daily dose greater than 6.5mg of hydroxychloroquine/kg/day, concurrent or past ophthalmological diseases, hepatic or renal insufficiency, age older than 65 years, and chloroquine intake. Retinopathy can occur in the absence of risk factors. The risk/benefit ratio favors therapy despite the time and expense of screening. Vigabatrin (VGB) is an effective drug for treatment of epilepsy and has been used in the treatment of West syndrome and epilepsy resistant to other drugs. VGB treatment improves quality of life, but it can induce characteristic bilateral nasal visual field defects and changes in retinal electrophysiology. Currently, the recommended procedure is to screen these patients before treatment, if possible, with a complete ophthalmological exam including perimetry and retinal electrophysiology every 6 months. It may be necessary to rely on retinal electrophysiology since some patients may not be able to undergo perimetry. The risk/benefit ratio sill clearly favors VGB treatment. Patients whose seizure incidence is reduced and have only minimal visual changes could continue VGB with strict monitoring. The others must discontinue VGB.

  8. Prescription drugs: issues of cost, coverage, and quality.

    PubMed

    Copeland, C

    1999-04-01

    This Issue Brief closely examines expenditures on prescription drugs, and discusses their potential to substitute for other types of health care services. In addition, it describes employer coverage of prescription drugs, direct-to-consumer advertising of prescription drugs, and potential legislation affecting the prescription drug market. Prescription drug expenditures grew at double-digit rates during almost every year since 1980, accelerating to 14.1 percent in 1997. In contrast, total national health expenditures, hospital service expenditures, and physician service expenditures growth rates decreased from approximately 13 percent in 1980 to less than 5 percent in 1997. Private insurance payments for prescription drugs increased 17.7 percent in 1997, after growing 22.1 percent in 1995 and 18.3 percent in 1996. This growth in prescription drug payments compares with 4 percent or less overall annual growth in private insurance payments for each of those three years. From 1993 to 1997, the overwhelming majority of the increases in expenditures on prescription drugs were attributable to increased volume, mix, and availability of pharmaceutical products. In 1997, these factors accounted for more than 80 percent of the growth in prescription drug expenditures. A leading explanation for the sharp growth in drug expenditures is that prescription drugs are a substitute for other forms of health care. While it is difficult to determine the extent to which this substitution occurs, various studies have associated cost savings with the use of pharmaceutical products in treating specific diseases. Evidence suggests that more appropriate utilization of prescription drugs has the potential to lower total expenditures and improve the quality of care. Also, some studies indicate the U.S. health care system needs to improve the way patients use and physicians prescribe current medications. Prescription drug plans offered by employers are likely to undergo changes to ensure that

  9. Modelling the time course of antimalarial parasite killing: a tour of animal and human models, translation and challenges.

    PubMed

    Patel, Kashyap; Simpson, Julie A; Batty, Kevin T; Zaloumis, Sophie; Kirkpatrick, Carl M

    2015-01-01

    Malaria remains a global public health concern and current treatment options are suboptimal in some clinical settings. For effective chemotherapy, antimalarial drug concentrations must be sufficient to remove completely all of the parasites in the infected host. Optimized dosing therefore requires a detailed understanding of the time course of antimalarial response, whilst simultaneously considering the parasite life cycle and host immune elimination. Recently, the World Health Organization (WHO) has recommended the development of mathematical models for understanding better antimalarial drug resistance and management. Other international groups have also suggested that mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) models can support the rationalization of antimalarial dosing strategies. At present, artemisinin-based combination therapy (ACT) is recommended as first line treatment of falciparum malaria for all patient groups. This review summarizes the PK-PD characterization of artemisinin derivatives and other partner drugs from both preclinical studies and human clinical trials. We outline the continuous and discrete time models that have been proposed to describe antimalarial activity on specific stages of the parasite life cycle. The translation of PK-PD predictions from animals to humans is considered, because preclinical studies can provide rich data for detailed mechanism-based modelling. While similar sampling techniques are limited in clinical studies, PK-PD models can be used to optimize the design of experiments to improve estimation of the parameters of interest. Ultimately, we propose that fully developed mechanistic models can simulate and rationalize ACT or other treatment strategies in antimalarial chemotherapy.

  10. Liposomal Drug Products: A Quality by Design Approach

    NASA Astrophysics Data System (ADS)

    Xu, Xiaoming

    Quality by Design (QbD) principles has been applied to the development of two liposomal formulations, containing a hydrophilic small molecule therapeutic (Tenofovir) and a protein therapeutic (superoxide dismutase). The goal of the research is to provide critical information on 1) how to reduce the preparation variability in liposome formulations, and 2) how to increase drug encapsulation inside liposomes to reduce manufacturing cost. Most notably, an improved liposome preparation method was developed which increased the encapsulation efficiency of hydrophilic molecules. In particular, this method allows for very high encapsulation efficiency. For example, encapsulation efficiencies of up to 50% have been achieved, whereas previously only 20% or less have been reported. Another significant outcome from this research is a first principle mathematical model to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes. This mathematical model will be useful in: formulation development to rapidly achieve optimized formulations; comparison of drug encapsulation efficiencies of liposomes prepared using different methods; and assisting in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during manufacturing. A novel two-stage reverse dialysis in vitro release testing method has also been developed for passively targeted liposomes, which uses the first stage to mimic the circulation of liposomes in the body and the second stage to imitate the drug release process at the target. The developed in vitro release testing method can be used to distinguish formulations with varied compositions for quality control testing purposes. This developed method may pave the way to the development of more biorelevant quality control testing methods for liposomal drug products in the future. The QbD case studies performed in this research are examples of how this approach can be used to

  11. The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

    PubMed Central

    Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H.; Bagrel, Denyse; Blandin, Stephanie; Lanzer, Michael

    2016-01-01

    Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers—a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. PMID:27297478

  12. Exploratory Study on Drug Users' Perspectives on Quality of Life: More than Health-Related Quality of Life?

    ERIC Educational Resources Information Center

    De Maeyer, Jessica; Vanderplasschen, Wouter; Broekaert, Eric

    2009-01-01

    In drug treatment outcome literature, a focus on objective and socially desirable indicators of change (e.g. no drug use) has predominated, while outcome indicators that are important for drug users themselves (e.g. quality of life, satisfaction with treatment) have largely been neglected. Nonetheless, Quality of Life (QoL) has become an important…

  13. Fixed Dose Combination of Arterolane and Piperaquine: A Newer Prospect in Antimalarial Therapy

    PubMed Central

    Patil, CY; Katare, SS; Baig, MS; Doifode, SM

    2014-01-01

    Malaria has been very prevalent vector-borne disease in India and until date bears enormous implications on health care services of the country. Over the period of time, the development of resistance to traditional antimalarials like chloroquine has been posed as major deterrent in efforts of malaria control. As the drug resistance is today universally prevalent, especially in Plasmodium falciparum species, major burden of malarial control resides with the new artemisinin drug class. However, arterolane is one of the first fully synthetic non-artemisinin antimalarial compound with rapid schizontocidal activity, hence offering an alternative to artemisinin drugs in malaria control. Piperaquine is a synthetic bisquinoline (4-amioquinoline Antimalarial) with slow and longer schizontocidal activity. Therefore their combination has been shown to provide rapid parasitemic clearance and quick relief of most malaria-related symptoms along with prevention of recrudescences. This combination was approved by Drugs Controller General of India in 2011 for treatment of uncomplicated P. falciparum malaria. The article is aimed at to review this newer prospect in antimalarial therapy for which comprehensive database search was done in Google, Google Scholar, PubMed using the terms “Malaria,” “Arterolane,” “OZ277,” “Piperaquine,” and “Artemisinin combination therapy.” A total of 323 articles were screened and 28 articles were considered for this review along with the World Health Organization and National malarial program guidelines. PMID:25221689

  14. 42 CFR 423.153 - Drug utilization management, quality assurance, and medication therapy management programs (MTMPs).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 3 2012-10-01 2012-10-01 false Drug utilization management, quality assurance, and... Drug utilization management, quality assurance, and medication therapy management programs (MTMPs). (a... D plan, a drug utilization management program, quality assurance measures and systems, and an...

  15. 42 CFR 423.153 - Drug utilization management, quality assurance, and medication therapy management programs (MTMPs).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 3 2013-10-01 2013-10-01 false Drug utilization management, quality assurance, and... Drug utilization management, quality assurance, and medication therapy management programs (MTMPs). (a... D plan, a drug utilization management program, quality assurance measures and systems, and an...

  16. 42 CFR 423.153 - Drug utilization management, quality assurance, and medication therapy management programs (MTMPs).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 3 2014-10-01 2014-10-01 false Drug utilization management, quality assurance, and... Drug utilization management, quality assurance, and medication therapy management programs (MTMPs). (a... D plan, a drug utilization management program, quality assurance measures and systems, and an...

  17. Antimalarial activity of anthothecol derived from Khaya anthotheca (Meliaceae).

    PubMed

    Lee, Sung-Eun; Kim, Mi-Ran; Kim, Jeong-Han; Takeoka, Gary R; Kim, Tae-Wan; Park, Byeoung-Soo

    2008-06-01

    Antimalarial activity of anthothecol, a limonoid of Khaya anthotheca (Meliaceae) against Plasmodium falciparum was tested using a [(3)H]-hypoxanthine and 48h culture assay in vitro. Anthotechol showed potent antimalarial activity against malaria parasites with IC(50) values of 1.4 and 0.17microM using two different assays. Also, gedunin had antimalarial activity with IC(50) values of 3.1 and 0.14microM. However, the citrus limonoids, limonin and obacunone did not show any antimalarial activity. The antimalarial activities were compared with the three currently used antimalarial medicines quinine, chloroquinine and artemisinin.

  18. Drug discovery from Nature: automated high-quality sample preparation

    PubMed Central

    Thiericke, Ralf

    2000-01-01

    Secondary metabolites from plants, animals and microorganisms have been proven to be an outstanding source for new and innovative drugs and show a striking structural diversity that supplements chemically synthesized compounds or libraries in drug discovery programs. Unfortunately, extracts from natural sources are usually complex mixtures of compounds:: often generated in time consuming and for the most part manual processes. As quality and quantity of the provided samples play a pivotal role in the success of high-throughput screening programs this poses serious problems. In order to make samples of natural origin competitive with synthetic compound libraries, we devised a novel, automated sample preparation procedure based on solid-phase extraction (SPE). By making use of a modified Zymark RapidTrace® SPE workstation an easy-to-handle and effective fractionation method has been developed which allows the generation of highquality samples from natural origin, fulfilling the requirements of an integration into high-throughput screening programs. PMID:18924703

  19. Antimalarial Properties of Aqueous Crude Extracts of Gynostemma pentaphyllum and Moringa oleifera Leaves in Combination with Artesunate in Plasmodium berghei-Infected Mice

    PubMed Central

    Borkaew, Preeyanuch; Klubsri, Chokdee; Dondee, Kittiyaporn; Bootprom, Panatda; Saiphet, Butsarat

    2016-01-01

    Due to the emergence and spread of malaria parasite with resistance to antimalarial drugs, discovery and development of new, safe, and affordable antimalarial are urgently needed. In this respect, medicinal plant extracts are targets to optimize antimalarial actions and restore efficacy of standard antimalarial drugs. The present study was aimed at determining the antimalarial activities of Gynostemma pentaphyllum and Moringa oleifera leaf extracts in combination with artesunate against Plasmodium berghei-infected mice. P. berghei ANKA maintained by serial passage in ICR mice were used based on intraperitoneal injection of 1 × 107 parasitized erythrocytes and subsequent development of parasitemia. These infected mice were used to investigate the antimalarial activity of artesunate (6 mg/kg) in combination with 500, 1,000, and 2,000 mg/kg of G. pentaphyllum and M. oleifera leaf extracts using 4-day suppressive test. It was found that these extracts showed significant (P < 0.05) antimalarial activity in dose-dependent manner with percentage of suppression of 45, 50, and 55% for G. pentaphyllum leaf extract and 35, 40, and 50% for M. oleifera leaf extract. Additionally, artesunate combined with these extracts presented higher antimalarial activity, compared to extract treated alone with percentage of suppression of 78, 91, and 96% for G. pentaphyllum leaf extract and 73, 82, and 91% for M. oleifera leaf extract. The results indicated that combination treatment of G. pentaphyllum or M. oleifera leaf extracts with artesunate was able to increase the antimalarial activity by using low dose of artesunate. Hence, these results justified the combination of these extracts and artesunate in antimalarial herbal remedies. PMID:27872647

  20. Haem polymerase as a novel target of antimalarial action of cyproheptadine.

    PubMed

    Agrawal, Rashmi; Tripathi, Renu; Tekwani, Babu L; Jain, S K; Dutta, Guru P; Shukla, Onkar P

    2002-11-01

    An antihistaminic drug, cyproheptadine (20-25mg/kg x 4 days), showed significant schizontocidal activity in the blood against a lethal multidrug-resistant (MDR) strain of Plasmodium yoelii nigeriensis (highly resistant to chloroquine, mefloquine, and quinine); the protection of mice ranged between 75 and 100%. A combination of cyproheptadine (15 mg/kg) and chloroquine improved antimalarial activity compared to treatment with either drug alone, whereas a combination of cyproheptadine with quinine or mefloquine did not improve its antimalarial activity. Chloroquine and cyproheptadine inhibited haem polymerization activity in cell-free extracts and in in vivo experiments with MDR P. yoelii, but the combination did not cause a more significant inhibition than found with either drug alone. Cyproheptadine has been shown to produce dose-dependent inhibition of haem polymerization activity both in vitro and in vivo. The mechanism of the antimalarial action of cyproheptadine and its enhanced antimalarial activity with chloroquine could be due, in part, to their inhibitory effect on haem polymerization.

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

    PubMed

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

    2016-05-01

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

  2. Road towards new antimalarials - overview of the strategies and their chemical progress.

    PubMed

    Wu, Tao; Nagle, Advait S; Chatterjee, Arnab K

    2011-01-01

    Malaria is a major health and economic threat to about 40% of the world's population. The absence of effective vaccines and widespread resistance to many of the current antimalarials make this disease an urgent target for the scientific community. As a developing world disease, most of the efforts towards new drugs have been from academic and government supported projects. This has recently changed with the emergence of new funding mechanisms and public-private partnerships (PPP). The purpose of this review is to highlight the different approaches used to discover new antimalarial agents, including target-based approaches, derivatization of known antimalarial pharmacophores, drug repositioning from non-malaria indication and cell-based screening. Specific examples are provided to illustrate the pros and cons in the context of how to best address the ever-increasing drug resistance and how to cost-effectively identify new antimalarials. More attention is given to relatively mature programs that have gone through extensive SAR study, pharmacology and/or toxicity studies in the last ten years.

  3. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 4 2011-04-01 2011-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  4. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 4 2014-04-01 2014-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  5. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 4 2013-04-01 2013-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  6. Susceptibility of human Plasmodium knowlesi infections to anti-malarials

    PubMed Central

    2013-01-01

    Background Evidence suggests that Plasmodium knowlesi malaria in Sarawak, Malaysian Borneo remains zoonotic, meaning anti-malarial drug resistance is unlikely to have developed in the absence of drug selection pressure. Therefore, adequate response to available anti-malarial treatments is assumed. Methods Here the ex vivo sensitivity of human P. knowlesi isolates in Malaysian Borneo were studied, using a WHO schizont maturation assay modified to accommodate the quotidian life cycle of this parasite. The in vitro sensitivities of P. knowlesi H strain adapted from a primate infection to in vitro culture (by measuring the production of Plasmodium lactate dehydrogenase) were also examined together with some assays using Plasmodium falciparum and Plasmodium vivax. Results Plasmodium knowlesi is uniformly highly sensitive to artemisinins, variably and moderately sensitive to chloroquine, and less sensitive to mefloquine. Conclusions Taken together with reports of clinical failures when P. knowlesi is treated with mefloquine, the data suggest that caution is required if using mefloquine in prevention or treatment of P. knowlesi infections, until further studies are undertaken. PMID:24245918

  7. 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.

    PubMed

    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.

  8. An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS.

    PubMed

    Calderón, Félix; Barros, David; Bueno, José María; Coterón, José Miguel; Fernández, Esther; Gamo, Francisco Javier; Lavandera, José Luís; León, María Luisa; Macdonald, Simon J F; Mallo, Araceli; Manzano, Pilar; Porras, Esther; Fiandor, José María; Castro, Julia

    2011-10-13

    In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.

  9. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    PubMed Central

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-01-01

    Summary There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. We describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the parasite, with good pharmacokinetic properties, and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery. PMID:26085270

  10. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    NASA Astrophysics Data System (ADS)

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-06-01

    There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

  11. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    PubMed Central

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

    2014-01-01

    Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral 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. Results: 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. Conclusion: Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection. PMID:25276063

  12. Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

    PubMed Central

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

    2016-01-01

    There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum. Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [14C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS. PMID:27270277

  13. Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity

    PubMed Central

    Sullivan, David J.; Liu, Yi; Mott, Bryan T.; Kaludov, Nikola; Martinov, Martin N.

    2015-01-01

    Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people) safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications. PMID:25951139

  14. 75 FR 70011 - Guidance for Industry, Mammography Quality Standards Act Inspectors, and Food and Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-16

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry, Mammography Quality Standards Act Inspectors, and Food and Drug Administration Staff; The Mammography Quality Standards Act Final Regulations: Modifications and Additions to Policy Guidance Help System 13; Availability AGENCY: Food and Drug...

  15. Unusual Antimalarial Meroditerpenes from Tropical Red Macroalgae

    PubMed Central

    Stout, E. Paige; Prudhomme, Jacques; Le Roch, Karine; Fairchild, Craig R.; Franzblau, Scott G.; Aalbersberg, William; Hay, Mark E.; Kubanek, Julia

    2010-01-01

    Three antimalarial meroditerpenes have been isolated from two Fijian red macroalgae. The absolute stereochemistry of callophycolide A (1), a unique macrolide from Callophycus serratus, was determined using a combination of Mosher’s ester analysis, circular dichroism analysis with a dimolybdenum tetraacetate complex, and conformational analysis using NOEs. In addition, two known tocopherols, β-tocopherylhydroquinone (4) and δ-tocopherylhydroquinone (5), were isolated from Amphiroa crassa. By oxidizing 5 to the corresponding δ-tocopherylquinone (6), antimalarial activity against the human malaria parasite Plasmodium falciparum was increased by more than 20-fold. PMID:20801038

  16. Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

    PubMed Central

    Wicht, Kathryn J.; Combrinck, Jill M.; Smith, Peter J.; Egan, Timothy J.

    2015-01-01

    A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against P. falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5,000 commercially available compounds (AldrichCPR) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively. PMID:25573118

  17. Antimalarial potential of leaves of Chenopodium ambrosioides L.

    PubMed

    Cysne, Dalila Nunes; Fortes, Thiare Silva; Reis, Aramys Silva; de Paulo Ribeiro, Bruno; Dos Santos Ferreira, Amália; do Amaral, Flavia Maria Mendonça; Guerra, Rosane Nassar Meireles; Marinho, Claudio Romero Farias; Nicolete, Roberto; Nascimento, Flávia Raquel Fernandes

    2016-11-01

    In an effort to identify novel therapeutic alternatives for the treatment of malaria, the present study evaluated the antimalarial effect of the crude hydroalcoholic extract (HCE) from the leaves of Chenopodium ambrosioides L. For this purpose, the molecular affinity between the total proteins from erythrocytes infected with Plasmodium falciparum and HCE or chloroquine was evaluated by surface plasmon resonance (SPR). Subsequently, the plasmodicidal potential of HCE was assessed in a P. falciparum culture. Using BALB/c mice infected with Plasmodium berghei intraperitoneally (ip.), we evaluated the effects of ip. treatment, for three consecutive days (day 7, 8, and 9 after infection), with chloroquine (45 mg/kg) or HCE (5 mg/kg), considering the survival index and the parasitaemia. The groups were compared to an untreated control group that receives only PBS at the same periods. The results indicated that HCE could bind to the total proteins of infected erythrocytes and could inhibit the parasite growth in vitro (IC50 = 25.4 g/mL). The in vivo therapeutic treatment with HCE increased the survival and decreased the parasitaemia in the infected animals. Therefore, the HCE treatment exhibited a significant antiplasmodial effect and may be considered as a potential candidate for the development of new antimalarial drugs.

  18. Antimalarial activity of Bergenia ciliata (Haw.) Sternb. against Plasmodium berghei.

    PubMed

    Walter, Neha Sylvia; Bagai, Upma; Kalia, Shagun

    2013-09-01

    The emergence of resistance against most of the drugs in current use against malaria has aggravated the disease burden in endemic regions. Several plants species have been used for treatment of malaria in traditional/cultural health systems. Bergenia ciliata, used traditionally for treatment of fever by local communities in the Himalayan Region, was evaluated for its plausible role as an antimalarial. Phytochemical screening of the ethanolic leaf extract of B. ciliata (ELEBC) revealed the presence of phenols, flavonoids, steroids and diterpenes. The extract showed good in vitro antiplasmodial activity, with an IC50 <10 μg/ml. Acute toxicity of the extract was observed to be >5 g/kg, which is considered toxicologically safe for oral administration. When tested in vivo, different concentrations of the extract (250 to 1,000 mg/kg) exhibited considerable chemosuppression on day 7, in a dose-dependent manner. Maximum chemosuppression was observed to be 87.50% at 1,000 mg/kg. Administration of ELEBC (750 and 1,000 mg/kg) significantly (p < 0.0005) enhanced the mean survival time of mice in comparison to infected control, which exhibited a mean survival time of 8.6 ± 1.5 days. Study reports presence of considerable in vitro and in vivo antimalarial activity in ethanolic leaf extract of B. ciliata for first time. Hence, the ethnopharmacological usage of the plant for treating fever is confirmed with experimental evidence.

  19. Liposomal Drug Product Development and Quality: Current US Experience and Perspective.

    PubMed

    Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M

    2017-02-03

    Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.

  20. N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity.

    PubMed

    Gomes, Ana; Pérez, Bianca; Albuquerque, Inês; Machado, Marta; Prudêncio, Miguel; Nogueira, Fátima; Teixeira, Cátia; Gomes, Paula

    2014-02-01

    Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N-cinnamoylaminobutyl)-amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P.falciparum, chloroquine-sensitive 3D7 (IC50 =17.0-39.0 nM) and chloroquine-resistant W2 and Dd2 strains (IC50 =3.2-41.2 and 27.1-131.0 nM, respectively), and liver-stage P.berghei (IC50 =1.6-4.9 μM) parasites. These findings bring new hope for the possible future "rise of a fallen angel" in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads.

  1. In vivo Antimalarial Activities of Russelia Equisetiformis in Plasmodium Berghei Infected Mice

    PubMed Central

    Ojurongbe, O.; Ojo, J. A.; Adefokun, D. I.; Abiodun, O. O.; Odewale, G.; Awe, E. O.

    2015-01-01

    The rising problem of resistance to most commonly used antimalarials remains a major challenge in the control of malaria suggesting the need for new antimalarial agents. This work explores the antiplasmodial potential of ethanol extract of Russelia equisetiformis in chloroquine Plasmodium berghei infected mice. Swiss albino mice were intraperitoneally infected with chloroquine-resistant P. berghei (ANKA). Experimental mice were treated for four days consecutively with graded doses of plant extracts and standard antimalarial drugs (artesunate and chloroquine) at a dose of 10 mg/kg body weight used as control. The extract showed a dose-dependent activity in the chemosuppression of P. berghei parasites by 31.6, 44.7, 48.4 and 86.5% at doses of 100, 200, 400 and 800 mg/kg, while chloroquine (10 mg/kg) and artesunate produced 59.4 and 68.4%, respectively. The extract showed a significant decrease in parasitaemia (P<0.05). The level of parasitemia and decrease in weight in all the treated groups was significantly lower (P<0.05) compared with the infected but untreated mice. The plant extract was devoid of toxicity at the highest dose tested (5000 mg/kg). The study concluded that the ethanol extract of R. equisetiformis possesses antimalarial effect, which supports the folk medicine claim of its use in the treatment of malaria. PMID:26664070

  2. Recent progress in the identification and development of anti-malarial agents using virtual screening based approaches.

