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Sample records for antimalarial drug quality

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2017-10-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

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

    2006-01-01

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

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

    Science.gov (United States)

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

    2012-06-01

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

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

    Science.gov (United States)

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

    2007-01-04

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

  8. Counterfeit and substandard antimalarial drugs in Cambodia.

    Science.gov (United States)

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

    2006-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Uzochukwu Benjamin

    2009-02-01

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

  10. Antimalarial drug induced decrease in creatinine clearance

    NARCIS (Netherlands)

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

    1995-01-01

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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Manuel W Hetzel

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    African Journals Online (AJOL)

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

  15. THE TRAGEDY CAUSED BY FAKE ANTIMALARIAL DRUGS

    Directory of Open Access Journals (Sweden)

    Pierre Ambroise-Thomas

    2012-01-01

    Full Text Available

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

     

     

  16. THE TRAGEDY CAUSED BY FAKE ANTIMALARIAL DRUGS

    Directory of Open Access Journals (Sweden)

    Pierre Ambroise-Thomas

    2012-05-01

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

  17. The tragedy caused by fake antimalarial drugs.

    Science.gov (United States)

    Ambroise-Thomas, Pierre

    2012-01-01

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

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

    Science.gov (United States)

    Foster, S. D.

    1991-01-01

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

  19. Terahertz absorption spectra of commonly used antimalarial drugs

    Science.gov (United States)

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

    2018-03-01

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

  20. Substandard anti-malarial drugs in Burkina Faso

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    Sie Ali

    2008-05-01

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

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

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    Avinaba Mukherjee

    2016-03-01

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

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

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

    2014-01-01

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

  3. The antimalarial drug artemisinin alkylates heme in infected mice

    Science.gov (United States)

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

    2005-01-01

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

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

    Science.gov (United States)

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

    2017-09-11

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    African Journals Online (AJOL)

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

  8. Artemisinin anti-malarial drugs in China

    Directory of Open Access Journals (Sweden)

    Zongru Guo

    2016-03-01

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

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

    Science.gov (United States)

    Drinkwater, Nyssa; McGowan, Sheena

    2014-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Nuno eVale

    2014-12-01

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

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

    OpenAIRE

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

    2013-01-01

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

  12. Phase I Clinical Testing Antimalarial Drugs.

    Science.gov (United States)

    1977-10-01

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

  13. Antimalarial drug use in general populations of tropical Africa

    Directory of Open Access Journals (Sweden)

    Gardella Florence

    2008-07-01

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

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

    Science.gov (United States)

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

    2017-01-05

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

  15. Towards histone deacetylase inhibitors as new antimalarial drugs.

    Science.gov (United States)

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

    2012-01-01

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

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

    African Journals Online (AJOL)

    Vihar

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

  17. Selection of a trioxaquine as an antimalarial drug candidate

    Science.gov (United States)

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

    2008-01-01

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

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

    CSIR Research Space (South Africa)

    Becker, J

    2008-11-01

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

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

    Science.gov (United States)

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

    2015-10-01

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

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

    Science.gov (United States)

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

    2015-09-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results...... women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform...... a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods: All drug shops selling...

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

    Science.gov (United States)

    Muregi, Francis W; Ishih, Akira

    2010-02-01

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

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

    Science.gov (United States)

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

    2018-04-03

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

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

    Science.gov (United States)

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

    2015-01-01

    The antimalarial drug mefloquine has previously been shown to stimulate apoptosis of nucleated cells. Similar to apoptosis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca2+-activity ([Ca2+]i), and ceramide. Phosphatidylserine abundance at the cell surface was estimated from annexin V binding, cell volume from forward scatter, reactive oxidant species (ROS) from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, [Ca2+]i from Fluo3- fluorescence, and ceramide abundance from specific antibody binding. A 48 h treatment of human erythrocytes with mefloquine significantly increased the percentage of annexin-V-binding cells (≥5 μg/ml), significantly decreased forward scatter (≥5 μg/ml), significantly increased ROS abundance (5 μg/ml), significantly increased [Ca2+]i (7.5 μg/ml) and significantly increased ceramide abundance (10 μg/ml). The up-regulation of annexin- V-binding following mefloquine treatment was significantly blunted but not abolished by removal of extracellular Ca2+. Even in the absence of extracellular Ca2+, mefloquine significantly increased annexin-V-binding. Mefloquine treatment leads to erythrocyte shrinkage and erythrocyte membrane scrambling, effects at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance. © 2015 S. Karger AG, Basel.