    PubMed

    Shah, Priyanka; Tiwari, Sunita; Siddiqi, Mohammad Imran

    2015-01-01

    Malaria has continued to be one of the most perplexing diseases for biological science community around the world due to its prevalent devastating nature and quick developing resistance against the frontline drugs. Artimisinin-based combination therapy (ACT) has been so far found to be among the best therapies against Plasmodium pathogens but alarming emergence of resistance in parasites against every known chemotherapy has prompted the scientific community to step up all the efforts towards development of new and affordable anti-malarial drugs. Computer-aided approaches have received enormous attention in recent years in the field of identification and design of novel drugs. In this review, we summarize recently published research concerning the identification and development of anti-malarial compounds using virtual screening approaches. It would be admirable to discern the successful application of in silico studies for anti-malarial drug discovery hitherto and would certainly help in generating new avenues for pursuing integrated studies between the experimentalists and computational chemists in a systematic manner as a time and cost efficient alternative for future antimalarial drug discovery projects.

  3. New quinoline di-Mannich base compounds with greater antimalarial activity than chloroquine, amodiaquine, or pyronaridine.

    PubMed Central

    Kotecka, B M; Barlin, G B; Edstein, M D; Rieckmann, K H

    1997-01-01

    We have compared the ex vivo antimalarial activity of 12 new quinoline di-Mannich base compounds containing the 7-dichloroquinoline or 7-trifluoromethylquinoline nucleus with amodiaquine, chloroquine, and pyronaridine using the Saimiri-bioassay model. Each compound was administered orally (30 mg/kg of body weight) to three or more noninfected Saimiri sciureus monkeys, and serum samples were collected at various times after drug administration and serially diluted with drug-free (control) serum. In vitro activity against the multidrug-resistant K1 isolate of Plasmodium falciparum was determined in serum samples by measuring the maximum inhibitory dilution at which the treated monkey serum inhibited schizont maturation in vitro. Of the 12 Mannich bases tested, 8 were associated with levels of ex vivo antimalarial activity in serum greater than those of amodiaquine, chloroquine, or pyronaridine 1 to 7 days after drug administration. Further studies were carried out with four of these compounds, and the results showed that the areas under the serum drug concentration-time curves for the four compounds were between 7- and 26-fold greater than that obtained for pyronaridine. Activity against four multidrug-resistant strains of P. falciparum was also much greater in serum samples collected from monkeys after administration of these four compounds than in serum samples collected after administration of pyronaridine or chloroquine. These findings suggest that these four quinoline Mannich base compounds possess a very marked and prolonged antimalarial activity and that further studies should be performed to determine their value as antimalarial drugs. PMID:9174201

  4. Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models

    PubMed Central

    Ray, Sunetra; Madrid, Peter B.; Catz, Paul; LeValley, Susanna E.; Furniss, Michael J.; Rausch, Linda L.; Guy, R. Kiplin; DeRisi, Joseph L.; Iyer, Lalitha V.; Green, Carol E.; Mirsalis, Jon C.

    2010-01-01

    Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability, yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMETa prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC50 values = 5.6 nM and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (IC50 for CQ = 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials. PMID:20361799

  5. New developments in anti-malarial target candidate and product profiles.

    PubMed

    Burrows, Jeremy N; Duparc, Stephan; Gutteridge, Winston E; Hooft van Huijsduijnen, Rob; Kaszubska, Wiweka; Macintyre, Fiona; Mazzuri, Sébastien; Möhrle, Jörg J; Wells, Timothy N C

    2017-01-13

    A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

  6. Antimalarial action of hydroxamate-based iron chelators and potentiation of desferrioxamine action by reversed siderophores.

    PubMed Central

    Golenser, J; Tsafack, A; Amichai, Y; Libman, J; Shanzer, A; Cabantchik, Z I

    1995-01-01

    Hydroxamate-based chelators of iron are potent inhibitors of in vitro growth of Plasmodium falciparum. Two types of such chelators, the natural desferrioxamine and the synthetic reversed siderophore RSFileum2, are prototypes of antimalarial agents whose action spectra differ in the speed of action, stage dependence, and degree of reversibility of effects. This work explores the possibility of improving the antimalarial efficacy of these agents by using them in various combinations on in vitro cultures of P. falciparum. Growth assessment was based both on total nucleic acid synthesis and on parasitemia. The results indicate that the synthetic reversed siderophore more than complements the antimalarial action of desferrioxamine when applied during either ring, trophozoite, or mixed stages. The combined drug effects were significantly higher than the additive effect of the individual drugs. Qualitatively similar results were obtained for both reversible effects and irreversible (i.e., sustained) effects. Following an 8-h window of exposure the combined drug treatment caused parasite growth arrest and prevented its recovery, even 3 days after the treatment. The fact that such a combination of iron chelators displays a wider action spectrum than either drug alone has implications for the design of chemotherapy regimens. PMID:7695330

  7. Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

    PubMed Central

    Seden, Kay; Gibbons, Sara; Marzolini, Catia; Schapiro, Jonathan M.; Burger, David M.; Back, David J.; Khoo, Saye H.

    2017-01-01

    Background In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria. Methods and findings This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs. Conclusions There is significant potential for DDIs between antiretrovirals and antimalarials. The application of

  8. Hollow Fiber Methodology for Pharmacokinetic/Pharmacodynamic Studies of Antimalarial Compounds

    PubMed Central

    Caton, Emily; Nenortas, Elizabeth; Bakshi, Rahul P.; Shapiro, Theresa A.

    2016-01-01

    Knowledge of pharmacokinetic/pharmacodynamic (PK/PD) relationships can enhance the speed and economy of drug development by enabling informed and rational decisions at every step, from lead selection to clinical dosing. For anti-infective agents in particular, dynamic in vitro hollow fiber cartridge experiments permit exquisite control of kinetic parameters and the study of their consequent impact on pharmacodynamic efficacy. Such information is of great interest for the cost-restricted but much-needed development of new antimalarial drugs, especially since major human pathogen Plasmodium falciparum can be cultivated in vitro but is not readily available in animal models. This protocol describes the materials and procedures for determining the PK/PD relationships of antimalarial compounds. PMID:26995353

  9. Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.

    PubMed

    Santos, Sofia A; Lukens, Amanda K; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra

    2015-09-18

    A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs.

  10. Antimalarial benzylisoquinoline alkaloid from the rainforest tree Doryphora sassafras.

    PubMed

    Buchanan, Malcolm S; Davis, Rohan A; Duffy, Sandra; Avery, Vicky M; Quinn, Ronald J

    2009-08-01

    Mass-directed isolation of the CH(2)Cl(2)/MeOH extract of Doryphora sassafras resulted in the purification of a new benzylisoquinoline alkaloid, 1-(4-hydroxybenzyl)-6,7-methylenedioxy-2-methylisoquinolinium trifluoroacetate (1), and the known aporphine alkaloid (S)-isocorydine (2). The structures of 1 and 2 were determined by 1D and 2D NMR and MS data analyses. The compounds were isolated during a drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 1 displayed IC(50) values of 3.0 and 4.4 microM, respectively. Compound 1 was tested for cytotoxicity toward a human embryonic kidney cell line (HEK293) and displayed no activity at 120 microM.

  11. Phototoxic reaction associated with Malarone (atovaquone/proguanil) antimalarial prophylaxis.

    PubMed

    Amelot, Aymeric; Dupouy-Camet, Jean; Jeanmougin, Michel

    2014-04-01

    Phototoxic reaction has not been reported previously as an adverse reaction to the combination of atovaquone and proguanil (AP) (Malarone) used for antimalarial prophylaxis and therapy. We report here a 32-year-old patient treated with AP who presented with clinical manifestations of photosensitivity. AP-induced phototoxicity in this patient was further supported by phototesting. Malarone is not known to photosensitize and render the skin more susceptible to severe sunburn-like reactions. That it may do so, as in this case, is of importance especially as this drug is used predominantly by those travelling to sunnier climes. A notification of potential phototoxic effects of AP should be published for the choice of prophylaxis made by tourists traveling in malarial areas.

  12. Optimization of endochin-like quinolones for antimalarial activity

    PubMed Central

    Winter, Rolf; Kelly, Jane X.; Smilkstein, Martin J.; Hinrichs, David; Koop, Dennis R.; Riscoe, Michael K.

    2010-01-01

    Structural analogs of the antimalarial Endochin were synthesized and screened for antiplasmodial activity against drug sensitive and multidrug resistant strains of Plasmodium falciparum. Structural features have been identified that are associated with improved potency while other features are associated with equipotency against an atovaquone-resistant clinical isolate. Relative to endochin the most active compound ELQ-121 shows ≈ 100-fold improvement in IC50 for inhibition of P. falciparum in vitro and it also exhibits enhanced metabolic stability. A polyethylene glycol carbonate ester prodrug of ELQ-121 demonstrated in vivo efficacy against P. yoelii in mice. This is the first report of an endochin-like quinolone that is efficacious in treating malaria in a mammalian host. PMID:21040724

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

    PubMed

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

    1995-12-22

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

  14. Case Study of Small Molecules As Antimalarials: 2-Amino-1-phenylethanol (APE) Derivatives

    PubMed Central

    2014-01-01

    Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4–0.5 μM are able to show in vivo activity. PMID:24944739

  15. Antimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of Action.

    PubMed

    Fernández-Álvaro, Elena; Hong, W David; Nixon, Gemma L; O'Neill, Paul M; Calderón, Félix

    2016-06-23

    Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compounds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chemistry efforts yielding molecules that have reached the clinic.

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

    PubMed

    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

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

    PubMed

    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.

  18. Synthesis and antimalarial activity of prodigiosenes.

    PubMed

    Marchal, Estelle; Smithen, Deborah A; Uddin, Md Imam; Robertson, Andrew W; Jakeman, David L; Mollard, Vanessa; Goodman, Christopher D; MacDougall, Kristopher S; McFarland, Sherri A; McFadden, Geoffrey I; Thompson, Alison

    2014-06-28

    Several analogues of the natural compound prodigiosin with modified A- and C-rings were synthesised as were some of their tin, cobalt, boron and zinc complexes. The antimalarial activity of these prodigiosenes was evaluated in vitro using the 3D7 Plasmodium falciparum strain. The presence of a nitrogen atom in the A-ring is needed for antimalarial activity but the presence of an alkyl group at the β'-position of the C-ring seems detrimental. Dibutyl tin complexes exhibit IC50 values mostly in the nanomolar range with equal or improved activity compared to the free-base prodigiosene ligand, despite the fact that the general toxicity of such tin complexes is demonstrably lower than that of the free-bases.

  19. Antimalarial compounds from Kniphofia foliosa roots.

    PubMed

    Wube, Abraham Abebe; Bucar, Franz; Asres, Kaleab; Gibbons, Simon; Rattray, Lauren; Croft, Simon L

    2005-06-01

    During the course of screening Ethiopian medicinal plants for their antimalarial properties, it was found that the dichloromethane extract of the roots of Kniphofia foliosa Hochst. (Asphodelaceae), which have long been used in the traditional medicine of Ethiopia for the treatment of abdominal cramps and wound healing, displayed strong in vitro antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum with an ED50 value of 3.8 microg/mL and weak cytotoxic activity against KB cells with an ED50 value of 35.2 microg/mL. Five compounds were isolated from the roots and evaluated for their in vitro antimalarial activity. Among the compounds tested, 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin, showed a high inhibition of the growth of the malaria parasite, P. falciparum with ED50 values of 0.260 and 0.537 microg/mL, respectively, while the naphthalene derivative, 2-acetyl-1-hydroxy-8-methoxy-3-methylnaphthalene, exhibited a less significant antimalarial activity with an ED50 value of 15.4 microg/mL. To compare the effect on the parasite with toxicity to mammalian cells, the cytotoxic activities of the isolated compounds against the KB cell line were evaluated and 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin displayed very low toxicity with ED50 values of 104 and 90 microg/mL, respectively. This is the first report of the inhibition of the growth of P. falciparum by anthraquinone-anthrone dimers and establishes them as a new class of potential antimalarial compounds with very little host cell toxicity.

  20. Small molecule screen for candidate antimalarials targeting Plasmodium Kinesin-5.

    PubMed

    Liu, Liqiong; Richard, Jessica; Kim, Sunyoung; Wojcik, Edward J

    2014-06-06

    Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually. Malaria parasites now show measured resistance to all currently utilized drugs. Novel antimalarial drugs are urgently needed. The Plasmodium Kinesin-5 mechanoenzyme is a suitable "next generation" target. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are "druggable." One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5; this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease.

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

    PubMed Central

    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

  2. 42 CFR 423.153 - Drug utilization management, quality assurance, and medication therapy management programs (MTMPs).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 3 2011-10-01 2011-10-01 false Drug utilization management, quality assurance, and... management, quality assurance, and medication therapy management programs (MTMPs). (a) General rule. Each... utilization management program, quality assurance measures and systems, and an MTMP as described in...

  3. 42 CFR 423.153 - Drug utilization management, quality assurance, and medication therapy management programs (MTMPs).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Drug utilization management, quality assurance, and... management, quality assurance, and medication therapy management programs (MTMPs). (a) General rule. Each... utilization management program, quality assurance measures and systems, and an MTMP as described in...

  4. Intervention to Promote Patients' Adherence to Antimalarial Medication: A Systematic Review

    PubMed Central

    Fuangchan, Anjana; Dhippayom, Teerapon; Kongkaew, Chuenjid

    2014-01-01

    Non-adherence as a major contributor to poor treatment outcomes. This study aimed to explore the effectiveness of existing interventions promoting adherence to antimalarial drugs by systematic review. The following databases were used to identify potential articles: MEDLINE, EMBASE, the Cochrane CENTRAL, and CINAHL (through March 2013). From 1,813 potential papers identified, 16 studies met the selection criteria comprising 9,247 patients. Interventions were classified as packaging aids, visual media, combined visual media and verbal information, community education, medication supervision, and convenient regimen. These interventions were shown to increase adherence to antimalarial drugs (median relative risk = 1.4, interquartile range 1.2–2.0). Although a most effective intervention did not emerge, community education and visual media/verbal information combinations may well have most potential to improve adherence to antimalarial medication. These interventions should be implemented in combination to optimize their beneficial effects. The current understanding on improved adherence would facilitate to contain outbreaks of malaria cost effectively. PMID:24166045

  5. Synthesis and evaluation of 7-substituted 4-aminoquinoline analogs for antimalarial activity

    PubMed Central

    Hwang, Jong Yeon; Kawasuji, Takashi; Lowes, David J.; Clark, Julie A.; Connelly, Michele C.; Zhu, Fangyi; Guiguemde, W. Armand; Sigal, Martina S.; Wilson, Emily B.; DeRisi, Joseph L.; Guy, R. Kiplin

    2013-01-01

    We previously reported that substituted 4-aminoquinolines with a phenylether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine’s alkyl substituents exhibited potent antimalarial activity against the multi-drug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogs, in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 and cytotoxicity mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1strain good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study. PMID:21910466

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

    PubMed

    de Andrade-Neto, Valter F; Pohlit, Adrian M; Pinto, Ana Cristina S; Silva, Ellen Cristina C; Nogueira, Karla L; Melo, Márcia R S; Henrique, Marycleuma C; Amorim, Rodrigo C N; Silva, Luis Francisco R; Costa, Mônica R F; Nunomura, Rita C S; Nunomura, Sergio M; Alecrim, Wilson D; Alecrim, M das Graças C; Chaves, F Célio M; Vieira, Pedro Paulo R

    2007-06-01

    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.

  7. Understanding Private Sector Antimalarial Distribution Chains: A Cross-Sectional Mixed Methods Study in Six Malaria-Endemic Countries

    PubMed Central

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Rueda, Sergio Torres; Kiefer, Sabine; O’Connell, Kathryn A.; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Chavasse, Desmond

    2014-01-01

    Background Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia). Methods and Findings We conducted nationally representative surveys of antimalarial wholesalers during 2009–2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4–6 steps between manufacturer and retailer; however, most likely pass through 2–3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine) dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs) were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important

  8. In vitro antimalarial activity of medicinal plant extracts against Plasmodium falciparum.

    PubMed

    Bagavan, Asokan; Rahuman, Abdul Abdul; Kaushik, Naveen Kumar; Sahal, Dinkar

    2011-01-01

    Malaria is a major global public health problem, and the alarming spread of drug resistance and limited number of effective drugs now available underline how important it is to discover new antimalarial compounds. In the present study, ten plants were extracted with ethyl acetate and methanol and tested for their antimalarial activity against chloroquine (CQ)-sensitive (3D7) and CQ-resistant (Dd2 and INDO) strains of Plasmodium falciparum in culture using the fluorescence-based SYBR Green assay. Plant extracts showed moderate to good antiparasitic effects. Promising antiplasmodial activity was found in the extracts from two plants, Phyllanthus emblica leaf 50% inhibitory concentration (IC₅₀) 3D7: 7.25 μg/mL (ethyl acetate extract), 3.125 μg/mL (methanol extract), and Syzygium aromaticum flower bud, IC₅₀ 3D7:13 μg/mL, (ethyl acetate extract) and 6.25 μg/mL (methanol extract). Moderate activity (30-75 μg/mL) was found in the ethyl acetate and methanol extracts of Abrus precatorius (seed) and Gloriosa superba (leaf); leaf ethyl acetate extracts of Annona squamosa and flower of Musa paradisiaca. The above mentioned plant extracts were also found to be active against CQ-resistant strains (Dd2 and INDO). Cytotoxicity study with P. emblica leaf and S. aromaticum flower bud, extracts showed good therapeutic indices. These results demonstrate that leaf ethyl acetate and methanol extracts of P. emblica and flower bud extract of S. aromaticum may serve as antimalarial agents even in their crude form. The isolation of compounds from P. emblica and S. aromaticum seems to be of special interest for further antimalarial studies.

  9. Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to anti-malarial agents we synthesized three cyclen analogs of chloroquine (4,6,7). Compound 4 displays the most potent in vitro and in vivo antimalarial activities. It displays an IC50 of 7.5 ...

  10. Augmentation of the Differentiation Response to Antitumor Antimalarials

    DTIC Science & Technology

    2005-07-01

    histone deacetylase, quinoline antimalarials, chloroquine, hydroxychloroquine , differentiation, hyperacetylation 16. SECURITY CLASSIFIATION OF: 17.’LMTTO...shown that the quinoline antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer... hydroxychloroquine (HCQ), inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-IOA breast cells. Hence, the

  11. Augmentation of the Differentiation Response to Antitumor Antimalarials

    DTIC Science & Technology

    2004-07-01

    Release; Distribution Unlimited 13. ABSTRACT (Maximum 200 Words) We have shown that the quinoline antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ...Introduction: Preliminary studies showed that two of the quinoline antimalarials, chloroquine (CQ) and hydroxychloroquine (HCQ), displayed selective... hydroxychloroquine upon pretreatment with ATRA or Aza on tumor cell survival (Figures 1 and 2, respectively). Clonogenic survival of MDA-MB-231 cells exposed to

  12. Antimalarial Activity of Anthothecol Derived from Khaya anthotheca (Meliaceae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antimalarial activity of anthothecol, a limonoid of Khaya anthotheca (Meliaceae) against Plasmodium falciparum was tested using a [3H]-hypoxanthine and 48 h culture assay in vitro. Anthothecol showed potent antimalarial activity against malarial parasites with IC50 values of 1.4 and 0.17 uM using t...

  13. Antimalarial activities of medicinal plants and herbal formulations used in Thai traditional medicine.

    PubMed

    Thiengsusuk, Artitaya; Chaijaroenkul, Wanna; Na-Bangchang, Kesara

    2013-04-01

    Malaria is one of the world's leading killer infectious diseases with high incidence and morbidity. The problem of multidrug-resistant Plasmodium falciparum has been aggravating particularly in Southeast Asia. Therefore, development of new potential antimalarial drugs is urgently required. The present study aimed to investigate antimalarial activities of a total of 27 medicinal plants and 5 herbal formulations used in Thai traditional medicine against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) P. falciparum clones. Antimalarial activity of the ethanolic extracts of all plants/herbal formulations against K1 and 3D7 P. falciparum clones was assessed using SYBR Green I-based assay. All plants were initially screened at the concentration of 50 μg/ml to select the candidate plants that inhibited malaria growth by ≥50%. Each candidate plant was further assessed for the IC50 value (concentration that inhibits malaria growth by 50%) to select the potential plants. Selectivity index (SI) of each extract was determined from the IC50 ratio obtained from human renal epithelial cell and K1 or 3D7 P. falciparum clone. The ethanolic extracts from 19 medicinal plants/herbal formulation exhibited promising activity against both K1 and 3D7 clones of P. falciparum with survival of less than 50% at the concentration of 50 μg/ml. Among these, the extracts from the eight medicinal plants (Plumbago indica Linn., Garcinia mangostana Linn., Dracaena loureiri Gagnep., Dioscorea membranacea Pierre., Artemisia annua Linn., Piper chaba Hunt., Myristica fragrans Houtt., Kaempferia galanga Linn.) and two herbal formulations (Benjakul Formulation 1 and Pra-Sa-Prao-Yhai Formulation) showed potent antimalarial activity with median range IC50 values of less than 10 μg/ml against K1 or 3D7 P. falciparum clone or both. All except G. mangostana Linn. and A. annua Linn. showed high selective antimalarial activity against both clones with SI>10. Further studies on antimalarial

  14. Preliminary LC-MS Based Screening for Inhibitors of Plasmodium falciparum Thioredoxin Reductase (PfTrxR) among a Set of Antimalarials from the Malaria Box.

    PubMed

    Tiwari, Neil K; Reynolds, Priscilla J; Calderón, Angela I

    2016-03-28

    Plasmodium falciparum thioredoxin reductase (PfTrxR) has been identified as a potential drug target to combat growing antimalarial drug resistance. Medicines for Malaria Venture (MMV) has pre-screened and identified a set of 400 antimalarial compounds called the Malaria Box. From those, we have evaluated their mechanisms of action through inhibition of PfTrxR and found new active chemical scaffolds. Five compounds with significant PfTrxR inhibitory activity, with IC50 values ranging from 0.9-7.5 µM against the target enzyme, were found out of the Malaria Box.

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

    PubMed Central

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

    2012-01-01

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

  16. Antimalarial action of artesunate involves DNA damage mediated by reactive oxygen species.

    PubMed

    Gopalakrishnan, Anusha M; Kumar, Nirbhay

    2015-01-01

    Artemisinin-based combination therapy (ACT) is the recommended first-line treatment for Plasmodium falciparum malaria. It has been suggested that the cytotoxic effect of artemisinin is mediated by free radicals followed by the alkylation of P. falciparum proteins. The endoperoxide bridge, the active moiety of artemisinin derivatives, is cleaved in the presence of ferrous iron, generating reactive oxygen species (ROS) and other free radicals. However, the emergence of resistance to artemisinin in P. falciparum underscores the need for new insights into the molecular mechanisms of antimalarial activity of artemisinin. Here we show that artesunate (ART) induces DNA double-strand breaks in P. falciparum in a physiologically relevant dose- and time-dependent manner. DNA damage induced by ART was accompanied by an increase in the intracellular ROS level in the parasites. Mannitol, a ROS scavenger, reversed the cytotoxic effect of ART and reduced DNA damage, and modulation of glutathione (GSH) levels was found to impact ROS and DNA damage induced by ART. Accumulation of ROS, increased DNA damage, and the resulting antiparasite effect suggest a causal relationship between ROS, DNA damage, and parasite death. Finally, we also show that ART-induced ROS production involves a potential role for NADPH oxidase, an enzyme involved in the production of superoxide anions. Our results with P. falciparum provide novel insights into previously unknown molecular mechanisms underlying the antimalarial activity of artemisinin derivatives and may help in the design of next-generation antimalarial drugs against the most virulent Plasmodium species.

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

    PubMed

    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.

  18. Testing of natural products and synthetic molecules aiming at new antimalarials.

    PubMed

    Krettli, Antoniana U; Adebayo, Joseph O; Krettli, Luisa G

    2009-03-01

    The search for new antimalarials, which in the past relied on animal models, is now usually performed with cultures of Plasmodium falciparum (PF) blood parasites by evaluation of parasite growth inhibition. Field isolates of PF human malaria parasite, parasite strains and clones, well characterized for their susceptibility to chloroquine and other standard antimalarials are available for the in vitro tests. The simplest method to evaluate parasite growth is the determination of parasitemias in Giemsa stained blood smears through light microscopy. Other methodologies have proven to be more precise and allow mass screening of new compounds against PF blood stages, such as: (i) measuring the incorporation of radioactive hypoxanthine by the parasites; (ii) indirect colorimetric assays in which specific parasite enzyme activities, and histidine-rich protein II (HRP2) production are measured with the help of monoclonal antibodies; (iii) the beta-haematin formation, and; (iv) assays using green fluorescent protein (GFP) in gene-expressing parasites. The advantages and disadvantages of the different in vitro screening methods, as well as the different in vivo models for antimalarial tests, are described in this review. Such tests can be used for the evaluation of medicinal plants, synthetic and hybrid molecules or drug combinations.

  19. Cross cultural adaptation of the Injection Drug User Quality Of Life Scale (IDUQOL) in Spanish drug dependent population, with or without injectable consumption: Drug User Quality of Life Scale-Spanish (DUQOL-Spanish).

    PubMed

    Morales-Manrique, C C; Valderrama-Zurián, J C; Castellano-Gómez, M; Aleixandre-Benavent, R; Palepu, A

    2007-09-01

    The Injection Drug User Quality of life Scale (IDUQOL) measures the unique and individual circumstances that determine the quality of life of injection drug users. This paper reports the psychometric properties of the Spanish version, for drug dependent persons with or without injectable consumption using a revised instrument: Drug user Quality of Life Scale-Spanish (DUQOL-Spanish). We studied 169 outpatients in 9 Spanish drug treatment centers. Factor analysis, internal consistency, test-retest reliability and criterion-related validity were assessed. The results show the essential unidimensionality of the scale, which supports the use of a total score. Both internal consistency (Cronbach's alpha: 0.86), and test-retest reliability (r=0.79) of the total score were high. Criterion-related validity supports the interpretation of the DUQOL-Spanish total score as measuring a construct consistent with quality of life. This study suggests that the DUQOL-Spanish is a valid instrument to measure subjective quality of life in Spanish drug users, and allows the identification of life areas that are considered by the patient important to change in order to improve their quality of life.

  20. Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents.

    PubMed

    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.

  1. Antimalarial activity of betulinic acid and derivatives in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice.

    PubMed

    de Sá, Matheus Santos; Costa, José Fernando Oliveira; Krettli, Antoniana Ursine; Zalis, Mariano Gustavo; Maia, Gabriela Lemos de Azevedo; Sette, Ivana Maria Fechine; Câmara, Celso de Amorim; Filho, José Maria Barbosa; Giulietti-Harley, Ana Maria; Ribeiro Dos Santos, Ricardo; Soares, Milena Botelho Pereira

    2009-07-01

    Malaria is one of the most important tropical diseases and mainly affects populations living in developing countries. Reduced sensitivity of Plasmodium sp. to formerly recommended antimalarial drugs places an increasing burden on malaria control programs as well as on national health systems in endemic countries. The present study aims to evaluate the antimalarial activity of betulinic acid and its derivative compounds, betulonic acid, betulinic acid acetate, betulinic acid methyl ester, and betulinic acid methyl ester acetate. These substances showed antiplasmodial activity against chloroquine-resistant Plasmodium falciparum parasites in vitro, with IC(50) values of 9.89, 10.01, 5.99, 51.58, and 45.79 microM, respectively. Mice infected with Plasmodium berghei and treated with betulinic acid acetate had a dose-dependent reduction of parasitemia. Our results indicate that betulinic acid and its derivative compounds are candidates for the development of new antimalarial drugs.

  2. Drug quality screening in developing countries: establishment of an appropriate laboratory in Swaziland.

    PubMed Central

    Kenyon, T. A.; Kenyon, A. S.; Sibiya, T.

    1994-01-01

    A simple, low-cost, accurate thin-layer chromatography (TLC) method has been used to establish the first drug quality screening laboratory in Swaziland. For this purpose, office space at the central medical stores was first converted into a simple laboratory. Basic equipment, supplies, and materials were purchased, existing manpower was trained to perform accurately the TLC procedure, and a system was established for the qualitative/quantitative screening of selected drugs purchased by the Ministry of Health prior to their distribution to user facilities. The TLC method described can be used to set up similar low-cost, drug quality screening laboratories in other developing countries where analytical chemistry expertise is lacking, resources are scarce, and sophisticated analytical laboratories to assess drug quality are not available. PMID:7923541

  3. In vitro antimalarial activity of different extracts of Eremostachys macrophylla Montbr. & Auch.

    PubMed Central

    Asnaashari, Solmaz; Heshmati Afshar, Fariba; Ebrahimi, Atefeh; Bamdad Moghadam, Sedigheh; Delazar, Abbas

    2015-01-01

    Introduction:The risk of drug resistance and the use of medicinal plants in malaria prevention and treatment have led to the search for new antimalarial compounds with natural origin. Methods:In the current study, six extracts with different polarity from aerial parts and rhizomes of Eremostachys macrophylla Montbr. & Auch., were screened for their antimalarial properties by cell-free β-hematin formation assay. Results: Dichloromethane (DCM) extracts of both parts of plant showed significant antimalarial activities with IC50 values of 0.797 ± 0.016 mg/mL in aerial parts and 0.324 ± 0.039 mg/mL in rhizomes compared to positive control (Chloroquine, IC50 = 0.014 ± 0.003 mg/mL, IC90 = 0.163 ± 0.004 mg/mL). Bioactivity-guided fractionation of the most potent part (DCM extract of rhizomes) by vacuum liquid chromatography (VLC) afforded seven fractions. Sixty percent ethyl acetate/n-hexane fraction showed considerable antimalarial activity with IC50 value of 0.047 ± 0.0003 mg/mL. Conclusion: From 6 extracts with different polarity of E. macrophylla,s aerial parts and rhizomes, the DCM extract of both parts were the most active extract in this assay. The preliminary phytochemical study on the VLC fractions of the most potent part persuades us to focus on purifying the active components of these extracts and to conduct further investigation towards in vivo evaluation. PMID:26457251

  4. High content live cell imaging for the discovery of new antimalarial marine natural products

    PubMed Central

    2012-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:22214291

  5. Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251.

    PubMed

    Morita, Masayuki; Sanai, Hitomi; Hiramoto, Akiko; Sato, Akira; Hiraoka, Osamu; Sakura, Takaya; Kaneko, Osamu; Masuyama, Araki; Nojima, Masatomo; Wataya, Yusuke; Kim, Hye-Sook

    2012-12-07

    The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarial's target.

  6. Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and FE(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry.

    PubMed

    Pashynska, Vlada A; Van den Heuvel, Hilde; Claeys, Magda; Kosevich, Marina V

    2004-08-01

    In this study, we demonstrate, using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS), that stable noncovalent complexes can be formed between Fe(III)-heme and antimalarial agents, i.e., quinine, artemisinin, and the artemisinin derivatives, dihydroartemisinin, alpha- and beta-artemether, and beta-arteether. Differences in the binding behavior of the examined drugs with Fe(III)-heme and the stability of the drug-heme complexes are demonstrated. The results show that all tested antimalarial agents form a drug-heme complex with a 1:1 stoichiometry but that quinine also results in a second complex with the heme dimer. ESI-MS performed on mixtures of pairs of various antimalarial agents with heme indicate that quinine binds preferentially to Fe(III)-heme, while ESI-MS/CID/MS shows that the quinine-heme complex is nearly two times more stable than the complexes formed between heme and artemisinin or its derivatives. Moreover, it is found that dihydroartemisinin, the active metabolite of the artemisinin-type drugs in vivo, results in a Na(+)-containing heme-drug complex, which is as stable as the heme-quinine complex. The efficiency of drug-heme binding of artemisinin derivatives is generally lower and the decomposition under CID higher compared with quinine, but these parameters are within the same order of magnitude. These results suggest that the efficiency of antimalarial agents of the artemisinin-type to form noncovalent complexes with Fe(III)-heme is comparable with that of the traditional antimalarial agent, quinine. Our study illustrates that electrospray ionization mass spectrometry and collision-induced dissociation tandem mass spectrometry are suitable tools to probe noncovalent interactions between heme and antimalarial agents. The results obtained provide insights into the underlying molecular modes of action of the traditional antimalarial agent quinine and of the antimalarials of

  7. Low Prevalence of Substandard and Falsified Antimalarial and Antibiotic Medicines in Public and Faith-Based Health Facilities of Southern Malawi.

    PubMed

    Khuluza, Felix; Kigera, Stephen; Heide, Lutz

    2017-02-20

    Substandard and falsified antimalarial and antibiotic medicines represent a serious problem for public health, especially in low- and middle-income countries. However, information on the prevalence of poor-quality medicines is limited. In the present study, samples of six antimalarial and six antibiotic medicines were collected from 31 health facilities and drug outlets in southern Malawi. Random sampling was used in the selection of health facilities. For sample collection, an overt approach was used in licensed facilities, and a mystery shopper approach in nonlicensed outlets. One hundred and fifty-five samples were analyzed by visual and physical examination and by rapid prescreening tests, that is, disintegration testing and thin-layer chromatography using the GPHF-Minilab. Fifty-six of the samples were analyzed according to pharmacopeial monographs in a World Health Organization-prequalified quality control laboratory. Seven out-of-specification medicines were identified. One sample was classified as falsified, lacking the declared active ingredients, and containing other active ingredients instead. Three samples were classified as substandard with extreme deviations from the pharmacopeial standards, and three further samples as substandard with nonextreme deviations. Of the substandard medicines, three failed in dissolution testing, two in the assay for the content of the active pharmaceutical ingredient, and one failed in both dissolution testing and assay. Six of the seven out-of-specification medicines were from private facilities. Only one out-of-specification medicine was found within the samples from public and faith-based health facilities. Although the observed presence of substandard and falsified medicines in Malawi requires action, their low prevalence in public and faith-based health facilities is encouraging.

  8. Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale

    PubMed Central

    Golldack, André; Henke, Björn; Wiechert, Marie; Blancke Soares, Alexandra

    2017-01-01

    Resistance against all available antimalarial drugs calls for novel compounds that hit unexploited targets in the parasite. Here, we show that the recently discovered Plasmodium falciparum lactate/proton symporter, PfFNT, is a valid druggable target, and describe a new class of fluoroalkyl vinylogous acids that potently block PfFNT and kill cultured parasites. The original compound, MMV007839, is derived from the malaria box collection of potent antimalarials with unknown targets and contains a unique internal prodrug principle that reversibly switches between a lipophilic transport form and a polar, substrate-analogous active form. Resistance selection of cultured P. falciparum parasites with sub-lethal concentrations of MMV007839 produced a single nucleotide exchange in the PfFNT gene; this, and functional characterization of the resulting PfFNT G107S validated PfFNT as a novel antimalarial target. From quantitative structure function relations we established the compound binding mode and the pharmacophore. The pharmacophore largely circumvents the resistance mutation and provides the basis for a medicinal chemistry program that targets lactate and proton transport as a new mode of antimalarial action. PMID:28178358

  9. Quality of drug stores: Storage practices & Regulatory compliance in Karachi, Pakistan

    PubMed Central

    Shah, Syed Shaukat Ali Muttaqi; Naqvi, Baqar Shyum; Fatima, Mashhad; Khaliq, Asif; Sheikh, Abdul Latif; Baqar, Muhammad

    2016-01-01

    Objective: To assess and evaluate the drug storage quality and regulatory compliance among privately operated drug stores of Karachi Pakistan. Methods: A cross-sectional survey of drug stores located in Karachi was conducted from May to December 2013. A total of 1003 drug stores that were involved in the sales, purchase and dispensing of pharmaceutical products were approached by non-probability purposive sampling technique, and the information was collected using a close ended, structured questionnaire. Results: Out of 1003 drug stores inspected only 4.1%(n=41) were found compliant to regulatory requirements. Most of the stores 74.9%(n=752) were selling general items along with the drugs. Only 12%(n=124) stores were having qualified person working on the store, out of which 33% were pharmacist. 47.4%(n=400) of the stores had drug sales license displayed in the premises and 33.4%(n=282) of the stores had expired drug sales license. 11.4%(n=94) stores were found selling vaccines without proper refrigerator and only 11.7% stores had the power backup for the refrigerator. Only 40.2%(n=403) of stores were protected from direct sunlight and 5.4%(n=54) having air conditioning in the premises. Conclusion: The regulatory compliance of majority of the drug stores operated privately in different areas of Karachi is below standard. Only a few drugs stores have adequate facilities to protect the drugs from extreme temperature, sunlight and provision of refrigeration. Very few of the drug stores carry out drug sales under the supervision of qualified pharmacist. There is a dire need to improve the storage practices in the drug stores by complying with the regulatory standards/laws as specified by the Drug Regulatory Authority of Pakistan. PMID:27881996

  10. [Individual quality of life of drug addicted patients during a drug withdrawal programme: Self assessment on a drug withdrawal and transition unit for adults].

    PubMed

    Frei-Rhein, Geneviève; Hantikainen, Virpi

    2009-04-01

    The aim of this study was twofold: to examine the individual quality of life of drug addicted patients after being admitted to a drug withdrawal programme in a psychiatric hospital in Switzerland, and to check whether the individual quality of life changes over a period of three weeks. Within three days following admission, thirty patients (23 men, 7 women) were interviewed, using the half structured instrument Schedule for the Evaluation of Individual Quality of Life: a Direct Weighting Procedure for Quality of Life Domains (SEIQoL-DW). Three weeks later, 16 patients (who were still participating in the drug withdrawal programme) were interviewed for a second time. The 46 interviews were analysed by means of qualitative content analysis according to Morse and Field (1998). In the 30 interviews that were conducted within the first three days following hospital admission, 269 individual quality of life domains (QLD) were described, from which 37 categories of QLD could be derived, which in turn were classified into nine main themes. In the second round of interviews conducted after three weeks in hospital, the QLD categories and the main themes remained nearly identical to those derived from the first round. Only one new category of QLD, , could be identified and was assigned to the main QLD "distress factors". The rankings of some QLDs changed. The median of the Global Quality of Life (GLQ) index of all 30 patients amounted to 48.5 out of 100 points. The initial value for 16 patients who were interviewed for a second time was 57.7 while the value for the 14 drop outs amounted to 39.9. After three weeks, the median of the GLQ of the remaining 16 patients increased from 57.7 to 63.1. Compared to a healthy population, drug addicts have a lower quality of life, while compared to other psychiatric groups similar quality of life can be observed. The SEIQoL-DW method was well accepted among patients without distressing them. This study shows that

  11. Basigin is a druggable target for host-oriented antimalarial interventions

    PubMed Central

    Zenonos, Zenon A.; Dummler, Sara K.; Müller-Sienerth, Nicole; Chen, Jianzhu; Preiser, Peter R.; Rayner, Julian C.

    2015-01-01

    Plasmodium falciparum is the parasite responsible for the most lethal form of malaria, an infectious disease that causes a large proportion of childhood deaths and poses a significant barrier to socioeconomic development in many countries. Although antimalarial drugs exist, the repeated emergence and spread of drug-resistant parasites limit their useful lifespan. An alternative strategy that could limit the evolution of drug-resistant parasites is to target host factors that are essential and universally required for parasite growth. Host-targeted therapeutics have been successfully applied in other infectious diseases but have never been attempted for malaria. Here, we report the development of a recombinant chimeric antibody (Ab-1) against basigin, an erythrocyte receptor necessary for parasite invasion as a putative antimalarial therapeutic. Ab-1 inhibited the PfRH5-basigin interaction and potently blocked erythrocyte invasion by all parasite strains tested. Importantly, Ab-1 rapidly cleared an established P. falciparum blood-stage infection with no overt toxicity in an in vivo infection model. Collectively, our data demonstrate that antibodies or other therapeutics targeting host basigin could be an effective treatment for patients infected with multi-drug resistant P. falciparum. PMID:26195724

  12. A carbamate-based approach to primaquine prodrugs: antimalarial activity, chemical stability and enzymatic activation.

    PubMed

    Mata, Graça; do Rosário, Virgílio E; Iley, Jim; Constantino, Luís; Moreira, Rui

    2012-01-15

    O-Alkyl and O-aryl carbamate derivatives of the antimalarial drug primaquine were synthesised as potential prodrugs that prevent oxidative deamination to the inactive metabolite carboxyprimaquine. Both O-alkyl and O-aryl carbamates undergo hydrolysis in alkaline and pH 7.4 phosphate buffers to the parent drug, with O-aryl carbamates being ca. 10(6)-10(10) more reactive than their O-alkyl counterparts. In human plasma O-alkyl carbamates were stable, whereas in contrast their O-aryl counterparts rapidly released the corresponding phenol product, with primaquine being released only slowly over longer incubation periods. Activation of the O-aryl carbamates in human plasma appears to be catalysed by butyrylcholinesterase (BuChE), which leads to carbamoylation of the catalytic serine of the enzyme followed by subsequent slow enzyme reactivation and release of parent drug. Most of the O-aryl and O-alkyl carbamates are activated in rat liver homogenates with half-lives ranging from 9 to 15 h, while the 4-nitrophenyl carbamate was hydrolysed too rapidly to determine an accurate rate constant. Antimalarial activity was studied using a model consisting of Plasmodium berghei, Balb C mice and Anopheles stephensi mosquitoes. When compared to controls, ethyl and n-hexyl carbamates were able to significantly reduce the percentage of infected mosquitos as well as the mean number of oocysts per infected mosquito, thus indicating that O-alkyl carbamates of primaquine have the potential to be developed as transmission-blocking antimalarial agents.

  13. Prescription Drugs: HCFA’s Proposed Drug Utilization Review System Ignores Quality of Care Issues

    DTIC Science & Technology

    1989-07-13

    Page 39 GAO/PEMD-W26ZBR HCFA’s Proposed Drug Utilization Review System Appendix I Major Contributors to This Report Program Evaluation Sushil K... Sharma , Project Manager Bruce Thompson, Project Staff and Methodology Gerald Dillingham, Advisor Division, Washington, Morgan Shulman, Intern D.C. Patrick

  14. Quality of life and antihypertensive drugs in the elderly.

    PubMed

    Fletcher, A; Bulpitt, C

    1992-06-01

    Hypertension is common in the elderly with estimates of around 10-20% showing a sustained level of pressure, either systolic (greater than or equal to 160 mmHg), or diastolic (greater than or equal to 90 mmHg) or both. The benefits of treating subjects with raised diastolic pressure was shown by the trials of the European Working Party on High Blood Pressure in the Elderly (EWPHE), the Hypertension in Elderly Patients in Primary Care (HEP), and the Swedish Trial in Old patients with Hypertension (STOP-Hypertension). Evidence for the benefit of treating isolated systolic hypertension in the elderly was provided in one trial (SHEP: Systolic Hypertension in the Elderly Program), and the results of two others are awaited. However, it is important to provide data on all treatment effects, including adverse reactions as well as benefits. In addition to traditional measures of mortality, morbidity and side effects, the quality of life in patients on antihypertensive treatment should be considered. The methods of measuring quality of life in trials is discussed, and some results presented.

  15. Antimalarial action of nitrobenzylthioinosine in combination with purine nucleoside antimetabolites.

    PubMed

    Gero, A M; Scott, H V; O'Sullivan, W J; Christopherson, R I

    1989-04-01

    The infection of human erythrocytes by two strains of the human malarial parasite, Plasmodium falciparum (FCQ-27 or the multi-drug-resistant strain K-1), markedly changed the transport characteristics of the nucleosides, adenosine and tubercidin, compared to uninfected erythrocytes. A component of the transport of these nucleosides was insensitive to the classical mammalian nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR). In vitro studies with tubercidin demonstrated ID50 values of 0.43 and 0.51 microM for FCQ-27 and K-1, respectively. In addition, the nucleoside transport inhibitors NBMPR, nitrobenzylthioguanosine (NBTGR), dilazep and dipyridamole also independently exhibited antimalarial activity in vitro. The combination of tubercidin and NBMPR or NBTGR in vitro demonstrated synergistic activity, whilst tubercidin together with dilazep or dipyridamole showed subadditive activity. Analysis by HPLC indicated that NBMPR could permeate the infected cell membrane and provided evidence for the catabolism of NBMPR in vitro, with subsequent alteration of the purine pool in the infected erythrocyte. These observations further indicated the possibility of the utilization of cytotoxic nucleosides against P. falciparum infection in conjunction with a nucleoside transport inhibitor to protect the host tissue.

  16. Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

    PubMed

    Yu, Hongbin; Balani, Suresh K; Chen, Weichao; Cui, Donghui; He, Ling; Humphreys, W Griffith; Mao, Jialin; Lai, W George; Lee, Anthony J; Lim, Heng-Keang; MacLauchlin, Christopher; Prakash, Chandra; Surapaneni, Sekhar; Tse, Susanna; Upthagrove, Alana; Walsky, Robert L; Wen, Bo; Zeng, Zhaopie

    2015-04-01

    Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

  17. Molecular markers associated with resistance to commonly used antimalarial drugs among Plasmodium falciparum isolates from a malaria-endemic area in Taiz governorate-Yemen during the transmission season.

    PubMed

    Alareqi, Lina M Q; Mahdy, Mohammed A K; Lau, Yee-Ling; Fong, Mun-Yik; Abdul-Ghani, Rashad; Mahmud, Rohela

    2016-10-01

    Since 2005, artesunate (AS) plus sulfadoxine/pyrimethamine (SP) combination has been adopted as the first-line treatment for uncomplicated malaria in Yemen in response to the high level of Plasmodium falciparum resistance to chloroquine (CQ). Therefore, the aim of the present study was to determine the frequency distribution of molecular markers associated with resistance to CQ and AS plus SP combination among P. falciparum isolates from a malaria-endemic area in Taiz governorate, Yemen. Fifty P. falciparum isolates were collected during a cross-sectional study in Mawza district, Taiz, in the period from October 2013 to April 2014. The isolates were investigated for drug resistance-associated molecular markers in five genes, including P. falciparum CQ resistance transporter (pfcrt) 76T and P. falciparum multidrug resistance 1 (pfmdr1) 86Y as markers of resistance to CQ, mutations in the Kelch 13 (K13) propeller domain for resistance to AS, and P. falciparum dihydrofolate reductase (pfdhfr) and P. falciparum dihydropteroate synthase (pfdhps) genes for resistance to SP. Nested polymerase chain reaction was used to amplify target genes in DNA extracts of the isolates followed by restriction fragment length polymorphism for detecting 76T and 86Y mutations in pfcrt and pfmdr1, respectively, and by DNA sequencing for detecting mutations in K13, pfdhfr and pfdhps. All the investigated isolates from Mawza district were harboring the pfcrt 76T mutant and the pfmdr1 N86 wild-type alleles. The pfdhfr 51I/108N double mutant allele was found in 2.2% (1/45) of the isolates; however, no mutations were detected at codons 436, 437, 540, 581 and 613 of pfdhps. All P. falciparum isolates that were successfully sequenced (n=47) showed the K13 Y493, R539, I543 and C580 wild-type alleles. In conclusion, the pfcrt 76T mutant allele is fixed in the study area about six years after the official withdrawal of CQ, possibly indicating its over-the-counter availability and continued use as a

  18. Experiences of drug use and ageing: health, quality of life, relationship and service implications

    PubMed Central

    Roe, Brenda; Beynon, Caryl; Pickering, Lucy; Duffy, Paul

    2010-01-01

    roe b., beynon c., pickering l. & duffy p. (2010)Experiences of drug use and ageing: health, quality of life, relationship and service implications. Journal of Advanced Nursing66(9), 1968–1979. Aim This paper is a report of an exploration of older people’s experiences of substance use in the context of ageing, and its impact on health, quality of life, relationships and service use. Background Use of illicit drugs by older people is a neglected policy, research and service provision and is generally perceived as a lifestyle of younger populations. Method A convenience sample of 11 people aged 49–61 years (mean 57 years) in contact with voluntary sector drug treatment services participated in qualitative semi-structured tape-recorded interviews and thematic content analysis was performed. The data were collected in 2008. Findings Drug use can have negative impacts on health status, quality of life, family relationships and social networks that accrue with age. Participants were identified as early or later onset users of drugs due to the impact of life events and relationships. A range of substances had been used currently and throughout their lives, with no single gateway drug identified as a prelude to personal drug careers. Life review and reflection were common, in keeping with ageing populations, along with regret of ever having started to use drugs. Living alone and their accommodation made them more susceptible to social isolation, and they reported experiences of death and dying of their contemporaries and family members earlier than usual in the life course. Conclusion Older people who continue to use drugs and require the support of services for treatment and care are an important emerging population and their specific needs should recognized. PMID:20626477

  19. Effect of quality chronic disease management for alcohol and drug dependence on addiction outcomes.

    PubMed

    Kim, Theresa W; Saitz, Richard; Cheng, Debbie M; Winter, Michael R; Witas, Julie; Samet, Jeffrey H

    2012-12-01

    We examined the effect of the quality of primary care-based chronic disease management (CDM) for alcohol and/or other drug (AOD) dependence on addiction outcomes. We assessed quality using (1) a visit frequency based measure and (2) a self-reported assessment measuring alignment with the chronic care model. The visit frequency based measure had no significant association with addiction outcomes. The self-reported measure of care-when care was at a CDM clinic-was associated with lower drug addiction severity. The self-reported assessment of care from any healthcare source (CDM clinic or elsewhere) was associated with lower alcohol addiction severity and abstinence. These findings suggest that high quality CDM for AOD dependence may improve addiction outcomes. Quality measures based upon alignment with the chronic care model may better capture features of effective CDM care than a visit frequency measure.

  20. Toxicity and side-effects of antimalarials in Africa: a critical review

    PubMed Central

    Salako, L. A.

    1984-01-01

    Notwithstanding the presence of resistance to chloroquine in some parts of Africa, this drug is still the most widely used antimalarial in the continent. One adverse reaction of chloroquine that has an important bearing on its use is pruritus. The risk of increasing the incidence of ocular toxicity through prolonged use of chloroquine for prophylaxis must be borne in mind by physicians. Another antimalarial that is likely to be used in increasing amounts in Africa is pyrimethamine—sulfadoxine. With prolonged use of this combination for prophylaxis, the adverse reactions usually associated with the long-acting sulfonamides are possible. Genetic abnormalities may also play a part in the incidence and severity of adverse reactions to certain drugs, e.g., primaquine and quinine. Most of the common adverse reactions are mild and have little or no influence on the acceptability and utilization of the drugs, with the exception of chloroquine-induced pruritus. Studies to define the precise epidemiology and pathophysiology of this reaction are urgently needed. PMID:6335683

  1. Antimalarial activity of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors.

    PubMed

    Dow, Geoffrey S; Chen, Yufeng; Andrews, Katherine T; Caridha, Diana; Gerena, Lucia; Gettayacamin, Montip; Johnson, Jacob; Li, Qigui; Melendez, Victor; Obaldia, Nicanor; Tran, Thanh N; Kozikowski, Alan P

    2008-10-01

    The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum. The range of 50% inhibitory concentrations (IC(50)s) was 0.0005 to >1 microM. Five analogs exhibited IC(50)s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum-infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.

  2. A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

    PubMed

    Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U

    2011-08-01

    Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.

  3. Quality Assurance for Alcohol, Drug Abuse, and Mental Health Services: An Annotated Bibliography.

    ERIC Educational Resources Information Center

    Towery, O. B.; And Others

    This is a comprehensive bibliography for all those in the alcohol, drug abuse and mental health fields who are developing and implementing programs for assuring quality in the services they provide. A major problem is the newness of the language and the unfamilarity with procedures required by the government and others seeking accountability from…

  4. A Repeat Random Survey of the Prevalence of Falsified and Substandard Antimalarials in the Lao PDR: A Change for the Better.

    PubMed

    Tabernero, Patricia; Mayxay, Mayfong; Culzoni, María Julia; Dwivedi, Prabha; Swamidoss, Isabel; Allan, Elizabeth Louise; Khanthavong, Maniphone; Phonlavong, Chindaphone; Vilayhong, Chantala; Yeuchaixiong, Sengchanh; Sichanh, Chanvilay; Sengaloundeth, Sivong; Kaur, Harparkash; Fernández, Facundo M; Green, Michael D; Newton, Paul N

    2015-06-01

    In 2003, a stratified random sample survey was conducted in the Lao People's Democratic Republic (Laos) to study the availability and quality of antimalarials in the private sector. In 2012, this survey was repeated to allow a statistically valid analysis of change through time. The counterfeit detection device 3 (CD-3) was used to assess packaging quality in the field and HPLC and mass spectroscopy analysis chemical analysis performed. The availability of oral artesunate monotherapies had significantly decreased from 22.9% (22) of 96 outlets in southern Laos in 2003 to 4.8% (7) of 144 outlets in 2012 (P < 0.0001). All the samples collected in the 2012 survey contained the correct active pharmaceutical ingredients (APIs) in contrast to the 21 (84%) falsified artesunate samples found in the 2003 survey. Although none of the medicines found in 2012 survey had evidence for falsification, 25.4% (37) of the samples were outside the 90-110% pharmacopeial limits of the label claim, suggesting that they were substandard or degraded. Results obtained from this survey show that patients are still exposed to poorly manufactured drugs or to ineffective medicines such as chloroquine. The quality of artemisinin-based combination therapies (ACTs) used in Laos needs to be monitored, since falsified ACTs would have devastating consequences in public health.

  5. A Repeat Random Survey of the Prevalence of Falsified and Substandard Antimalarials in the Lao PDR: A Change for the Better

    PubMed Central

    Tabernero, Patricia; Mayxay, Mayfong; Culzoni, María Julia; Dwivedi, Prabha; Swamidoss, Isabel; Allan, Elizabeth Louise; Khanthavong, Maniphone; Phonlavong, Chindaphone; Vilayhong, Chantala; Yeuchaixiong, Sengchanh; Sichanh, Chanvilay; Sengaloundeth, Sivong; Kaur, Harparkash; Fernández, Facundo M.; Green, Michael D.; Newton, Paul N.

    2015-01-01

    In 2003, a stratified random sample survey was conducted in the Lao People's Democratic Republic (Laos) to study the availability and quality of antimalarials in the private sector. In 2012, this survey was repeated to allow a statistically valid analysis of change through time. The counterfeit detection device 3 (CD-3) was used to assess packaging quality in the field and HPLC and mass spectroscopy analysis chemical analysis performed. The availability of oral artesunate monotherapies had significantly decreased from 22.9% (22) of 96 outlets in southern Laos in 2003 to 4.8% (7) of 144 outlets in 2012 (P < 0.0001). All the samples collected in the 2012 survey contained the correct active pharmaceutical ingredients (APIs) in contrast to the 21 (84%) falsified artesunate samples found in the 2003 survey. Although none of the medicines found in 2012 survey had evidence for falsification, 25.4% (37) of the samples were outside the 90–110% pharmacopeial limits of the label claim, suggesting that they were substandard or degraded. Results obtained from this survey show that patients are still exposed to poorly manufactured drugs or to ineffective medicines such as chloroquine. The quality of artemisinin-based combination therapies (ACTs) used in Laos needs to be monitored, since falsified ACTs would have devastating consequences in public health. PMID:25897062

  6. Metabolism of 8-aminoquinoline antimalarial agents*

    PubMed Central

    Strother, A.; Fraser, I. M.; Allahyari, Reza; Tilton, B. E.

    1981-01-01

    Some of the most effective antimalarial agents are derivatives of 8-aminoquinoline. The metabolic products of many of these compounds appear to be toxic to the erythrocytes of certain human subjects, especially those deficient in glucose-6-phosphate dehydrogenase. Although a number of studies have been conducted over many years, the metabolism of most of these compounds has not been determined. These studies are reviewed. Adult dogs dosed with tritium-labelled primaquine were observed to excrete approximately 16% of the injected radioactivity in the urine within 8 hours. Organic extracts of the urine were fractionated by thin-layer chromatography and the metabolic pattern obtained. Some primaquine was excreted along with at least five metabolites including 5-hydroxy-6-methoxy-8-(4-amino-1-methylbutylamino)quinoline (5HPQ) and a small amount of 6-hydroxy-8-(4-amino-1-methylbutylamino)quinoline (6HPQ). The 5HPQ could form a quinoneimine-type compound which may be a methaemoglobin-forming compound. This and other metabolites isolated from urine were found to be active methaemoglobin formers in in vitro studies. In vitro metabolism of primaquine by mouse liver enzymes also produced compounds capable of methaemoglobin formation. One of these had a blue colour when exposed to alkaline conditions, air, and light, and mass spectral data and nuclear magnetic resonance analysis indicated a structure similar to a 5,6-dihydroxy derivative of primaquine. However, the chemical structure of the metabolite was not identified in these studies. PMID:6976849

  7. Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development--A Systematic Review.

    PubMed

    Martić-Kehl, Marianne Isabelle; Wernery, Jannis; Folkers, Gerd; Schubiger, Pius August

    2015-01-01

    Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti-angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill

  8. Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development – A Systematic Review

    PubMed Central

    Martić-Kehl, Marianne Isabelle; Wernery, Jannis; Folkers, Gerd; Schubiger, Pius August

    2015-01-01

    Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti-angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill

  9. Role of quassinoids as potential antimalarial agents: An in silico approach

    PubMed Central

    Rampogu, Shailima

    2015-01-01

    Background: Malaria is an infection caused by mosquitoes in human beings which can be dangerous if untreated. A well known plant product, quassinoids are known to have antimalarial activity. These bioactive phytochemicals belong to the triterpene family. Quassinoids are used in the present study to act against malarial dihydrofolate reductase (Pf-DHFR), a potential antimalarial target. Nevertheless, viṣama jvara (~malaria) has been treated with the bark of Cinchona since a long time. Aim: The aim of the present experiment is to perform the protein-ligand docking for Pf- DHFR and Quassinoids and study their binding affinities. Setting and Design: The software used for the present study is the discovery studio (Accelrys 2.1), Protein Data Bank (PDB), and Chemsketch. Materials and Methods: The protein for the present study was imported from protein data bank with the PDB Id, 4dpd and was prepared for docking. The ligands used for the study are the quassinoids. They were drawn using chemsketch and the 3D structures were generated. The docking was done subsequently. Statistical Analysis Used: Molecular modeling technique was used for the protein-ligand docking analysis. Results: The docking results showed that the Quassinoids Model_1 showed the highest dock score of 40.728. Conclusion: The present study proves the promising potential of quassinoids as novel drugs against malaria. The dock results conclude that the quassinoids can be adopted as an alternative drug against malaria. PMID:26865740

  10. Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

    PubMed Central

    Starobinets, Hanna; Ye, Jordan; Broz, Miranda; Barry, Kevin; Goldsmith, Juliet; Marsh, Timothy; Rostker, Fanya

    2016-01-01

    The rising success of cancer immunotherapy has produced immense interest in defining the clinical contexts that may benefit from this therapeutic approach. To this end, there is a need to ascertain how the therapeutic modulation of intrinsic cancer cell programs influences the anticancer immune response. For example, the role of autophagy as a tumor cell survival and metabolic fitness pathway is being therapeutically targeted in ongoing clinical trials that combine cancer therapies with antimalarial drugs for the treatment of a broad spectrum of cancers, many of which will likely benefit from immunotherapy. However, our current understanding of the interplay between autophagy and the immune response remains incomplete. Here, we have evaluated how autophagy inhibition impacts the antitumor immune response in immune-competent mouse models of melanoma and mammary cancer. We observed equivalent levels of T cell infiltration and function within autophagy-competent and -deficient tumors, even upon treatment with the anthracycline chemotherapeutic doxorubicin. Similarly, we found equivalent T cell responses upon systemic treatment of tumor-bearing mice with antimalarial drugs. Our findings demonstrate that antitumor adaptive immunity is not adversely impaired by autophagy inhibition in these models, allowing for the future possibility of combining autophagy inhibitors with immunotherapy in certain clinical contexts. PMID:27775547

  11. A Pharmacokinetic Study of Antimalarial 3,5-Diaryl-2-aminopyridine Derivatives

    PubMed Central

    Dambuza, Ntokozo; Smith, Peter; Evans, Alicia; Taylor, Dale; Chibale, Kelly; Wiesner, Lubbe

    2015-01-01

    Malaria caused by Plasmodium falciparum is responsible for approximately 80% of the incidence and 90% of deaths which occur in the World Health Organization (WHO) African region, with children and pregnant women having the highest incidence. P. falciparum has developed resistance, and therefore new effective candidate antimalarial drugs need to be developed. Previous studies identified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates; therefore, derivatives of these compounds were synthesized in order to improve their desired properties and pharmacokinetic (PK) properties of the derivatives were investigated in a mouse model which was dosed orally and intravenously. Collected blood samples were analyzed using liquid chromatography coupled to mass spectrometer (LC-MS/MS). The mean peak plasma level of 1.9 μM was obtained at 1 hour for compound 1 and 3.3 μM at 0.5 hours for compound 2. A decline in concentration was observed with a half-life of 2.53 and 0.87 hours for compound 1 in mice dosed orally and intravenously, respectively. For compound 2 a half-life of 2.96 and 0.68 hours was recorded. The bioavailability was 69% and 59.7% for compound 1 and compound 2, respectively. PMID:25893131

  12. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

    PubMed Central

    2010-01-01

    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. PMID:20462416

  13. Influence of amodiaquine on the antimalarial activity of ellagic acid: crystallographic and biological studies.

    PubMed

    Żesławska, Ewa; Oleksyn, Barbara; Fabre, Aude; Benoit-Vical, Françoise

    2014-12-01

    In the search for new antimalarial drugs, design of hybrid molecules is recommended to improve biological activity and to decrease the risk of parasite resistance development. Ellagic acid, as an inhibitor of Plasmodium glutathione, presents an original mode of action and thus appears as a promising antiplasmodial compound. A new complex (AQ-EA) consisting of the well-known antimalarial drug, amodiaquine, and ellagic acid was obtained. The studied crystal structure of AQ-EA showed that the triclinic centrosymmetrical unit cell of the crystal contains two molecules of amodiaquine (AQ) and two symmetrically independent molecules of ellagic acid (EA). The packing of the molecules in the crystal is dominated by hydrogen bonds between AQ and EA. The antiplasmodial activity of the hybrid complex AQ-EA was also determined and compared with the values of IC50 for AQ and EA separately. Potentiation assays between both molecules were conducted to understand the pharmacological interactions between AQ and EA against Plasmodium falciparum in vitro. The hybrid complex AQ-EA (IC50 of 47 nm) showed improved antiplasmodial activity in comparison with EA alone.

  14. New heterocyclic hybrids of pyrazole and its bioisosteres: design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents.

    PubMed

    Bekhit, Adnan A; Hassan, Ahmed M M; Abd El Razik, Heba A; El-Miligy, Mostafa M M; El-Agroudy, Eman J; Bekhit, Alaa El-Din A

    2015-04-13

    A new series of pyrazole derivatives were synthesized by hybridization with five-membered heterocyclic moieties such as thiazoles, thiazolidinones, 1,3,4-thiadiazoles and pyrazolines. The compounds were evaluated for their in vivo antimalarial activity against Plasmodium berghei infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum. Compounds 2c, 2d, 4b, 4c, 4d, 5a, 6c, 8c and 9b had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC50 values than chloroquine. Compounds 4b and 9b were the most active derivatives, and their activities were 5-fold higher than chloroquine. All the newly synthesized compounds were evaluated for their in vitro antileishmanial activity against Leishmania aethiopica promastigotes and amastigote. The results showed that compounds 2c, 2d, 3d, 4b, 4c, 4d and 5a had lower or similar IC50 values than the reference standard drugs, amphotericin B and miltefosine. Compound 3d had the highest antileishmanial activity. Collectively, compounds 2c, 2d, 4b, 4c, 4d and 5a exhibited dual activity against malaria and leishmaniasis and were safe and well tolerated by the experimental animals orally up to 300 mg/kg and parenterally up to 100 mg/kg.

  15. Fourier transform infrared spectroscopy as a tool for identification of crude microbial extracts with anti-malarial potential.

    PubMed

    Sankarganesh, P; Joseph, Baby

    2016-01-01

    Fourier transform infrared (FT-IR) spectroscopy is an indispensable tool for identifying biologically active functional groups in uncharacterized crude samples. Here, using FT-IR spectrum analysis, we identified crude extracts of Streptomyces that have anti-malarial activities and conducted a statistical analysis of their spectra. Among the three crude microbial extracts tested herein, an aromatic amine C-N stretching functional group was observed in the spectra of Streptomyces sp. BJSG1 and BJSG4 crude extracts. These extracts showed promising activity against Plasmodium falciparum in vitro cultures with IC50 values of 0.5 for BJSG1 and 0.4μg/mL for BJSG4. The present results showed that FT-IR analysis is necessary for the primary analysis of unknown samples in anti-malarial drug development.

  16. Use of near-infrared spectroscopy and multipoint measurements for quality control of pharmaceutical drug products.

    PubMed

    Boiret, Mathieu; Chauchard, Fabien

    2017-01-01

    Near-infrared (NIR) spectroscopy is a non-destructive analytical technique that enables better-understanding and optimization of pharmaceutical processes and final drug products. The use in line is often limited by acquisition speed and sampling area. This work focuses on performing a multipoint measurement at high acquisition speed at the end of the manufacturing process on a conveyor belt system to control both the distribution and the content of active pharmaceutical ingredient within final drug products, i.e., tablets. A specially designed probe with several collection fibers was developed for this study. By measuring spectral and spatial information, it provides physical and chemical knowledge on the final drug product. The NIR probe was installed on a conveyor belt system that enables the analysis of a lot of tablets. The use of these NIR multipoint measurement probes on a conveyor belt system provided an innovative method that has the potential to be used as a new paradigm to ensure the drug product quality at the end of the manufacturing process and as a new analytical method for the real-time release control strategy. Graphical abstract Use of near-infrared spectroscopy and multipoint measurements for quality control of pharmaceutical drug products.

  17. Benefits of Exercise for the Quality of Life of Drug-Dependent Patients.

    PubMed

    Giménez-Meseguer, Jorge; Tortosa-Martínez, Juan; de los Remedios Fernández-Valenciano, María

    2015-01-01

    This study combined quantitative and qualitative research methods to evaluate quality-of-life changes in drug-dependent patients after participation in a group-based exercise program. Quality of life (SF-36) and physical fitness (six-minute Walk Test, Timed Get Up and Go Test, and Chair Stand Test) were quantitatively determined in a group (n=37) of drug-dependent patients before and after a 12-week group exercise program (n=18) or routine care (n=19). Additionally, in-depth interviews were conducted at the end of the program with a subsample of 11 participants from the exercise group. Quantitative results showed improvements in fitness and different aspects of quality of life, such as physical function, mental health, vitality, social function, and general health perception. Qualitative results showed specific physical benefits (decreased injuries and muscle pain, decreased weight, and increased vitality with improvement in activities of daily living), psychological benefits (forgetting about everyday problems, improved mood, decreased stress and anxiety), social benefits, and a reduction in craving. The results of this study provide insight into the importance of exercise for the quality of life and recovery process of drug-dependent patients.

  18. Self-reported data: a major tool to assess compliance with anti-malarial combination therapy among children in Senegal

    PubMed Central

    2009-01-01

    Background Although there are many methods available for measuring compliance, there is no formal gold standard. Different techniques used to measure compliance were compared among children treated by the anti-malarial amodiaquine/sulphadoxine-pyrimethamine (AQ/SP) combination therapy, in use in Senegal between 2004 and 2006. Methods The study was carried out in 2004, in five health centres located in the Thies region (Senegal). Children who had AQ/SP prescribed for three and one day respectively at the health centre were recruited. The day following the theoretical last intake of AQ, venous blood, and urine samples were collected for anti-malarial drugs dosage. Caregivers and children above five years were interviewed concerning children's drug intake. Results Among the children, 64.7% adhered to 80% of the prescribed dose and only 37.7% were strict full adherent to the prescription. There was 72.7% agreement between self-reported data and blood drug dosage for amodiaquine treatment. Concerning SP, results found that blood dosages were 91.4% concordant with urine tests and 90% with self-reported data based on questionnaires. Conclusion Self-reported data could provide useful quantitative information on drug intake and administration. Under strict methodological conditions this method, easy to implement, can be used to describe patients' behaviors and their use of new anti-malarial treatment. Self-reported data is a major tool for assessing compliance in resource poor countries. Blood and urine drug dosages provide qualitative results that confirm any drug intake. Urine assays for SP could be useful to obtain public health data, for example on chemoprophylaxis among pregnant women. PMID:19922609

  19. Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling

    PubMed Central

    2014-01-01

    Background Successful programmatic use of anti-malarials faces challenges that are not covered by standard drug development processes. The development of appropriate pragmatic dosing regimens for low-resource settings or community-based use is not formally regulated, even though these may alter factors which can substantially affect individual patient and population level outcome, such as drug exposure, patient adherence and the spread of drug resistance and can affect a drug’s reputation and its eventual therapeutic lifespan. Methods An in silico pharmacological model of anti-malarial drug treatment with the pharmacokinetic/pharmacodynamic profiles of artemether-lumefantrine (AM-LF, Coartem®) and dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) was constructed to assess the potential impact of programmatic factors, including regionally optimized, age-based dosing regimens, poor patient adherence, food effects and drug resistance on treatment outcome at population level, and compared both drugs’ susceptibility to these factors. Results Compared with DHA-PPQ, therapeutic effectiveness of AM-LF seems more robust to factors affecting drug exposure, such as age- instead of weight-based dosing or poor adherence. The model highlights the sub-optimally low ratio of DHA:PPQ which, in combination with the narrow therapeutic dose range of PPQ compared to DHA that drives the weight or age cut-offs, leaves DHA at a high risk of under-dosing. Conclusion Pharmacological modelling of real-life scenarios can provide valuable supportive data and highlight modifiable determinants of therapeutic effectiveness that can help optimize the deployment of anti-malarials in control programmes. PMID:24708571

  20. Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids

    PubMed Central

    2013-01-01

    Background Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. Methods In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 – 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. Results Hybrids 1 – 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os. Conclusions These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated. PMID:23433124

  1. Esterase mutation is a mechanism of resistance to antimalarial compounds

    PubMed Central

    Istvan, Eva S.; Mallari, Jeremy P.; Corey, Victoria C.; Dharia, Neekesh V.; Marshall, Garland R.; Winzeler, Elizabeth A.; Goldberg, Daniel E.

    2017-01-01

    Pepstatin is a potent peptidyl inhibitor of various malarial aspartic proteases, and also has parasiticidal activity. Activity of pepstatin against cultured Plasmodium falciparum is highly variable depending on the commercial source. Here we identify a minor contaminant (pepstatin butyl ester) as the active anti-parasitic principle. We synthesize a series of derivatives and characterize an analogue (pepstatin hexyl ester) with low nanomolar activity. By selecting resistant parasite mutants, we find that a parasite esterase, PfPARE (P. falciparum Prodrug Activation and Resistance Esterase) is required for activation of esterified pepstatin. Parasites with esterase mutations are resistant to pepstatin esters and to an open source antimalarial compound, MMV011438. Recombinant PfPARE hydrolyses pepstatin esters and de-esterifies MMV011438. We conclude that (1) pepstatin is a potent but poorly bioavailable antimalarial; (2) PfPARE is a functional esterase that is capable of activating prodrugs; (3) Mutations in PfPARE constitute a mechanism of antimalarial resistance. PMID:28106035

  2. In vitro and in vivo antimalarial activity of amphiphilic naphthothiazolium salts with amine-bearing side chains.

    PubMed

    Ulrich, Peter; Gipson, Gregory R; Clark, Martha A; Tripathi, Abhai; Sullivan, David J; Cerami, Carla

    2014-10-01

    Because of emerging resistance to existing drugs, new chemical classes of antimalarial drugs are urgently needed. We have rationally designed a library of compounds that were predicted to accumulate in the digestive vacuole and then decrystallize hemozoin by breaking the iron carboxylate bond in hemozoin. We report the synthesis of 16 naphthothiazolium salts with amine-bearing side chains and their activities against the erythrocytic stage of Plasmodium falciparum in vitro. KSWI-855, the compound with the highest efficacy against the asexual stages of P. falciparum in vitro, also had in vitro activity against P. falciparum gametocytes and in vivo activity against P. berghei in a murine malaria model.

  3. Antimalarial activity of plumbagin in vitro and in animal models

    PubMed Central

    2014-01-01

    Background Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. Methods In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test). Results Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270–640) and 370 (270–490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time. Conclusions Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability. PMID:24410949

  4. Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries.

    PubMed

    Fernandez, Facundo M; Hostetler, Dana; Powell, Kristen; Kaur, Harparkash; Green, Michael D; Mildenhall, Dallas C; Newton, Paul N

    2011-08-07

    Throughout history, poor quality medicines have been a persistent problem, with periodical crises in the supply of antimicrobials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Regrettably, this problem seems to have grown in the last decade, especially afflicting unsuspecting patients and those seeking medicines via on-line pharmacies. Here we discuss some of the challenges related to the fight against poor quality drugs, and counterfeits in particular, with an emphasis on the analytical tools available, their relative performance, and the necessary workflows needed for distinguishing between genuine, substandard, degraded and counterfeit medicines.

  5. Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries†

    PubMed Central

    Fernandez, Facundo M.; Hostetler, Dana; Powell, Kristen; Kaur, Harparkash; Green, Michael D.; Mildenhall, Dallas C.; Newton, Paul N.

    2012-01-01

    Throughout history, poor quality medicines have been a persistent problem, with periodical crises in the supply of antimicrobials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Regrettably, this problem seems to have grown in the last decade, especially afflicting unsuspecting patients and those seeking medicines via on-line pharmacies. Here we discuss some of the challenges related to the fight against poor quality drugs, and counterfeits in particular, with an emphasis on the analytical tools available, their relative performance, and the necessary workflows needed for distinguishing between genuine, substandard, degraded and counterfeit medicines. PMID:21107455

  6. Modeling structure-activity relationships of prodiginines with antimalarial activity using GA/MLR and OPS/PLS.

    PubMed

    de Campos, Luana Janaína; de Melo, Eduardo Borges

    2014-11-01

    In the present study, we performed a multivariate quantitative structure-activity relationship (QSAR) analysis of 52 prodiginines with antimalarial activity. Variable selection was based on the genetic algorithm (GA) and ordered predictor selection (OPS) approaches, and the models were built using the multiple linear regression (MLR) and partial least squares (PLS) regression methods. The leave-N-out crossvalidation and y-randomization tests showed that the models were robust and free from chance correlation. The mechanistic interpretation of the results was supported by earlier findings. In addition, the comparison of our models with those previously described indicated that the OPS/PLS-based model had a higher quality of external prediction. Thus, this study provides a comprehensive approach to the evaluation of the antimalarial activity of prodiginines, which may be used as a support tool in designing new therapeutic agents for malaria.

  7. Antimalarial activity of physalins B, D, F, and G.

    PubMed

    Sá, Matheus S; de Menezes, Maria N; Krettli, Antoniana U; Ribeiro, Ivone M; Tomassini, Therezinha C B; Ribeiro dos Santos, Ricardo; de Azevedo, Walter F; Soares, Milena B P

    2011-10-28

    The antimalarial activities of physalins B, D, F, and G (1-4), isolated from Physalis angulata, were investigated. In silico analysis using the similarity ensemble approach (SEA) database predicted the antimalarial activity of each of these compounds, which were shown using an in vitro assay against Plasmodium falciparum. However, treatment of P. berghei-infected mice with 3 increased parasitemia levels and mortality, whereas treatment with 2 was protective, causing a parasitemia reduction and a delay in mortality in P. berghei-infected mice. The exacerbation of in vivo infection by treatment with 3 is probably due to its potent immunosuppressive activity, which is not evident for 2.

  8. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes

    PubMed Central

    Goodman, Christopher D.; Siregar, Josephine E.; Mollard, Vanessa; Vega-Rodríguez, Joel; Syafruddin, Din; Matsuoka, Hiroyuki; Matsuzaki, Motomichi; Toyama, Tomoko; Sturm, Angelika; Cozijnsen, Anton; Jacobs-Lorena, Marcelo; Kita, Kiyoshi; Marzuki, Sangkot; McFadden, Geoffrey I.

    2016-01-01

    Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control. PMID:27081071

  9. Biological activities of nitidine, a potential anti-malarial lead compound

    PubMed Central

    2012-01-01

    Background Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action. Methods In this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated. Results Nitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine. Conclusion Nitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase

  10. Anti-malarial market and policy surveys in sub-Saharan Africa.

    PubMed

    Diap, Graciela; Amuasi, John; Boakye, Isaac; Sevcsik, Ann-Marie; Pecoul, Bernard

    2010-04-23

    At a recent meeting (Sept 18, 2009) in which reasons for the limited access to artemisinin-based combination therapy (ACT) in sub-Saharan Africa were discussed, policy and market surveys on anti-malarial drug availability and accessibility in Burundi and Sierra Leone were presented in a highly interactive brainstorming session among key stakeholders across private, public, and not-for-profit sectors. The surveys, the conduct of which directly involved the national malaria control programme managers of the two countries, provides the groundwork for evidence-based policy implementation. The results of the surveys could be extrapolated to other countries with similar socio-demographic and malaria profiles. The meeting resulted in recommendations on key actions to be taken at the global, national, and community level for better ACT accessibility. At the global level, both public and private sectors have actions to take to strengthen policies that lead to the replacement of loose blister packs with fixed-dose ACT products, develop strategies to ban inappropriate anti-malarials and regulate those bans, and facilitate technology and knowledge transfer to scale up production of fixed-dose ACT products, which should be readily available and affordable to those patients who are in the greatest need of these medicines. At the national level, policies that regulate the anti-malarial medicines market should be enacted and enforced. The public sector, including funding donors, should participate in ensuring that the private sector is engaged in the ACT implementation process. Research similar to the surveys discussed is important for other countries to develop and evaluate the right incentives at a local level. At the community level, community outreach and education about appropriate preventive and treatment measures must continue and be strengthened, with service delivery systems developed within both public and private sectors, among other measures, to decrease access to

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

    PubMed Central

    Maranz, Steven

    2012-01-01

    Most investigations into the antimalarial activity of African plants are centered on finding an indigenous equivalent to artemisinin, the compound from which current frontline antimalarial drugs are synthesized. As a consequence, the standard practice in ethnopharmacological research is to use in vitro assays to identify compounds that inhibit parasites at nanomolar concentrations. This approach fails to take into consideration the high probability of acquisition of resistance to parasiticidal compounds since parasite populations are placed under direct selection for genetic that confers a survival advantage. Bearing in mind Africa's long exposure to malaria and extensive ethnobotanical experimentation with both therapies and diet, it is more likely that compounds not readily overcome by Plasmodium parasites would have been retained in the pharmacopeia and cuisine. Such compounds are characterized by acting primarily on the host rather than directly targeting the parasite and thus cannot be adequately explored in vitro. If Africa's long history with malaria has in fact produced effective plant therapies, their scientific elucidation will require a major emphasis on in vivo investigation. PMID:22593717

  12. Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents

    PubMed Central

    Wang, Jiayi; Kaiser, Marcel; Copp, Brent R.

    2014-01-01

    Pure compound screening has previously identified the indolglyoxylamidospermidine ascidian metabolites didemnidine A and B (2 and 3) to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 41 and 15 μM, respectively), but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively). To expand the structure–activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic “capping acids”, and polyamines including spermine (PA3-4-3) and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10–92 nM) but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM) identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM). There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia. PMID:24879541

  13. Mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents.

    PubMed

    Gemma, Sandra; Camodeca, Caterina; Brindisi, Margherita; Brogi, Simone; Kukreja, Gagan; Kunjir, Sanil; Gabellieri, Emanuele; Lucantoni, Leonardo; Habluetzel, Annette; Taramelli, Donatella; Basilico, Nicoletta; Gualdani, Roberta; Tadini-Buoninsegni, Francesco; Bartolommei, Gianluca; Moncelli, Maria Rosa; Martin, Rowena E; Summers, Robert L; Lamponi, Stefania; Savini, Luisa; Fiorini, Isabella; Valoti, Massimo; Novellino, Ettore; Campiani, Giuseppe; Butini, Stefania

    2012-12-13

    The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum ) and in vivo (against Plasmodium berghei ). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei -infected mice.

  14. Synthesis, biological evaluation and molecular docking of novel chalcone-coumarin hybrids as anticancer and antimalarial agents.

    PubMed

    Pingaew, Ratchanok; Saekee, Amporn; Mandi, Prasit; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2014-10-06

    A new series of chalcone-coumarin derivatives (9-19) linked by the 1,2,3-triazole ring were synthesized through the azide/alkyne dipolar cycloaddition. Hybrid molecules were evaluated for their cytotoxic activity against four cancer cell lines (e.g., HuCCA-1, HepG2, A549 and MOLT-3) and antimalarial activity toward Plasmodium falciparum. Most of the synthesized hybrids, except for analogs 10 and 16, displayed cytotoxicity against MOLT-3 cell line without affecting normal cells. Analogs (10, 11, 16 and 18) exhibited higher inhibitory efficacy than the control drug, etoposide, in HepG2 cells. Significantly, the high cytotoxic potency of the hybrid 11 was shown to be non-toxic to normal cells. Interestingly, the chalcone-coumarin 18 was the most potent antimalarial compound affording IC50 value of 1.60 μM. Molecular docking suggested that the cytotoxicity of reported hybrids could be possibly due to their dual inhibition of α- and β-tubulins at GTP and colchicine binding sites, respectively. Furthermore, falcipain-2 was identified to be a plausible target site of the hybrids given their antimalarial potency.

  15. Nurses' perception of the quality of care they provide to hospitalized drug addicts: testing the theory of reasoned action.

    PubMed

    Natan, Merav Ben; Beyil, Valery; Neta, Okev

    2009-12-01

    A correlational design was used to examine nursing staff attitudes and subjective norms manifested in intended and actual care of drug users based on the Theory of Reasoned Action. One hundred and thirty-five nursing staff from three central Israeli hospitals completed a questionnaire examining theory-based variables as well as sociodemographic and professional characteristics. Most respondents reported a high to very high level of actual or intended care of drug users. Nurses' stronger intentions to provide quality care to drug users were associated with more positive attitudes. Nursing staff members had moderately negative attitudes towards drug users. Nurses were found to hold negative stereotypes of drug addict patients and most considered the management of this group difficult. Positive attitudes towards drug users, perceived expectations of others and perceived correctness of the behaviour are important in their effect on the intention of nurses to provide high-quality care to hospitalized patients addicted to drugs.

  16. mQC: A Heuristic Quality-Control Metric for High-Throughput Drug Combination Screening

    PubMed Central

    Chen, Lu; Wilson, Kelli; Goldlust, Ian; Mott, Bryan T.; Eastman, Richard; Davis, Mindy I.; Zhang, Xiaohu; McKnight, Crystal; Klumpp-Thomas, Carleen; Shinn, Paul; Simmons, John; Gormally, Mike; Michael, Sam; Thomas, Craig J.; Ferrer, Marc; Guha, Rajarshi

    2016-01-01

    Quality control (QC) metrics are critical in high throughput screening (HTS) platforms to ensure reliability and confidence in assay data and downstream analyses. Most reported HTS QC metrics are designed for plate level or single well level analysis. With the advent of high throughput combination screening there is a need for QC metrics that quantify the quality of combination response matrices. We introduce a predictive, interpretable, matrix-level QC metric, mQC, based on a mix of data-derived and heuristic features. mQC accurately reproduces the expert assessment of combination response quality and correctly identifies unreliable response matrices that can lead to erroneous or misleading characterization of synergy. When combined with the plate-level QC metric, Z’, mQC provides a more appropriate determination of the quality of a drug combination screen. Retrospective analysis on a number of completed combination screens further shows that mQC is able to identify problematic screens whereas plate-level QC was not able to. In conclusion, our data indicates that mQC is a reliable QC filter that can be used to identify problematic drug combinations matrices and prevent further analysis on erroneously active combinations as well as for troubleshooting failed screens. The R source code of mQC is available at http://matrix.ncats.nih.gov/mQC. PMID:27883049

  17. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya

    PubMed Central

    Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L.; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E. Jane

    2016-01-01

    Objective To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB) in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS) methodology. Design The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance. Results This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains. Conclusion Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints. PMID:27167381

  18. A Quality by Design Approach to Developing and Manufacturing Polymeric Nanoparticle Drug Products.

    PubMed

    Troiano, Greg; Nolan, Jim; Parsons, Donald; Van Geen Hoven, Christina; Zale, Stephen

    2016-11-01

    The translation of nanomedicines from concepts to commercial products has not reached its full potential, in part because of the technical and regulatory challenges associated with chemistry, manufacturing, and controls (CMC) development of such complex products. It is critical to take a quality by design (QbD) approach to developing nanomedicines-using a risk-based approach to identifying and classifying product attributes and process parameters and ultimately developing a deep understanding of the products, processes, and platform. This article exemplifies a QbD approach used by BIND Therapeutics, Inc., to industrialize a polymeric targeted nanoparticle drug delivery platform. The focus of the approach is on CMC affairs but consideration is also given to preclinical, clinical, and regulatory aspects of pharmaceutical development. Processes are described for developing a quality target product profile and designing supporting preclinical studies, defining critical quality attributes and process parameters, building a process knowledge map, and employing QbD to support outsourced manufacturing.

  19. Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

    PubMed Central

    2012-01-01

    Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro. PMID:22401346

  20. Quality of Reporting of Serious Adverse Drug Events to an Institutional Review Board

    PubMed Central

    Dorr, David A.; Burdon, Rachel; West, Dennis P.; Lagman, Jennifer; Georgopoulos, Christina; Belknap, Steven M.; McKoy, June M.; Djulbegovic, Benjamin; Edwards, Beatrice J.; Weitzman, Sigmund A.; Boyle, Simone; Tallman, Martin S.; Talpaz, Moshe; Sartor, Oliver; Bennett, Charles L.

    2009-01-01

    Purpose Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB. Experimental Design sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed. Results Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources. Conclusions The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients. PMID:19458059

  1. Preparation and antimalarial activity of semisynthetic lycorenine derivatives.

    PubMed

    Cedrón, Juan C; Gutiérrez, David; Flores, Ninoska; Ravelo, Ángel G; Estévez-Braun, Ana

    2013-05-01

    A set of twenty one lycorenine derivatives has been prepared from the alkaloid hippeastrine (1). The modifications performed on hippeastrine included some functional group transformations, structural simplification and preparation of dimers. All alkaloids were tested as potential antimalarial agents, being the hippeastrine dimers the most active compounds.

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

    PubMed

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

    2017-03-05

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

  3. Anti-malarial Activities of Two Soil Actinomycete Isolates from Sabah via Inhibition of Glycogen Synthase Kinase 3β

    PubMed Central

    Dahari, Dhiana Efani; Salleh, Raifana Mohamad; Mahmud, Fauze; Chin, Lee Ping; Embi, Noor; Sidek, Hasidah Mohd

    2016-01-01

    Exploiting natural resources for bioactive compounds is an attractive drug discovery strategy in search for new anti-malarial drugs with novel modes of action. Initial screening efforts in our laboratory revealed two preparations of soil-derived actinomycetes (H11809 and FH025) with potent anti-malarial activities. Both crude extracts showed glycogen synthase kinase 3β (GSK3β)-inhibitory activities in a yeast-based kinase assay. We have previously shown that the GSK3 inhibitor, lithium chloride (LiCl), was able to suppress parasitaemia development in a rodent model of malarial infection. The present study aims to evaluate whether anti-malarial activities of H11809 and FH025 involve the inhibition of GSK3β. The acetone crude extracts of H11809 and FH025 each exerted strong inhibition on the growth of Plasmodium falciparum 3D7 in vitro with 50% inhibitory concentration (IC50) values of 0.57 ± 0.09 and 1.28 ± 0.11 µg/mL, respectively. The tested extracts exhibited Selectivity Index (SI) values exceeding 10 for the 3D7 strain. Both H11809 and FH025 showed dosage-dependent chemo-suppressive activities in vivo and improved animal survivability compared to non-treated infected mice. Western analysis revealed increased phosphorylation of serine (Ser 9) GSK3β (by 6.79 to 6.83-fold) in liver samples from infected mice treated with H11809 or FH025 compared to samples from non-infected or non-treated infected mice. A compound already identified in H11809 (data not shown), dibutyl phthalate (DBP) showed active anti-plasmodial activity against 3D7 (IC50 4.87 ± 1.26 µg/mL which is equivalent to 17.50 µM) and good chemo-suppressive activity in vivo (60.80% chemo-suppression at 300 mg/kg body weight [bw] dosage). DBP administration also resulted in increased phosphorylation of Ser 9 GSK3β compared to controls. Findings from the present study demonstrate that the potent anti-malarial activities of H11809 and FH025 were mediated via inhibition of host GSK3β. In addition

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

    PubMed Central

    2011-01-01

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

  5. Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats

    PubMed Central

    Bielitza, Max; Belorgey, Didier; Ehrhardt, Katharina; Johann, Laure; Lanfranchi, Don Antoine; Gallo, Valentina; Schwarzer, Evelin; Mohring, Franziska; Jortzik, Esther; Williams, David L.; Becker, Katja; Arese, Paolo; Elhabiri, Mourad

    2015-01-01

    Abstract Aims: Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism of a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, to understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic the natural protection of G6PD deficiency. Results: We demonstrated that the key benzoylmenadione metabolite of the lead compound acts as an efficient redox-cycler in NADPH-dependent methaemoglobin reduction, leading to the continuous formation of reactive oxygen species, ferrylhaemoglobin, and subsequent haemichrome precipitation. Structure–activity relationships evidenced that both drug metabolites and haemoglobin catabolites contribute to potentiate drug effects and inhibit parasite development. Disruption of redox homeostasis by the lead benzylmenadione was specifically induced in Plasmodium falciparum parasitized erythrocytes and not in non-infected cells, and was visualized via changes in the glutathione redox potential of living parasite cytosols. Furthermore, the redox-cycler shows additive and synergistic effects in combination with compounds affecting the NADPH flux in vivo. Innovation: The lead benzylmenadione 1c is the first example of a novel redox-active agent that mimics the behavior of a falciparum parasite developing inside a G6PD-deficient red blood cell (RBC) giving rise to malaria protection, and it exerts specific additive effects that are inhibitory to parasite development, without harm for non-infected G6PD-sufficient or -deficient RBCs. Conclusion: This strategy offers an innovative perspective for the development of future antimalarial drugs for G6PD-sufficient and -deficient populations. Antioxid. Redox Signal. 22, 1337–1351. PMID:25714942

  6. A pilot study on quality of artesunate and amodiaquine tablets used in the fishing community of Tema, Ghana

    PubMed Central

    2013-01-01

    Background The ineffectiveness of artesunate and amodiaquine tablets in malaria treatment remains a health burden to WHO and governments of malaria-endemic countries, including Ghana. The proliferation of illegitimate anti-malarial drugs and its use by patients is of primary concern to international and local drug regulatory agencies because such drugs are known to contribute to the development of the malaria-resistant parasites in humans. No data exist on quality of these drugs in the fishing village communities in Ghana although the villagers are likely users of such drugs. A pilot study on the quality of anti-malarial tablets in circulation during the major fishing season at a malarious fishing village located along the coast of Tema in southern Ghana was determined. Methods Blisterpacks of anti-malarial tablets were randomly sampled. The International Pharmacopoeia and Global Pharma Health Fund Minilab protocols were used to assess the quality of anti-malarial tablets per blisterpacks allegedly manufactured by Guilin Pharmaceutical Co Ltd, China (GPCL) and Letap Pharmaceuticals Ltd, Ghana (LPL) and sold in chemical sales outlets at Kpone-on–Sea. Ferric chloride and cobaltous thiocyanate tests confirmed the presence of active ingredients in the tablets. A confirmatory test for the active ingredient was achieved with artesunate (ICRS1409) and amodiaquine (ICRS0209) reference standards. A high performance liquid chromatography analysis confirmed the amount of artesunate found in tablets. Results Based on the International Pharmacopoeia acceptable range of 96/98 to 102% for genuine artesunate per tablet, 10% [relative standard deviation (RSD): 3.2%] of field-selected artesunate blisterpack per tablets manufactured by GPCL, and 50% (RSD: 5.1%) of a similar package per tablet by LPL, passed the titrimetric test. However, 100% (RSD: 2.2%) of amodiaquine blisterpack per tablet by GPCL were found to be within the International Pharmacopeia acceptable range of 90 to

  7. CoMFA, CoMSIA, and docking studies on thiolactone-class of potent anti-malarials: identification of essential structural features modulating anti-malarial activity.

    PubMed

    Roy, Kuldeep K; Bhunia, Shome S; Saxena, Anil K

    2011-09-01

    The integrated ligand- and structure-based drug design techniques have been applied on a homogeneous dataset of thiolactone-class of potent anti-malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum. Developed CoMFA (q(2) = 0.716) and CoMSIA (q(2) = 0.632) models well explained structure-activity variation in both the training (CoMFA R(2) = 0.948 & CoMSIA R(2) = 0.849) and test set (CoMFA R(2) (pred) = 0.789 & CoMSIA R(2) (pred) = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high-resolution (2.35 Å) structure of FabB-TLM binary complex (PDB-ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H-bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein-ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone-class of compounds that could furnish improved anti-malarial activity.

  8. Quality of Online Pharmacies and Websites Selling Prescription Drugs: A Systematic Review

    PubMed Central

    Merla, Anna; Schulz, Peter J; Gelatti, Umberto

    2011-01-01

    Background Online pharmacies are companies that sell pharmaceutical preparations, including prescription-only drugs, on the Internet. Very little is known about this phenomenon because many online pharmacies operate from remote countries, where legal bases and business practices are largely inaccessible to international research. Objective The aim of the study was to perform an up-to-date and comprehensive review of the scientific literature focusing on the broader picture of online pharmacies by scanning several scientific and institutional databases, with no publication time limits. Methods We searched 4 electronic databases up to January 2011 and the gray literature on the Internet using the Google search engine and its tool Google Scholar. We also investigated the official websites of institutional agencies (World Health Organization, and US and European centers for disease control and drug regulation authorities). We focused specifically on online pharmacies offering prescription-only drugs. We decided to analyze and report only articles with original data, in order to review all the available data regarding online pharmacies and their usage. Results We selected 193 relevant articles: 76 articles with original data, and 117 articles without original data (editorials, regulation articles, or the like) including 5 reviews. The articles with original data cover samples of online pharmacies in 47 cases, online drug purchases in 13, consumer characteristics in 15, and case reports on adverse effects of online drugs in 12. The studies show that random samples with no specific limits to prescription requirements found that at least some websites sold drugs without a prescription and that an online questionnaire was a frequent tool to replace prescription. Data about geographical characteristics show that this information can be concealed in many websites. The analysis of drug offer showed that online a consumer can get virtually everything. Regarding quality of drugs

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

    PubMed

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

    2010-02-01

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

  10. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    PubMed Central

    Restrepo Valencia, Piedad

    2015-01-01

    Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. PMID:26600625

  11. Injection Drug User Quality of Life Scale (IDUQOL): Findings from a content validation study

    PubMed Central

    Hubley, Anita M; Palepu, Anita

    2007-01-01

    Background Quality of life studies among injection drug users have primarily focused on health-related measures. The chaotic life-style of many injection drug users (IDUs), however, extends far beyond their health, and impacts upon social relationships, employment opportunities, housing, and day to day survival. Most current quality of life instruments do not capture the realities of people living with addictions. The Injection Drug Users' Quality of Life Scale (IDUQOL) was developed to reflect the life areas of relevance to IDUs. The present study examined the content validity of the IDUQOL using judgmental methods based on subject matter experts' (SMEs) ratings of various elements of this measure (e.g., appropriateness of life areas or items, names and descriptions of life areas, instructions for administration and scoring). Methods Six SMEs were provided with a copy of the IDUQOL and its administration and scoring manual and a detailed content validation questionnaire. Two commonly used judgmental measures of inter-rater agreement, the Content Validity Index (CVI) and the Average Deviation Mean Index (ADM), were used to evaluate SMEs' agreement on ratings of IDUQOL elements. Results A total of 75 elements of the IDUQOL were examined. The CVI results showed that all elements were endorsed by the required number of SMEs or more. The ADM results showed that acceptable agreement (i.e., practical significance) was obtained for all elements but statistically significant agreement was missed for nine elements. For these elements, SMEs' feedback was examined for ways to improve the elements. Open-ended feedback also provided suggestions for other revisions to the IDUQOL. Conclusion The results of the study provided strong evidence in support of the content validity of the IDUQOL and direction for the revision of some IDUQOL elements. PMID:17663783

  12. Hypothesis driven drug design: improving quality and effectiveness of the design-make-test-analyse cycle.

    PubMed

    Plowright, Alleyn T; Johnstone, Craig; Kihlberg, Jan; Pettersson, Jonas; Robb, Graeme; Thompson, Richard A

    2012-01-01

    In drug discovery, the central process of constructing and testing hypotheses, carefully conducting experiments and analysing the associated data for new findings and information is known as the design-make-test-analyse cycle. Each step relies heavily on the inputs and outputs of the other three components. In this article we report our efforts to improve and integrate all parts to enable smooth and rapid flow of high quality ideas. Key improvements include enhancing multi-disciplinary input into 'Design', increasing the use of knowledge and reducing cycle times in 'Make', providing parallel sets of relevant data within ten working days in 'Test' and maximising the learning in 'Analyse'.

  13. Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation.

    PubMed

    Shah, Syed Muhammad Hassan; Ullah, Farhat; Khan, Shahzeb; Shah, Syed Muhammad Mukarram; de Matas, Marcel; Hussain, Zahid; Minhas, Muhammad Usman; AbdEl-Salam, Naser M; Assi, Khaled Hafez; Isreb, Mohammad

    2016-01-01

    Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena(®) DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C-8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena(®) DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.

  14. Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation

    PubMed Central

    Shah, Syed Muhammad Hassan; Ullah, Farhat; Khan, Shahzeb; Shah, Syed Muhammad Mukarram; de Matas, Marcel; Hussain, Zahid; Minhas, Muhammad Usman; AbdEl-Salam, Naser M; Assi, Khaled Hafez; Isreb, Mohammad

    2016-01-01

    Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities. PMID:27920499

  15. Discovery of new antimalarial chemotypes through chemical methodology and library development

    PubMed Central

    Brown, Lauren E.; Chih-Chien Cheng, Ken; Wei, Wan-Guo; Yuan, Pingwei; Dai, Peng; Trilles, Richard; Ni, Feng; Yuan, Jing; MacArthur, Ryan; Guha, Rajarshi; Johnson, Ronald L.; Su, Xin-zhuan; Dominguez, Melissa M.; Snyder, John K.; Beeler, Aaron B.; Schaus, Scott E.; Inglese, James; Porco, John A.

    2011-01-01

    In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC50’s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development. PMID:21498685

  16. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

    PubMed Central

    Ashton, Thomas M.; Fokas, Emmanouil; Kunz-Schughart, Leoni A.; Folkes, Lisa K.; Anbalagan, Selvakumar; Huether, Melanie; Kelly, Catherine J.; Pirovano, Giacomo; Buffa, Francesca M.; Hammond, Ester M.; Stratford, Michael; Muschel, Ruth J.; Higgins, Geoff S.; McKenna, William Gillies

    2016-01-01

    Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. PMID:27453292

  17. Discovery of new antimalarial chemotypes through chemical methodology and library development.

    PubMed

    Brown, Lauren E; Chih-Chien Cheng, Ken; Wei, Wan-Guo; Yuan, Pingwei; Dai, Peng; Trilles, Richard; Ni, Feng; Yuan, Jing; MacArthur, Ryan; Guha, Rajarshi; Johnson, Ronald L; Su, Xin-zhuan; Dominguez, Melissa M; Snyder, John K; Beeler, Aaron B; Schaus, Scott E; Inglese, James; Porco, John A

    2011-04-26

    In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC(50)'s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.

  18. Data quality in drug discovery: the role of analytical performance in ligand binding assays

    NASA Astrophysics Data System (ADS)

    Wätzig, Hermann; Oltmann-Norden, Imke; Steinicke, Franziska; Alhazmi, Hassan A.; Nachbar, Markus; El-Hady, Deia Abd; Albishri, Hassan M.; Baumann, Knut; Exner, Thomas; Böckler, Frank M.; El Deeb, Sami

    2015-09-01

    Despite its importance and all the considerable efforts made, the progress in drug discovery is limited. One main reason for this is the partly questionable data quality. Models relating biological activity and structures and in silico predictions rely on precisely and accurately measured binding data. However, these data vary so strongly, such that only variations by orders of magnitude are considered as unreliable. This can certainly be improved considering the high analytical performance in pharmaceutical quality control. Thus the principles, properties and performances of biochemical and cell-based assays are revisited and evaluated. In the part of biochemical assays immunoassays, fluorescence assays, surface plasmon resonance, isothermal calorimetry, nuclear magnetic resonance and affinity capillary electrophoresis are discussed in details, in addition radiation-based ligand binding assays, mass spectrometry, atomic force microscopy and microscale thermophoresis are briefly evaluated. In addition, general sources of error, such as solvent, dilution, sample pretreatment and the quality of reagents and reference materials are discussed. Biochemical assays can be optimized to provide good accuracy and precision (e.g. percental relative standard deviation <10 %). Cell-based assays are often considered superior related to the biological significance, however, typically they cannot still be considered as really quantitative, in particular when results are compared over longer periods of time or between laboratories. A very careful choice of assays is therefore recommended. Strategies to further optimize assays are outlined, considering the evaluation and the decrease of the relevant error sources. Analytical performance and data quality are still advancing and will further advance the progress in drug development.

  19. A Novel Way to Grow Hemozoin-Like Crystals In Vitro and Its Use to Screen for Hemozoin Inhibiting Antimalarial Compounds

    PubMed Central

    Ritts, Bruce; Burke, Peter; Hänscheid, Thomas; McDonnell, Gerald

    2012-01-01

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

  20. Effects of solvent composition and ionic strength on the interaction of quinoline antimalarials with ferriprotoporphyrin IX.

    PubMed

    Egan, Timothy J; Ncokazi, Kanyile K

    2004-01-01

    Enthalpy-entropy compensation in the interaction of quinoline antimalarials with ferriprotoporphyrin IX (Fe(III)PPIX) in 40% aqueous dimethyl sulfoxide (DMSO) has been compared with that in pure aqueous solution. The data indicate that the degree of desolvation and loss of conformational freedom is virtually identical in both systems. Taken together with previous findings showing that the molar free energies of association of these drugs with Fe(III)PPIX in both solvent systems are very similar, this suggests that the recognition site on the metalloporphyrin is comparable in both cases. This is despite the fact that Fe(III)PPIX exists as a dimer in aqueous solution, but is monomeric in 40% DMSO. Free energies of association of chloroquine, quinine and quinidine with Fe(III)PPIX are largely insensitive to the concentration of sodium perchlorate in 40% DMSO. This demonstrates that electrostatic interactions play only a minor role in the overall stability of these complexes under these conditions. Increasing DMSO concentration greatly weakens the interactions of chloroquine, amodiaquine, quinine, quinidine and 9-epiquinine with Fe(III)PPIX. This suggests that hydrophobic interaction plays a major role in the stability of these complexes. Further investigation of chloroquine has revealed that the free energy of association with Fe(III)PPIX also weakens as a function of decreasing solvent polarity in pure organic solvents. However, the free energies of association are weaker in the mixed aqueous solvent than in pure organic solvents. This indicates that dispersion and electrostatic interactions are relatively strong in the non-aqueous environment. The results demonstrate that any successful model of antimalarial drug-Fe(III)PPIX interactions will need to take both solvation and electrostatic factors into account.

  1. The Stapled AKAP Disruptor Peptide STAD-2 Displays Antimalarial Activity through a PKA-Independent Mechanism.

    PubMed

    Flaherty, Briana R; Wang, Yuxiao; Trope, Edward C; Ho, Tienhuei G; Muralidharan, Vasant; Kennedy, Eileen J; Peterson, David S

    2015-01-01

    Drug resistance poses a significant threat to ongoing malaria control efforts. Coupled with lack of a malaria vaccine, there is an urgent need for the development of new antimalarials with novel mechanisms of action and low susceptibility to parasite drug resistance. Protein Kinase A (PKA) has been implicated as a critical regulator of pathogenesis in malaria. Therefore, we sought to investigate the effects of disrupted PKA signaling as a possible strategy for inhibition of parasite replication. Host PKA activity is partly regulated by a class of proteins called A Kinase Anchoring Proteins (AKAPs), and interaction between HsPKA and AKAP can be inhibited by the stapled peptide Stapled AKAP Disruptor 2 (STAD-2). STAD-2 was tested for permeability to and activity against Plasmodium falciparum blood stage parasites in vitro. The compound was selectively permeable only to infected red blood cells (iRBC) and demonstrated rapid antiplasmodial activity, possibly via iRBC lysis (IC50 ≈ 1 μM). STAD-2 localized within the parasite almost immediately post-treatment but showed no evidence of direct association with PKA, indicating that STAD-2 acts via a PKA-independent mechanism. Furosemide-insensitive parasite permeability pathways in the iRBC were largely responsible for uptake of STAD-2. Further, peptide import was highly specific to STAD-2 as evidenced by low permeability of control stapled peptides. Selective uptake and antiplasmodial activity of STAD-2 provides important groundwork for the development of stapled peptides as potential antimalarials. Such peptides may also offer an alternative strategy for studying protein-protein interactions critical to parasite development and pathogenesis.

  2. Fractions of an antimalarial neem-leaf extract have activities superior to chloroquine, and are gametocytocidal.

    PubMed

    Udeinya, I J; Brown, N; Shu, E N; Udeinya, F I; Quakeyie, I

    2006-01-01

    The antimalarial activities of two fractions (IRDN-A and IRDN-B) of an extract from the leaves of the neem tree (Azadirachta indica) were compared with those of chloroquine, in in-vitro assays against Plasmodium falciparum. The asexual stages of a chloroquine-sensitive clone (ITG2F6) and a chloroquine-resistant isolate (W2) and the gametocytes of the NF 54 (BD-7) isolate of P. falciparum were used as the drug targets. Activity against the asexual stages was generally evaluated as the concentrations inhibiting the parasitaemias recorded in the control cultures, after an incubation of 48-72 h, by 50% (IC50) or 100% (IC100). For the ITG2F6 strain, the IC50 and IC100 (in microg/ml) were, respectively, 10(-5) and 10(-4) for IRDN-A, 10(-3) and 10(-2) for IRDN-B, and 10(-2) and 1.0 for chloroquine. The corresponding values for the W2 strain were 10(-5) and 1.0 for IRDN-A, and 10.0 and >100 for chloroquine (even at 100 microg/ml, chloroquine only inhibited the parasitaemia by 85%). Each of the two neem-leaf fractions lysed 50% and 100% of developing gametocytes, at 10(-3) and 1.0 microg/ml, respectively; and 50% and 100% of mature gametocytes at 10(-3) and 10(2) microg/ml, respectively. If they are found safe and effective in vivo, the neem-leaf fractions may form the basis of new antimalarial drugs that not only cure chloroquine-sensitive and chloroquine-resistant malaria but also markedly reduce transmission.

  3. In Vivo Antimalarial Activity of Annona muricata Leaf Extract in Mice Infected with Plasmodium berghei

    PubMed Central

    Somsak, Voravuth; Polwiang, Natsuda; Chachiyo, Sukanya

    2016-01-01

    Malaria is one of the most important infectious diseases in the world. The choice for the treatment is highly limited due to drug resistance. Hence, finding the new compounds to treat malaria is urgently needed. The present study was attempted to evaluate the antimalarial activity of the Annona muricata aqueous leaf extract in Plasmodium berghei infected mice. Aqueous leaf extract of A. muricata was prepared and tested for acute toxicity in mice. For efficacy test in vivo, standard 4-day suppressive test was carried out. ICR mice were inoculated with 107 parasitized erythrocytes of P. berghei ANKA by intraperitoneal injection. The extracts (100, 500, and 1000 mg/kg) were then given orally by gavage once a day for 4 consecutive days. Parasitemia, percentage of inhibition, and packed cell volume were subsequently calculated. Chloroquine (10 mg/kg) was given to infected mice as positive control while untreated control was given only distilled water. It was found that A. muricata aqueous leaf extract at doses of 100, 500, and 1000 mg/kg resulted in dose dependent parasitemia inhibition of 38.03%, 75.25%, and 85.61%, respectively. Survival time was prolonged in infected mice treated with the extract. Moreover, no mortality to mice was observed with this extract up to a dose of 4000 mg/kg. In conclusion, the A. muricata aqueous leaf extract exerted significant antimalarial activity with no toxicity and prolonged survival time. Therefore, this extract might contain potential lead molecule for the development of a new drug for malaria treatment. PMID:27092277

  4. Quality control of the paracetamol drug by chemometrics and imaging spectroscopy in the near infrared region

    NASA Astrophysics Data System (ADS)

    Baptistao, Mariana; Rocha, Werickson Fortunato de Carvalho; Poppi, Ronei Jesus

    2011-09-01

    In this work, it was used imaging spectroscopy and chemometric tools for the development and analysis of paracetamol and excipients in pharmaceutical formulations. It was also built concentration maps to study the distribution of the drug in the tablets surface. Multivariate models based on PLS regression were developed for paracetamol and excipients concentrations prediction. For the construction of the models it was used 31 samples in the tablet form containing the active principle in a concentration range of 30.0-90.0% (w/w) and errors below to 5% were obtained for validation samples. Finally, the study of the distribution in the drug was performed through the distribution maps of concentration of active principle and excipients. The analysis of maps showed the complementarity between the active principle and excipients in the tablets. The region with a high concentration of a constituent must have, necessarily, absence or low concentration of the other one. Thus, an alternative method for the paracetamol drug quality monitoring is presented.

  5. Application of quality by design to the process development of botanical drug products: a case study.

    PubMed

    Zhang, Lei; Yan, Binjun; Gong, Xingchu; Yu, Lawrence X; Qu, Haibin

    2013-03-01

    This paper was designed to assess the value of quality by design (QbD) to improve the manufacturing process understanding of botanical drug products. Ethanol precipitation, a widely used unit operation in the manufacture of botanical drug products was employed to illustrate the use of QbD, taking the process of danshen (the dry root of Salvia miltiorrhiza Bunge) as an example. The recovery of four active pharmaceutical ingredients (APIs) and the removal of saccharides were used to represent the performance of ethanol precipitation. Potentially critical variables, including density of concentrate, ethanol consumption, and settling temperature were identified through risk assessment methods. Design of experiments (DOE) was used to evaluate the effects of the potentially critical factors on the performance of ethanol precipitation. It was observed that higher density of concentrate leads to higher removal of saccharides, but results in lower recovery of APIs. With the rise of ethanol consumption, the recovery of different APIs behaves in different ways. A potential design space of ethanol precipitation operation was established through DOE studies. The results in this work facilitate the enhanced understanding of the relationships between multiple factors (material attributes and process parameters) and the performance of ethanol precipitation. This case study demonstrated that QbD is a powerful tool to develop manufacturing process of botanical drug products.

  6. Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

    PubMed

    Kesisoglou, Filippos; Mitra, Amitava

    2015-09-01

    Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

  7. Batch-to-batch quality consistency evaluation of botanical drug products using multivariate statistical analysis of the chromatographic fingerprint.

    PubMed

    Xiong, Haoshu; Yu, Lawrence X; Qu, Haibin

    2013-06-01

    Botanical drug products have batch-to-batch quality variability due to botanical raw materials and the current manufacturing process. The rational evaluation and control of product quality consistency are essential to ensure the efficacy and safety. Chromatographic fingerprinting is an important and widely used tool to characterize the chemical composition of botanical drug products. Multivariate statistical analysis has showed its efficacy and applicability in the quality evaluation of many kinds of industrial products. In this paper, the combined use of multivariate statistical analysis and chromatographic fingerprinting is presented here to evaluate batch-to-batch quality consistency of botanical drug products. A typical botanical drug product in China, Shenmai injection, was selected as the example to demonstrate the feasibility of this approach. The high-performance liquid chromatographic fingerprint data of historical batches were collected from a traditional Chinese medicine manufacturing factory. Characteristic peaks were weighted by their variability among production batches. A principal component analysis model was established after outliers were modified or removed. Multivariate (Hotelling T(2) and DModX) control charts were finally successfully applied to evaluate the quality consistency. The results suggest useful applications for a combination of multivariate statistical analysis with chromatographic fingerprinting in batch-to-batch quality consistency evaluation for the manufacture of botanical drug products.

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

    PubMed Central

    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. Methods for implementing a medicine outlet survey: lessons from the anti-malarial market

    PubMed Central

    2013-01-01

    Background In recent years an increasing number of public investments and policy changes have been made to improve the availability, affordability and quality of medicines available to consumers in developing countries, including anti-malarials. It is important to monitor the extent to which these interventions are successful in achieving their aims using quantitative data on the supply side of the market. There are a number of challenges related to studying supply, including outlet sampling, gaining provider cooperation and collecting accurate data on medicines. This paper provides guidance on key steps to address these issues when conducting a medicine outlet survey in a developing country context. While the basic principles of good survey design and implementation are important for all surveys, there are a set of specific issues that should be considered when conducting a medicine outlet survey. Methods This paper draws on the authors’ experience of designing and implementing outlet surveys, including the lessons learnt from ACTwatch outlet surveys on anti-malarial retail supply, and other key studies in the field. Key lessons and points of debate are distilled around the following areas: selecting a sample of outlets; techniques for collecting and analysing data on medicine availability, price and sales volumes; and methods for ensuring high quality data in general. Results and conclusions The authors first consider the inclusion criteria for outlets, contrasting comprehensive versus more focused approaches. Methods for developing a reliable sampling frame of outlets are then presented, including use of existing lists, key informants and an outlet census. Specific issues in the collection of data on medicine prices and sales volumes are discussed; and approaches for generating comparable price and sales volume data across products using the adult equivalent treatment dose (AETD) are explored. The paper concludes with advice on practical considerations

  10. Review of pyronaridine anti-malarial properties and product characteristics

    PubMed Central

    2012-01-01

    Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure. PMID:22877082

  11. Muddled mechanisms: recent progress towards antimalarial target identification

    PubMed Central

    Edwards, Rachel L.; Odom John, Audrey R.

    2016-01-01

    In the past decade, malaria rates have plummeted as a result of aggressive infection control measures and the adoption of artemisinin-based combination therapies (ACTs). However, a potential crisis looms ahead. Treatment failures to standard antimalarial regimens have been reported in Southeast Asia, and devastating consequences are expected if resistance spreads to the African continent. To prevent a potential public health emergency, the antimalarial arsenal must contain therapeutics with novel mechanisms of action (MOA). An impressive number of high-throughput screening (HTS) campaigns have since been launched, identifying thousands of compounds with activity against one of the causative agents of malaria, Plasmodium falciparum. Now begins the difficult task of target identification, for which studies are often tedious, labor intensive, and difficult to interpret. In this review, we highlight approaches that have been instrumental in tackling the challenges of target assignment and elucidation of the MOA for hit compounds. Studies that apply these innovative techniques to antimalarial target identification are described, as well as the impact of the data in the field. PMID:27803804

  12. Increasing the use of 'smart' pump drug libraries by nurses: a continuous quality improvement project.

    PubMed

    Harding, Andrew D

    2012-01-01

    The use of infusion pumps that incorporate "smart" technology (smart pumps) can reduce the risks associated with receiving IV therapies. Smart pump technology incorporates safeguards such as a list of high-alert medications, soft and hard dosage limits, and a drug library that can be tailored to specific patient care areas. Its use can help to improve patient safety and to avoid potentially catastrophic harm associated with medication errors. But when one independent community hospital in Massachusetts switched from older mechanical pumps to smart pumps, it neglected to assign an "owner" to oversee the implementation process. One result was that nurses were using the smart pump library for only 37% of all infusions.To increase pump library usage percentage-thereby reducing the risks associated with infusion and improving patient safety-the hospital undertook a continuous quality improvement project over a four-month period in 2009. With the involvement of direct care nurses, and using quantitative data available from the smart pump software, the nursing quality and pharmacy quality teams identified ways to improve pump and pump library use. A secondary goal was to calculate the hospital's return on investment for the purchase of the smart pumps. Several interventions were developed and, on the first of each month, implemented. By the end of the project, pump library usage had nearly doubled; and the hospital had completely recouped its initial investment.

  13. [Definition of priority medicines for monitoring laboratory quality in Brazil: the interface between health surveillance and the National Drug Policy].

    PubMed

    Pontes Junior, Durval Martins; Pepe, Vera Lúcia Edais; Osorio-de-Castro, Claudia Garcia Serpa; Massena, Elisa Prestes; Portela, Margareth Crisóstomo; Miranda, Maria do Carmo; Silva, Raulino Sabino da

    2008-09-01

    A key objective of the Brazilian National Drug Policy is the quality of medicines supplied to the population. This study aimed to set priorities for the analysis of the National Program for Quality Control of Medicines. The main criterion was the drug's presence in at least three Pharmaceutical Care Programs under the Ministry of Health. Additional criteria were presence on the National List of Essential Drugs (RENAME) in 2002 and its indication for the 20 main causes of disability-adjusted life years (DALY). The sources were data from the Ministry of Health and related legislation. The drugs were classified according to the Anatomical Therapeutic Chemical Classification System (ATC) of the WHO. The 13 pharmaceutical care programs included 893 products classified in 449 different ATC codes. Twenty-eight drugs were considered priorities, 26 of which were listed on the RENAME and 12 indicated as causes of DALY. It is recommended that the National Health Surveillance Agency and Secretariat of Science, Technology, and Strategic Inputs establish an integrated strategy to guarantee comprehensive quality of these drugs, including laboratory quality, registration, good manufacturing practices, and information for health professionals and the general population.

  14. Plasmodium Drug Targets Outside the Genetic Control of the Parasite

    PubMed Central

    Sullivan, David J.

    2014-01-01

    Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition. PMID:22973888

  15. The Quality of Selected Essential Medicines Sold in Accredited Drug Dispensing Outlets and Pharmacies in Tanzania

    PubMed Central

    Manyanga, Vicky; Chambuso, Mhina; Liana, Jafary; Rutta, Edmund; Embrey, Martha; Layloff, Thomas; Johnson, Keith

    2016-01-01

    Introduction The purpose of this study was to investigate the quality of a select group of medicines sold in accredited drug dispensing outlets (ADDOs) and pharmacies in different regions of Tanzania as part of an in-depth cross-sectional assessment of community access to medicines and community use of medicines. Methods We collected 242 samples of amoxicillin trihydrate, artemether-lumefantrine (ALu), co-trimoxazole, ergometrine maleate, paracetamol, and quinine from selected ADDOs and pharmacies in Mbeya, Morogoro, Singida, and Tanga regions. The analysis included physical examination and testing with validated analytical techniques. Assays for eight of nine products were conducted using high-performance thin-layer chromatography (HPTLC). For ALu tablets, we used a two-tiered approach, where tier 1 was a semi-quantitative Global Pharma Health Fund-Minilab® method and tier 2 was high-performance liquid chromatography (HPLC) as described in The International Pharmacopoeia’s monograph for artemether-lumefantrine. Results and Discussion The physical examination of samples revealed no defects in the solid and oral liquid dosage forms, but unusual discoloration in an injectable solution, ergometrine maleate. For ALu, the results showed that of 38 samples, 31 (81.6%) passed tier 1 testing and 7 (18.4%) gave inconclusive drug content results. The inconclusive ALu samples were submitted for tier 2 testing and all met the quality standards. The pass rate using the HPTLC and TLC/HPLC assays was 93.8%; the failures were the ergometrine maleate samples purchased from both ADDOs and pharmacies. The disintegration testing of the solid dosage forms was conducted in accordance with US Pharmacopeia monographs. Only two samples of paracetamol, 1.2% of the solid dosage forms, failed to comply to standards. The study revealed a high overall rate of 92.6% of samples that met the quality standards. Although the overall failure rate was 7.4%, it is important to note that this was

  16. Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols

    PubMed Central

    Corrêa Soares, Juliana B. R.; Menezes, Diego; Vannier-Santos, Marcos A.; Ferreira-Pereira, Antonio; Almeida, Giulliana T.; Venancio, Thiago M.; Verjovski-Almeida, Sergio; Zishiri, Vincent K.; Kuter, David; Hunter, Roger; Egan, Timothy J.; Oliveira, Marcus F.

    2009-01-01

    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 11th to 17th 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 valid

  17. Effects of an antimalarial quinazoline derivative on human erythrocytes and on cell membrane molecular models.

    PubMed

    Rojas-Aguirre, Yareli; Hernández-Luis, Francisco; Mendoza-Martínez, César; Sotomayor, Carlos Patricio; Aguilar, Luis Felipe; Villena, Fernando; Castillo, Ivan; Hernández, David J; Suwalsky, Mario

    2012-03-01

    Plasmodium, the parasite which causes malaria in humans multiplies in the liver and then infects circulating erythrocytes. Thus, the role of the erythrocyte cell membrane in antimalarial drug activity and resistance has key importance. The effects of the antiplasmodial N(6)-(4-methoxybenzyl)quinazoline-2,4,6-triamine (M4), and its inclusion complex (M4/HPβCD) with 2-hydroxypropyl-β-cyclodextrin (HPβCD) on human erythrocytes and on cell membrane molecular models are herein reported. This work evidences that M4/HPβCD interacts with red cells as follows: a) in scanning electron microscopy (SEM) studies on human erythrocytes induced shape changes at a 10μM concentration; b) in isolated unsealed human erythrocyte membranes (IUM) a concentration as low as 1μM induced sharp DPH fluorescence anisotropy decrease whereas increasing concentrations produced a monotonically decrease of DPH fluorescence lifetime at 37°C; c) X-ray diffraction studies showed that 200μM induced a complete structural perturbation of dimyristoylphosphatidylcholine (DMPC) bilayers whereas no significant effects were detected in dimyristoylphosphatidylethanolamine (DMPE) bilayers, classes of lipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively; d) fluorescence spectroscopy data showed that increasing concentrations of the complex interacted with the deep hydrophobic core of DMPC large unilamellar vesicles (LUV) at 18°C. All these experiments are consistent with the insertion of M4/HPβCD in the outer monolayer of the human erythrocyte membrane; thus, it can be considered a promising and novel antimalarial agent.

  18. Pharmacological Properties of a New Antimalarial Bisthiazolium Salt, T3, and a Corresponding Prodrug, TE3

    PubMed Central

    Nicolas, Olivier; Margout, Delphine; Taudon, Nicolas; Wein, Sharon; Calas, Michèle; Vial, Henri J.; Bressolle, Françoise M. M.

    2005-01-01

    A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM). PMID:16127032

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

    PubMed

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

    2015-01-01

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

  20. Influence of anaesthetic drugs on the epididymal sperm quality in domestic cats.

    PubMed

    Jiménez, E; Pérez-Marín, C C; Millán, Y; Agüera, E

    2011-02-01

    The present study investigated the effect of different anaesthetic agents commonly used in cats on the fresh and frozen-thawed epididymal sperm. Seventeen male domestic cats were castrated using pentobarbital, ketamine HCl or isoflurane. Sperm samples were recovered from epididymides and evaluated before and after freezing, determining the vigor, motility, morphology, acrosome status, sperm viability and functional membrane integrity. Fresh epididymal sperm was influenced by the drugs used, noting that motility features, i.e. vigor (p≤0.05) and progressive motility (p≤0.05), were higher for the inhalation anaesthetic while the others did not showed statistical differences. In frozen-thawed sperm samples, cats treated with barbiturics showed lower values for acrosome status (p≤0.05) and integrity and functionality of membrane (p≤0.05 and p≤0.01, respectively) than in the others groups. Results suggested that drugs used for castration in cats could affect the sperm quality and this should be considered when implementing sperm cryopreservation in the feline.

  1. Quality by design case study: an integrated multivariate approach to drug product and process development.

    PubMed

    Huang, Jun; Kaul, Goldi; Cai, Chunsheng; Chatlapalli, Ramarao; Hernandez-Abad, Pedro; Ghosh, Krishnendu; Nagi, Arwinder

    2009-12-01

    To facilitate an in-depth process understanding, and offer opportunities for developing control strategies to ensure product quality, a combination of experimental design, optimization and multivariate techniques was integrated into the process development of a drug product. A process DOE was used to evaluate effects of the design factors on manufacturability and final product CQAs, and establish design space to ensure desired CQAs. Two types of analyses were performed to extract maximal information, DOE effect & response surface analysis and multivariate analysis (PCA and PLS). The DOE effect analysis was used to evaluate the interactions and effects of three design factors (water amount, wet massing time and lubrication time), on response variables (blend flow, compressibility and tablet dissolution). The design space was established by the combined use of DOE, optimization and multivariate analysis to ensure desired CQAs. Multivariate analysis of all variables from the DOE batches was conducted to study relationships between the variables and to evaluate the impact of material attributes/process parameters on manufacturability and final product CQAs. The integrated multivariate approach exemplifies application of QbD principles and tools to drug product and process development.

  2. Quality evaluation of investigator-initiated trials using post-approval cancer drugs in Japan.

    PubMed

    Kondo, Shunsuke; Hosoi, Hiroko; Hashimoto, Jun

    2017-03-07

    Investigator-initiated trials (IITs) are important aspects of medical research and have contributed substantially to modern oncology. IITs using post-approval drugs have been conducted by domestic institutions in Japan. Data from this study were obtained by all IITs registered clinical trials for five cancers (lung, colorectal cancer, gastric cancer, liver cancer, and breast cancer) using drugs approved from 1999 to 2009 in Japan. The Kaplan-Meier method, analysis of variance (ANOVA), and Kruskal-Wallis test were used to estimate time to enrolment completion (TTEC) and time to enrolment per patient (TTEP). Of 1,222 trials eligible for analysis, 465 trials (38%) completed enrolment to the studies, and 203 trials (17%) published results. In the distribution according to trial phase, 98 (8%) were phase I, 1,058 (87%) were phase I/II + II, and 66 (5%) were phase II/III + III. The accrual achievement and publication rates were higher in late-phase than in early-phase trials. The median TTEC was 1,387 days (95% confidence interval [CI], 1,302 to 1,472). The median TTEP was 38.5 days (95% CI, 34.5 to 42.5). The median TTEC and TTEP were significantly different in each trial phase (P < 0.01), funding source (P < 0.01), and publication status (median TTEC published trials vs. unpublished trial; 720 days vs. 1,672 days, median TTEP; 16 days vs. 55.8 days; P < 0.001). Many IITs using approved cancer drugs have been conducted; however, the quality of the clinical trials was low in terms of accrual achievement, publication rate, and time to publication of trial results. This article is protected by copyright. All rights reserved.

  3. Development and Optimization of a Novel 384-Well Anti-Malarial Imaging Assay Validated for High-Throughput Screening

    PubMed Central

    Duffy, Sandra; Avery, Vicky M.

    2012-01-01

    With the increasing occurrence of drug resistance in the malaria parasite, Plasmodium falciparum, there is a great need for new and novel anti-malarial drugs. We have developed a 384-well, high-throughput imaging assay for the detection of new anti-malarial compounds, which was initially validated by screening a marine natural product library, and subsequently used to screen more than 3 million data points from a variety of compound sources. Founded on another fluorescence-based P. falciparum growth inhibition assay, the DNA-intercalating dye 4′,6-diamidino-2-phenylindole, was used to monitor changes in parasite number. Fluorescent images were acquired on the PerkinElmer Opera High Throughput confocal imaging system and analyzed with a spot detection algorithm using the Acapella data processing software. Further optimization of this assay sought to increase throughput, assay stability, and compatibility with our high-throughput screening equipment platforms. The assay typically yielded Z'-factor values of 0.5–0.6, with signal-to-noise ratios of 12. PMID:22232455

  4. Phytochemical screening and in vivo antimalarial activity of extracts from three medicinal plants used in malaria treatment in Nigeria.

    PubMed

    Bankole, A E; Adekunle, A A; Sowemimo, A A; Umebese, C E; Abiodun, O; Gbotosho, G O

    2016-01-01

    The use of plant to meet health-care needs has greatly increased worldwide in the recent times. The search for new plant-derived bioactive agents that can be explored for the treatment of drug-resistant malaria infection is urgently needed. Thus, we evaluated the antimalarial activity of three medicinal plants used in Nigerian folklore for the treatment of malaria infection. A modified Peter's 4-day suppressive test was used to evaluate the antimalarial activity of the plant extracts in a mouse model of chloroquine-resistant Plasmodium berghei ANKA strain. Animals were treated with 250, 500, or 800 mg/kg of aqueous extract. It was observed that of all the three plants studied, Markhamia tomentosa showed the highest chemosuppression of parasites of 73 % followed by Polyalthia longifolia (53 %) at day 4. All the doses tested were well tolerated. Percentage suppression of parasite growth on day 4 post-infection ranged from 1 to 73 % in mice infected with P. berghei and treated with extracts when compared with chloroquine diphosphate, the standard reference drug which had a chemosuppression of 90 %. The percentage survival of mice that received extract ranged from 0 to 60 % (increased as the dose increases to 800 mg/kg). Phytochemical analysis revealed the presence of tannins, saponins, and phenolic compounds in all the three plants tested.

  5. Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains

    PubMed Central

    Yang, Tuo; Xie, Stanley C.; Cao, Pengxing; Giannangelo, Carlo; McCaw, James; Creek, Darren J.; Charman, Susan A.; Klonis, Nectarios

    2016-01-01

    Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective. PMID:27161632

  6. The potential of anti-malarial compounds derived from African medicinal plants, part I: a pharmacological evaluation of alkaloids and terpenoids

    PubMed Central

    2013-01-01

    Traditional medicine caters for about 80% of the health care needs of many rural populations around the world, especially in developing countries. In addition, plant-derived compounds have played key roles in drug discovery. Malaria is currently a public health concern in many countries in the world due to factors such as chemotherapy faced by resistance, poor hygienic conditions, poorly managed vector control programmes and no approved vaccines. In this review, an attempt has been made to assess the value of African medicinal plants for drug discovery by discussing the anti-malarial virtue of the derived phytochemicals that have been tested by in vitro and in vivo assays. This survey was focused on pure compounds derived from African flora which have exhibited anti-malarial properties with activities ranging from “very active” to “weakly active”. However, only the compounds which showed anti-malarial activities from “very active” to “moderately active” are discussed in this review. The activity of 278 compounds, mainly alkaloids, terpenoids, flavonoids, coumarines, phenolics, polyacetylenes, xanthones, quinones, steroids, and lignans have been discussed. The first part of this review series covers the activity of 171 compounds belonging to the alkaloid and terpenoid classes. Data available in the literature indicated that African flora hold an enormous potential for the development of phytomedicines for malaria. PMID:24330395

  7. The potential of anti-malarial compounds derived from African medicinal plants, part I: a pharmacological evaluation of alkaloids and terpenoids.

    PubMed

    Amoa Onguéné, Pascal; Ntie-Kang, Fidele; Lifongo, Lydia Likowo; Ndom, Jean Claude; Sippl, Wolfgang; Mbaze, Luc Meva'a

    2013-12-13

    Traditional medicine caters for about 80% of the health care needs of many rural populations around the world, especially in developing countries. In addition, plant-derived compounds have played key roles in drug discovery. Malaria is currently a public health concern in many countries in the world due to factors such as chemotherapy faced by resistance, poor hygienic conditions, poorly managed vector control programmes and no approved vaccines. In this review, an attempt has been made to assess the value of African medicinal plants for drug discovery by discussing the anti-malarial virtue of the derived phytochemicals that have been tested by in vitro and in vivo assays. This survey was focused on pure compounds derived from African flora which have exhibited anti-malarial properties with activities ranging from "very active" to "weakly active". However, only the compounds which showed anti-malarial activities from "very active" to "moderately active" are discussed in this review. The activity of 278 compounds, mainly alkaloids, terpenoids, flavonoids, coumarines, phenolics, polyacetylenes, xanthones, quinones, steroids, and lignans have been discussed. The first part of this review series covers the activity of 171 compounds belonging to the alkaloid and terpenoid classes. Data available in the literature indicated that African flora hold an enormous potential for the development of phytomedicines for malaria.

  8. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  9. Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1

    PubMed Central

    Capper, Michael J.; O’Neill, Paul M.; Fisher, Nicholas; Strange, Richard W.; Moss, Darren; Ward, Stephen A.; Berry, Neil G.; Lawrenson, Alexandre S.; Hasnain, S. Samar; Biagini, Giancarlo A.; Antonyuk, Svetlana V.

    2015-01-01

    Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles. PMID:25564664

  10. Identifying and assessing highly hazardous drugs within quality risk management programs.

    PubMed

    Sussman, Robert G; Schatz, Anthony R; Kimmel, Tracy A; Ader, Allan; Naumann, Bruce D; Weideman, Patricia A

    2016-08-01

    Historically, pharmaceutical industry regulatory guidelines have assigned certain active pharmaceutical ingredients (APIs) to various categories of concern, such as "cytotoxic", "hormones", and "steroids". These categories have been used to identify APIs requiring segregation or dedication in order to prevent cross-contamination and protect the quality and safety of drug products. Since these terms were never defined by regulatory authorities, and many novel pharmacological mechanisms challenge these categories, there is a recognized need to modify the historical use of these terms. The application of a risk-based approach using a health-based limit, such as an acceptable daily exposure (ADE), is more appropriate for the development of a Quality Risk Management Program (QRMP) than the use of categories of concern. The toxicological and pharmacological characteristics of these categories are discussed to help identify and prioritize compounds requiring special attention. Controlling airborne concentrations and the contamination of product contact surfaces in accordance with values derived from quantitative risk assessments can prevent adverse effects in workers and patients, regardless of specific categorical designations to which these APIs have been assigned. The authors acknowledge the movement away from placing compounds into categories and, while not yet universal, the importance of basing QRMPs on compound-specific ADEs and risk assessments. Based on the results of a risk assessment, segregation and dedication may also be required for some compounds to prevent cross contamination during manufacture of APIs.

  11. Comparison of indicators assessing the quality of drug prescribing for asthma.

    PubMed Central

    Veninga, C C; Denig, P; Pont, L G; Haaijer-Ruskamp, F M

    2001-01-01

    OBJECTIVE: To compare different indicators for assessing the quality of drug prescribing and establish their agreement in identifying doctors who may not adhere to treatment guidelines. DATA SOURCES/STUDY SETTING: Data from 181 general practitioners (GPs) from The Netherlands. The case of asthma is used as an example because, in this area, different quality indicators exist whose validity is questioned. The study is part of the European Drug Education Project. STUDY DESIGN: Spearman rank correlations were assessed among the GPs' scores on self-report instruments, aggregated prescribing indicators, and individualized prescribing indicators. Kappa values were calculated as agreement measures for identifying low adherence to the guidelines. DATA COLLECTION: Prescribing data from GPs were collected through pharmacies, public health insurance companies, or computerized GP databases. Two self-report instruments were mailed to the GPs. The GPs first received a questionnaire assessing their competence regarding the treatment of asthma patients. Three months later they received a series of 16 written asthma cases asking for their intended treatment for each case. PRINCIPAL FINDINGS: Correlations between scores based on self-report instruments and indicators based on actual prescribing data were mostly nonsignificant and varied between 0 and 0.21. GPs identified as not adhering to the guidelines by the prescribing indicators often had high scores on the self-report instruments. Correlations between 0.20 and 0.55 were observed among indicators based on aggregated prescribing data and those based on individualized data. The agreement for identifying low adherence was small, with kappa values ranging from 0.19 to 0.30. CONCLUSIONS: Indicators based on self-report instruments seem to overestimate guideline adherence. Indicators assessing prescribing quality at an aggregated level give clearly different results, as compared to indicators evaluating prescribing data on an

  12. When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis

    PubMed Central

    Scannell, Jack W.; Bosley, Jim

    2016-01-01

    A striking contrast runs through the last 60 years of biopharmaceutical discovery, research, and development. Huge scientific and technological gains should have increased the quality of academic science and raised industrial R&D efficiency. However, academia faces a "reproducibility crisis"; inflation-adjusted industrial R&D costs per novel drug increased nearly 100 fold between 1950 and 2010; and drugs are more likely to fail in clinical development today than in the 1970s. The contrast is explicable only if powerful headwinds reversed the gains and/or if many "gains" have proved illusory. However, discussions of reproducibility and R&D productivity rarely address this point explicitly. The main objectives of the primary research in this paper are: (a) to provide quantitatively and historically plausible explanations of the contrast; and (b) identify factors to which R&D efficiency is sensitive. We present a quantitative decision-theoretic model of the R&D process. The model represents therapeutic candidates (e.g., putative drug targets, molecules in a screening library, etc.) within a “measurement space", with candidates' positions determined by their performance on a variety of assays (e.g., binding affinity, toxicity, in vivo efficacy, etc.) whose results correlate to a greater or lesser degree. We apply decision rules to segment the space, and assess the probability of correct R&D decisions. We find that when searching for rare positives (e.g., candidates that will successfully complete clinical development), changes in the predictive validity of screening and disease models that many people working in drug discovery would regard as small and/or unknowable (i.e., an 0.1 absolute change in correlation coefficient between model output and clinical outcomes in man) can offset large (e.g., 10 fold, even 100 fold) changes in models’ brute-force efficiency. We also show how validity and reproducibility correlate across a population of simulated screening and

  13. When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis.

    PubMed

    Scannell, Jack W; Bosley, Jim

    2016-01-01

    A striking contrast runs through the last 60 years of biopharmaceutical discovery, research, and development. Huge scientific and technological gains should have increased the quality of academic science and raised industrial R&D efficiency. However, academia faces a "reproducibility crisis"; inflation-adjusted industrial R&D costs per novel drug increased nearly 100 fold between 1950 and 2010; and drugs are more likely to fail in clinical development today than in the 1970s. The contrast is explicable only if powerful headwinds reversed the gains and/or if many "gains" have proved illusory. However, discussions of reproducibility and R&D productivity rarely address this point explicitly. The main objectives of the primary research in this paper are: (a) to provide quantitatively and historically plausible explanations of the contrast; and (b) identify factors to which R&D efficiency is sensitive. We present a quantitative decision-theoretic model of the R&D process. The model represents therapeutic candidates (e.g., putative drug targets, molecules in a screening library, etc.) within a "measurement space", with candidates' positions determined by their performance on a variety of assays (e.g., binding affinity, toxicity, in vivo efficacy, etc.) whose results correlate to a greater or lesser degree. We apply decision rules to segment the space, and assess the probability of correct R&D decisions. We find that when searching for rare positives (e.g., candidates that will successfully complete clinical development), changes in the predictive validity of screening and disease models that many people working in drug discovery would regard as small and/or unknowable (i.e., an 0.1 absolute change in correlation coefficient between model output and clinical outcomes in man) can offset large (e.g., 10 fold, even 100 fold) changes in models' brute-force efficiency. We also show how validity and reproducibility correlate across a population of simulated screening and

  14. In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria

    PubMed Central

    Nondo, Ramadhani S.O.; Erasto, Paul; Moshi, Mainen J.; Zacharia, Abdallah; Masimba, Pax J.; Kidukuli, Abdul W.

    2016-01-01

    Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 107 erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria. PMID:27144154

  15. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    PubMed Central

    Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

    2016-01-01

    Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

  16. Antimalarials during pregnancy: a cost-effectiveness analysis.

    PubMed Central

    Schultz, L. J.; Steketee, R. W.; Chitsulo, L.; Wirima, J. J.

    1995-01-01

    Antenatal clinics (ANC) provide an avenue for interventions that promote maternal and infant health. In areas hyperendemic for Plasmodium falciparum, malaria infection during pregnancy contributes to low birth weight (LBW), which is the greatest risk factor for neonatal mortality. Using current data and costs from studies in Malawi, a decision-analysis model was constructed to predict the number of LBW cases prevented by three antimalarial regimens, in an area with a high prevalence of chloroquine (CQ)-resistant malaria. Factors considered included local costs of antimalarials, number of ANC visits, compliance with dispensed antimalarials, prevalence of placental malaria, and LBW incidence. For a hypothetical cohort of 10,000 women in their first or second pregnancy, a regimen consisting of one dose of sulfadoxine-pyrimethamine (SP) in the second trimester followed by a second dose at the beginning of the third trimester would prevent 205 cases of LBW at a cost of US$ 9.66 per case of LBW prevented. A regimen using a treatment dose of SP followed by CQ 300 mg (base) weekly would prevent 59 cases of LBW at a cost of $62 per case prevented, compared with only 30 cases of LBW prevented at a cost of $113 per case when the regimen involves initial treatment with CQ (25 mg/kg) followed by CQ 300 mg (base) weekly. In areas hyperendemic for CQ-resistant P. falciparum, a two-dose SP regimen is a cost-effective intervention to reduce LBW incidence and it should be included as part of the antenatal care package. PMID:7743592

  17. An Exploration of Quality of Life and Its Predictors in Patients with Addictive Disorders: Gambling, Alcohol and Drugs

    ERIC Educational Resources Information Center

    Manning, Victoria; Gomez, Brenda; Guo, Song; Low, Yee Deng; Koh, Puay Kee; Wong, Kim Eng

    2012-01-01

    The study set out to examine Quality of Life (QoL), specifically subjective well being in three different addiction populations (260 alcohol-dependent, 282 drug-dependent, and 132 pathological gambling outpatients) at their first visit to treatment, using the Personal Well being Index (PWI). The mean PWI score for all patients was significantly…

  18. A rapid HPLC procedure for analysis of analgesic pharmaceutical mixtures for quality assurance and drug diversion testing.

    PubMed

    Wolf, Carl E; Poklis, Alphonse

    2005-10-01

    A simple high-performance liquid chromatographic (HPLC) method that allows for the rapid identification and quantification of analgesic and anesthetic solutions typically used in surgical procedures or patient controlled analgesia is presented. The separation of bupivacaine, clonidine, fentanyl, hydromorphone, midazolam, and morphine is complete in less than 20 min. The method allows test solutions to be either directly injected or diluted prior to injection into the HPLC system. The method is useful from the standpoint that pharmaceutical preparations are usually submitted with the known drug of interest and expected concentration. The method is also useful for initial screening of solutions submitted that are either unknown or of questionable identity. The method has been successfully applied as part of hospital-based quality control and quality assurance programs to detect not only errors in the preparation of solutions of scheduled drugs, but also to uncover illegal diversion of drugs of abuse by medical personnel.

  19. Quality of life, depression, anxiety and suicidal ideation among men who inject drugs in Delhi, India

    PubMed Central

    2013-01-01

    Background Mental disorders such as depression, anxiety and suicide represent an important public health problem in India. Elsewhere in the world a high prevalence of symptoms of common mental disorders have been found among people who inject drugs (PWID). Research in India has largely overlooked symptoms of common mental disorders among this high risk group. This paper reports on the results of a survey examining quality of life, depression, anxiety and suicidal ideation among adult males who inject drugs living in Delhi. Methods Participants (n = 420) were recruited from needle and syringe programs using time location sampling and were interviewed using an interviewer-administered questionnaire. Self-report symptom scales were used to measure the severity of symptoms of depression (PHQ-9) and anxiety (GAD-2) within the preceding 2 weeks. We assessed the presence of suicidal thoughts and attempts within the past 12 months. Results The mean length of injecting career was 20.9 years indicating a sample of chronic injecting drug users, of whom only one-third (38%) were born in Delhi. The level of illiteracy was very high (62%), and just 2% had completed class 12. Scavenging / rag picking was the main form of income for 48%, and many were homeless (69%). One-third (33%) had been beaten up at least twice during the preceding 6 months, and many either never (45%) or rarely (27%) attended family events. We found a high prevalence of depressive (84%, cut-off ≥10) and anxiety (71%, cut-off score of ≥3) symptoms. Fifty-three percent thought about killing themselves in the past 12 months, and 36% had attempted to kill themselves. Conclusions Our findings revealed a socially excluded population of PWID in Delhi who have minimal education and are often homeless, leaving them vulnerable to physical violence, poverty, poor health, imprisonment and disconnection from family. The high prevalence of psychological distress found in this study has implications for

  20. Application of quality by design (QbD) approach to ultrasonic atomization spray coating of drug-eluting stents.

    PubMed

    McDermott, Martin; Chatterjee, Sharmista; Hu, Xiaoli; Ash-Shakoor, Ariel; Avery, Reginald; Belyaeva, Anastasiya; Cruz, Celia; Hughes, Minerva; Leadbetter, Joanne; Merkle, Conrad; Moot, Taylor; Parvinian, Sepideh; Patwardhan, Dinesh; Saylor, David; Tang, Nancy; Zhang, Tina

    2015-08-01

    The drug coating process for coated drug-eluting stents (DES) has been identified as a key source of inter- and intra-batch variability in drug elution rates. Quality-by-design (QbD) principles were applied to gain an understanding of the ultrasonic spray coating process of DES. Statistically based design of experiments (DOE) were used to understand the relationship between ultrasonic atomization spray coating parameters and dependent variables such as coating mass ratio, roughness, drug solid state composite microstructure, and elution kinetics. Defect-free DES coatings composed of 70% 85:15 poly(DL-lactide-co-glycolide) and 30% everolimus were fabricated with a constant coating mass. The drug elution profile was characterized by a mathematical model describing biphasic release kinetics. Model coefficients were analyzed as a DOE response. Changes in ultrasonic coating processing conditions resulted in substantial changes in roughness and elution kinetics. Based on the outcome from the DOE study, a design space was defined in terms of the critical coating process parameters resulting in optimum coating roughness and drug elution. This QbD methodology can be useful to enhance the quality of coated DES.

  1. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries

    PubMed Central

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Torres Rueda, Sergio; Kiefer, Sabine; O’Connell, Kate; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Poyer, Stephen; Chavasse, Desmond

    2016-01-01

    The private for-profit sector is an important source of treatment for malaria. However, private patients face high prices for the recommended treatment for uncomplicated malaria, artemisinin combination therapies (ACTs), which makes them more likely to receive cheaper, less effective non-artemisinin therapies (nATs). This study seeks to better understand consumer antimalarial prices by documenting and exploring the pricing behaviour of retailers and wholesalers. Using data collected in 2009–10, we present survey estimates of antimalarial retail prices, and wholesale- and retail-level price mark-ups from six countries (Benin, Cambodia, the Democratic Republic of Congo, Nigeria, Uganda and Zambia), along with qualitative findings on factors affecting pricing decisions. Retail prices were lowest for nATs, followed by ACTs and artemisinin monotherapies (AMTs). Retailers applied the highest percentage mark-ups on nATs (range: 40% in Nigeria to 100% in Cambodia and Zambia), whereas mark-ups on ACTs (range: 22% in Nigeria to 71% in Zambia) and AMTs (range: 22% in Nigeria to 50% in Uganda) were similar in magnitude, but lower than those applied to nATs. Wholesale mark-ups were generally lower than those at retail level, and were similar across antimalarial categories in most countries. When setting prices wholesalers and retailers commonly considered supplier prices, prevailing market prices, product availability, product characteristics and the costs related to transporting goods, staff salaries and maintaining a property. Price discounts were regularly used to encourage sales and were sometimes used by wholesalers to reward long-term customers. Pricing constraints existed only in Benin where wholesaler and retailer mark-ups are regulated; however, unlicensed drug vendors based in open-air markets did not adhere to the pricing regime. These findings indicate that mark-ups on antimalarials are reasonable. Therefore, improving ACT affordability would be most readily

  2. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries.

    PubMed

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Torres Rueda, Sergio; Kiefer, Sabine; O'Connell, Kate; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Poyer, Stephen; Chavasse, Desmond

    2016-03-01

    The private for-profit sector is an important source of treatment for malaria. However, private patients face high prices for the recommended treatment for uncomplicated malaria, artemisinin combination therapies (ACTs), which makes them more likely to receive cheaper, less effective non-artemisinin therapies (nATs). This study seeks to better understand consumer antimalarial prices by documenting and exploring the pricing behaviour of retailers and wholesalers. Using data collected in 2009-10, we present survey estimates of antimalarial retail prices, and wholesale- and retail-level price mark-ups from six countries (Benin, Cambodia, the Democratic Republic of Congo, Nigeria, Uganda and Zambia), along with qualitative findings on factors affecting pricing decisions. Retail prices were lowest for nATs, followed by ACTs and artemisinin monotherapies (AMTs). Retailers applied the highest percentage mark-ups on nATs (range: 40% in Nigeria to 100% in Cambodia and Zambia), whereas mark-ups on ACTs (range: 22% in Nigeria to 71% in Zambia) and AMTs (range: 22% in Nigeria to 50% in Uganda) were similar in magnitude, but lower than those applied to nATs. Wholesale mark-ups were generally lower than those at retail level, and were similar across antimalarial categories in most countries. When setting prices wholesalers and retailers commonly considered supplier prices, prevailing market prices, product availability, product characteristics and the costs related to transporting goods, staff salaries and maintaining a property. Price discounts were regularly used to encourage sales and were sometimes used by wholesalers to reward long-term customers. Pricing constraints existed only in Benin where wholesaler and retailer mark-ups are regulated; however, unlicensed drug vendors based in open-air markets did not adhere to the pricing regime. These findings indicate that mark-ups on antimalarials are reasonable. Therefore, improving ACT affordability would be most readily

  3. A novel prediction approach for antimalarial activities of Trimethoprim, Pyrimethamine, and Cycloguanil analogues using extremely randomized trees.

    PubMed

    Nattee, Cholwich; Khamsemanan, Nirattaya; Lawtrakul, Luckhana; Toochinda, Pisanu; Hannongbua, Supa

    2017-01-01

    Malaria is still one of the most serious diseases in tropical regions. This is due in part to the high resistance against available drugs for the inhibition of parasites, Plasmodium, the cause of the disease. New potent compounds with high clinical utility are urgently needed. In this work, we created a novel model using a regression tree to study structure-activity relationships and predict the inhibition constant, Ki of three different antimalarial analogues (Trimethoprim, Pyrimethamine, and Cycloguanil) based on their molecular descriptors. To the best of our knowledge, this work is the first attempt to study the structure-activity relationships of all three analogues combined. The most relevant descriptors and appropriate parameters of the regression tree are harvested using extremely randomized trees. These descriptors are water accessible surface area, Log of the aqueous solubility, total hydrophobic van der Waals surface area, and molecular refractivity. Out of all possible combinations of these selected parameters and descriptors, the tree with the strongest coefficient of determination is selected to be our prediction model. Predicted Ki values from the proposed model show a strong coefficient of determination, R(2)=0.996, to experimental Ki values. From the structure of the regression tree, compounds with high accessible surface area of all hydrophobic atoms (ASA_H) and low aqueous solubility of inhibitors (Log S) generally possess low Ki values. Our prediction model can also be utilized as a screening test for new antimalarial drug compounds which may reduce the time and expenses for new drug development. New compounds with high predicted Ki should be excluded from further drug development. It is also our inference that a threshold of ASA_H greater than 575.80 and Log S less than or equal to -4.36 is a sufficient condition for a new compound to possess a low Ki.

  4. Antimalarial evaluation of the chemical constituents of hairy root culture of Bixa orellana L.

    PubMed

    Zhai, Bo; Clark, Julie; Ling, Taotao; Connelly, Michele; Medina-Bolivar, Fabricio; Rivas, Fatima

    2014-01-08

    Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug-resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

  5. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials.

    PubMed

    Mackenzie, A H

    1983-07-18

    No eye disease was detected in over 900 rheumatoid arthritis patients treated with less than 4.0 mg/kg per day of chloroquine or less than 6.5 mg/kg per day of hydroxychloroquine for a mean of about seven years. I therefore consider these dosage rates safe, since they are below the threshold of retinal toxicity. This is based on more than 6,000 patient-years of drug exposure. That dosage threshold for retinopathy appears to be 5.1 mg/kg per day for chloroquine and 7.8 mg/kg per day for hydroxychloroquine according to my studies with these compounds. The daily dosage rate, rather than total drug accumulation, seems to determine the development of eye disease. To prevent overdosage, dosing should be calculated not on the actual weight of the patient but on ideal (lean) body weight. Furthermore, the patient's renal and liver function should also be taken into account to avoid overdosage. Since exposure to light amplifies the risk of retinopathy in patients treated with antimalarials, dark sunglasses are recommended for patients spending much time in sunlight.

  6. Synthesis, antimalarial activity in vitro and docking studies of novel neolignan derivatives.

    PubMed

    Pereira, Glaécia A N; Souza, Gisele C; Santos, Lourivaldo S; Barata, Lauro E S; Meneses, Carla C F; Krettli, Antoniana U; Daniel-Ribeiro, Cláudio Tadeu; Alves, Cláudio Nahum

    2017-02-28

    The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors has left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and Anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and, (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain-2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine-resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs. This article is protected by copyright. All rights reserved.

  7. Exploring the scope of new arylamino alcohol derivatives: Synthesis, antimalarial evaluation, toxicological studies, and target exploration.

    PubMed

    Quiliano, Miguel; Mendoza, Adela; Fong, Kim Y; Pabón, Adriana; Goldfarb, Nathan E; Fabing, Isabelle; Vettorazzi, Ariane; López de Cerain, Adela; Dunn, Ben M; Garavito, Giovanny; Wright, David W; Deharo, Eric; Pérez-Silanes, Silvia; Aldana, Ignacio; Galiano, Silvia

    2016-12-01

    Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 μM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 μM and C235 IC50 ≤ 0.28 μM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism.

  8. Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

    PubMed Central

    Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

    2012-01-01

    Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation. PMID:22649514

  9. Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds.

    PubMed

    Skinner-Adams, Tina S; Lowther, Jonathan; Teuscher, Franka; Stack, Colin M; Grembecka, Jolanta; Mucha, Artur; Kafarski, Pawel; Trenholme, Katharine R; Dalton, John P; Gardiner, Donald L

    2007-11-29

    Previous studies have pinpointed the M17 leucyl aminopeptidase of Plasmodium falciparum (PfLAP) as a target for the development of new antimalarials. This metallo-exopeptidase functions in the terminal stages of hemoglobin digestion and is inhibited by bestatin, a natural analog of Phe-Leu. By screening novel phosphinate dipeptide analogues for inhibitory activity against recombinant PfLAP, we have discovered two compounds, 4 (hPheP[CH2]Phe) and 5 (hPheP[CH2]Tyr), with inhibitory constants better than bestatin. These compounds are fast, tight-binding inhibitors that make improved contacts within the active site of PfLAP. Both compounds inhibit the growth of P. falciparum in vitro, exhibiting IC50 values against the chloroquine-resistant clone Dd2 of 20-40 and 12-23 muM, respectively. While bestatin exhibited some in vivo activity against Plasmodium chabaudi chabaudi, compound 4 reduced parasite burden by 92%. These studies establish the PfLAP as a prime target for the development of antimalarial drugs and provide important new lead compounds.

  10. Synthesis and biological evaluation of acridine derivatives as antimalarial agents.

    PubMed

    Yu, Xiao-Min; Ramiandrasoa, Florence; Guetzoyan, Lucie; Pradines, Bruno; Quintino, Edgar; Gadelle, Daniele; Forterre, Patrick; Cresteil, Thierry; Mahy, Jean-Pierre; Pethe, Stéphanie

    2012-04-01

    New N-alkylaminoacridine derivatives attached to nitrogen heterocycles were synthesized, and their antimalarial potency was examined. They were tested in vitro against the growth of Plasmodium falciparum, including chloroquine (CQ)-susceptible and CQ-resistant strains. This biological evaluation has shown that the presence of a heterocyclic ring significantly increases the activity against P. falciparum. The best compound shows a nanomolar IC(50) value toward parasite proliferation on both CQ-susceptible and CQ-resistant strains. The antimalarial activity of these new acridine derivatives can be explained by the two mechanisms studied in this work. First, we showed the capacity of these compounds to inhibit heme biocrystallization, a detoxification process specific to the parasite and essential for its survival. Second, in our search for alternative targets, we evaluated the in vitro inhibitory activity of these compounds toward Sulfolobus shibatae topoisomerase VI-mediated DNA relaxation. The preliminary results obtained reveal that all tested compounds are potent DNA intercalators, and significantly inhibit the activity of S. shibatae topoisomerase VI at concentrations ranging between 2.0 and 2.5 μM.

  11. Cytotoxic and antimalarial constituents from the roots of Eurycoma longifolia.

    PubMed

    Kuo, Ping-Chung; Damu, Amooru G; Lee, Kuo-Hsiung; Wu, Tian-Shung

    2004-02-01

    Sixty-five compounds were isolated from the roots of Eurycoma longifolia and characterized by comprehensive analyses of their 1D and 2D NMR, and mass spectral data. Among these isolates, four quassinoid diterpenoids were reported from natural sources for the first time, namely eurycomalide A (1), eurycomalide B (2), 13beta, 21-dihydroxyeurycomanol (3), and 5alpha, 14beta, 15beta-trihydroxyklaineanone (4). Screening of cytotoxicity, anti-HIV and antimalarial activity of these isolated compounds was also furnished by in vitro assays. Compounds 12, 13, 17, 18, 36, 38, 59, and 62 demonstrated strong cytotoxicity toward human lung cancer (A-549) cell lines, however, 12, 13, 17, 38, 57, 58, and 59 exhibited strong cytoxicity toward human breast cancer (MCF-7) cell lines. Compounds 57 and 58 displayed potent antimalarial activity against the resistant Plasmodium falciparum. The thorough studies on the stereochemistry of the different quassinoid diterpenoids provide a clear reference to the scientists who are interested on this field.

  12. Mass drug administration for malaria

    PubMed Central

    Poirot, Eugenie; Skarbinski, Jacek; Sinclair, David; Kachur, S Patrick; Slutsker, Laurence; Hwang, Jimee

    2013-01-01

    Background Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended. With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission. Objectives To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA-associated adverse events. Search methods We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013. We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings. Selection criteria Cluster-randomized trials and non-randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before-and-after studies comparing post-MDA to baseline data were selected. Studies administering intermittent preventive treatment (IPT) to sub-populations (for example, pregnant women, children or infants) were excluded. Data collection and analysis Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias. Studies were stratified by study design and then subgrouped by endemicity, by co-administration of 8-aminoquinoline plus schizonticide drugs and by plasmodium species. The quality of evidence was assessed using the GRADE approach. Main results Two cluster-randomized trials, eight non-randomized controlled studies and 22 uncontrolled before-and-after studies are included in this review. Twenty-two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were

  13. The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death.

    PubMed

    Qiao, Shuxi; Tao, Shasha; Rojo de la Vega, Montserrat; Park, Sophia L; Vonderfecht, Amanda A; Jacobs, Suesan L; Zhang, Donna D; Wondrak, Georg T

    2013-12-01

    Pharmacological inhibition of autophagic-lysosomal function has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Repurposing approved and abandoned non-oncological drugs is an alternative approach to the identification and development of anticancer therapeutics, and antimalarials that target autophagic-lysosomal functions have recently attracted considerable attention as candidates for oncological repurposing. Since cumulative research suggests that dependence on autophagy represents a specific vulnerability of malignant melanoma cells, we screened a focused compound library of antimalarials for antimelanoma activity. Here we report for the first time that amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine. Monitoring an established set of protein markers (LAMP1, LC3-II, SQSTM1) and cell ultrastructural changes detected by electron microscopy, we observed that AQ treatment caused autophagic-lysosomal blockade in malignant A375 melanoma cells, a finding substantiated by detection of rapid inactivation of lysosomal cathepsins (CTSB, CTSL, CTSD). AQ-treatment was associated with early induction of energy crisis (ATP depletion) and sensitized melanoma cells to either starvation- or chemotherapeutic agent-induced cell death. AQ displayed potent antiproliferative effects, and gene expression array analysis revealed changes at the mRNA (CDKN1A, E2F1) and protein level (TP53, CDKN1A, CCND1, phospho-RB1 [Ser 780]/[Ser 807/811], E2F1) consistent with the observed proliferative blockade in S-phase. Taken together, our data suggest that the clinical antimalarial AQ is a promising candidate for repurposing efforts that aim at targeting autophagic-lysosomal function and proliferative control in malignant melanoma cells.

  14. Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether.

    PubMed

    Honda, Masashi; Muroi, Yuka; Tamaki, Yuichiro; Saigusa, Daisuke; Suzuki, Naoto; Tomioka, Yoshihisa; Matsubara, Yoichi; Oda, Akifumi; Hirasawa, Noriyasu; Hiratsuka, Masahiro

    2011-10-01

    Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin. The intrinsic clearance (V(max)/K(m)) of CYP2B6 was 6-fold higher than that of CYP3A4. AM demethylation activity was correlated with CYP2B6 protein levels (P = 0.004); however, it was not correlated with CYP3A4 protein levels (P = 0.27) in human liver microsomes. Wild-type CYP2B6.1 and 25 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.21 and CYP2B6.23-CYP2B6.27) were heterologously expressed in COS-7 cells. In vitro analysis revealed no enzymatic activity in 5 variants (CYP2B6.8, CYP2B6.12, CYP2B6.18, CYP2B6.21, and CYP2B6.24), lower activity in 7 variants (CYP2B6.10, CYP2B6.11, CYP2B6.14, CYP2B6.15, CYP2B6.16, CYP2B6.20, and CYP2B6.27), and higher activity in 4 variants (CYP2B6.2, CYP2B6.4, CYP2B6.6, and CYP2B6.19), compared with that of wild-type CYP2B6.1. In kinetic analysis, 3 variants (CYP2B6.2, CYP2B6.4, and CYP2B6.6) exhibited significantly higher V(max), and 3 variants (CYP2B6.14, CYP2B6.20 and CYP2B6.27) exhibited significantly lower V(max) compared with that of CYP2B6.1. This functional analysis of CYP2B6 variants could provide useful information for individualization of antimalarial drug therapy.

  15. 78 FR 31943 - Draft Guidance for Industry on Contract Manufacturing Arrangements for Drugs: Quality Agreements...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-28

    ... each party (or all parties) involved in the contract manufacturing of drugs subject to Current Good... for the manufacturing of drugs. This draft guidance is being issued consistent with FDA's good... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Contract...

  16. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... operations. You must oversee production operations to ensure that each PET drug meets the requirements of the... of a PET drug. (c) Specifications and processes. You must approve or reject, before implementation..., and purity of a PET drug. You must demonstrate that any change does not adversely affect the...

  17. Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

    PubMed Central

    Nunes, Renata Rachide; Costa, Marina dos Santos; Santos, Bianca dos Reis; da Fonseca, Amanda Luisa; Ferreira, Lorena Sales; Chagas, Rafael Cesar Russo; da Silva, Alisson Marques; Varotti, Fernando de Pilla; Taranto, Alex Gutterres

    2016-01-01

    The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays. PMID:27982302

  18. A high efficiency, high quality and low cost internal regulated bioanalytical laboratory to support drug development needs.

    PubMed

    Song, Yan; Dhodda, Raj; Zhang, Jun; Sydor, Jens

    2014-05-01

    In the recent past, we have seen an increase in the outsourcing of bioanalysis in pharmaceutical companies in support of their drug development pipeline. This trend is largely driven by the effort to reduce internal cost, especially in support of late-stage pipeline assets where established bioanalytical assays are used to analyze a large volume of samples. This article will highlight our perspective of how bioanalytical laboratories within pharmaceutical companies can be developed into the best partner in the advancement of drug development pipelines with high-quality support at competitive cost.

  19. Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional foods.

    PubMed

    Graziose, Rocky; Lila, Mary Ann; Raskin, Ilya

    2010-03-01

    Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements.

  20. Merging Traditional Chinese Medicine with Modern Drug Discovery Technologies to Find Novel Drugs and Functional Foods

    PubMed Central

    Graziose, Rocky; Lila, Mary Ann; Raskin, Ilya

    2011-01-01

    Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements. PMID:20156139

  1. Effect of a Primary Care based Brief Intervention Trial among Risky Drug Users on Health-related Quality of Life

    PubMed Central

    Baumeister, Sebastian E.; Gelberg, Lillian; Leake, Barbara D.; Yacenda-Murphy, Julia; Vahidi, Mani; Andersen, Ronald M.

    2014-01-01

    Background Improvement in quality of life (QOL) is a long term goal of drug treatment. Although some brief interventions have been found to reduce illicit drug use, no trial among adult risky (moderate non-dependent) drug users has tested effects on health-related quality of life. Methods A single-blind randomized controlled trial of patients enrolled from February 2011 to November 2012 was conducted in waiting rooms of five federally qualified health centers. 413 adult primary care patients were identified as risky drug users using the WHO-ASSIST and 334 (81% response; 171 intervention, 163 control) consented to participate in the trial. Three-month follow-ups were completed by 261 patients (78%). Intervention patients received the QUIT intervention of brief clinician advice and up to two drug-use health telephone sessions. The control group received usual care and information on cancer screening. Outcomes were three-month changes in the Short Form Health Survey (SF-12) mental health component summary score (MCS) and physical health component summary score (PCS). Results The average treatment effect (ATE) was non-significant for MCS (0.2 points, p-value=0.87) and marginally significant for PCS (1.7 points, p-value=0.08). The average treatment effect on the treated (ATT) was 0.1 (p-value=0.93) for MCS and 1.9 (p-value=0.056) for PCS. The effect on PCS was stronger at higher (above median) baseline number of drug use days: ATE=2.7, p-value=0.04; ATT=3.21, p-value=0.02. Conclusions The trial found a marginally significant effect on improvement in PCS, and significant and stronger effect on the SF-12 physical component among patients with greater frequency of initial drug use. PMID:25042213

  2. Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria

    PubMed Central

    White, Nicholas J.; Duong, Tran T.; Uthaisin, Chirapong; Nosten, François; Phyo, Aung P.; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chuthasmit, Kittiphum; Cheung, Ming S.; Feng, Yiyan; Li, Ruobing; Magnusson, Baldur; Sultan, Marc; Wieser, Daniela; Xun, Xiaolei; Zhao, Rong; Diagana, Thierry T.; Pertel, Peter; Leong, F. Joel

    2016-01-01

    Background KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. Methods We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). Results Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. Conclusions KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P

  3. Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further structure-activity relationships, in vivo studies, and preliminary toxicity profiling.

    PubMed

    Gemma, Sandra; Camodeca, Caterina; Sanna Coccone, Salvatore; Joshi, Bhupendra P; Bernetti, Matteo; Moretti, Vittoria; Brogi, Simone; Bonache de Marcos, Maria Cruz; Savini, Luisa; Taramelli, Donatella; Basilico, Nicoletta; Parapini, Silvia; Rottmann, Matthias; Brun, Reto; Lamponi, Stefania; Caccia, Silvio; Guiso, Giovanna; Summers, Robert L; Martin, Rowena E; Saponara, Simona; Gorelli, Beatrice; Novellino, Ettore; Campiani, Giuseppe; Butini, Stefania

    2012-08-09

    Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.

  4. Alkoxide coordination of iron(III) protoporphyrin IX by antimalarial quinoline methanols: a key interaction observed in the solid-state and solution.

    PubMed

    Gildenhuys, Johandie; Sammy, Chandre J; Müller, Ronel; Streltsov, Victor A; le Roex, Tanya; Kuter, David; de Villiers, Katherine A

    2015-10-14

    The quinoline methanol