  5. Estimated Under-Five Deaths Associated with Poor-Quality Antimalarials in Sub-Saharan Africa

    Science.gov (United States)

    Renschler, John P.; Walters, Kelsey M.; Newton, Paul N.; Laxminarayan, Ramanan

    2015-01-01

    Many antimalarials sold in sub-Saharan Africa are poor-quality (falsified, substandard, or degraded), and the burden of disease caused by this problem is inadequately quantified. In this article, we estimate the number of under-five deaths caused by ineffective treatment of malaria associated with consumption of poor-quality antimalarials in 39 sub-Saharan countries. Using Latin hypercube sampling our estimates were calculated as the product of the number of private sector antimalarials consumed by malaria-positive children in 2013; the proportion of private sector antimalarials consumed that were of poor-quality; and the case fatality rate (CFR) of under-five malaria-positive children who did not receive appropriate treatment. An estimated 122,350 (interquartile range [IQR]: 91,577–154,736) under-five malaria deaths were associated with consumption of poor-quality antimalarials, representing 3.75% (IQR: 2.81–4.75%) of all under-five deaths in our sample of 39 countries. There is considerable uncertainty surrounding our results because of gaps in data on case fatality rates and prevalence of poor-quality antimalarials. Our analysis highlights the need for further investigation into the distribution of poor-quality antimalarials and the need for stronger surveillance and regulatory efforts to prevent the sale of poor-quality antimalarials. PMID:25897068

  6. Simple field assays to check quality of current artemisinin-based antimalarial combination formulations.

    Directory of Open Access Journals (Sweden)

    Jean-Robert Ioset

    Full Text Available INTRODUCTION: Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT for use as first line treatment against malaria. This class of drugs is now first-line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. METHODS AND FINDINGS: Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5-dimethoxybenzenediazonium chloride hemi (zinc chloride salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP--artesunate/amodiaquine, Coartem--artemether/lumefantrine and Duocortexcin--dihydroartemisinin/piperaquine. The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. CONCLUSIONS: Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible

  7. Simple field assays to check quality of current artemisinin-based antimalarial combination formulations.

    Science.gov (United States)

    Ioset, Jean-Robert; Kaur, Harparkash

    2009-09-30

    Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin) derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO) has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT) for use as first line treatment against malaria. This class of drugs is now first-line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5-dimethoxybenzenediazonium chloride hemi (zinc chloride) salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP--artesunate/amodiaquine, Coartem--artemether/lumefantrine and Duocortexcin--dihydroartemisinin/piperaquine). The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible, inexpensive and, have successfully resulted in detecting two

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Udomsangpetch Rachanee

    2010-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Rusk Andria

    2012-08-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2013-07-11

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

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

    Science.gov (United States)

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

    2013-03-01

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

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

    African Journals Online (AJOL)

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

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

    OpenAIRE

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

    2014-01-01

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

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

    Science.gov (United States)

    Ojha, Probir Kumar; Roy, Kunal

    2015-01-01

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

  17. POTENCY OF THE INDONESIAN MEDICINAL PLANTS AS ANTIMALARIAL DRUGS

    Directory of Open Access Journals (Sweden)

    Subeki Subeki

    2012-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Lucio H. Freitas-Junior

    2013-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Tatyana Andreyevna Lisitsyna

    2010-01-01

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

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

    OpenAIRE

    Tatyana Andreyevna Lisitsyna; N M Kosheleva

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Shweta Sinha

    2017-10-01

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

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

    Science.gov (United States)

    Severini, Carlo; Menegon, Michela

    2015-06-01

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

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

    Science.gov (United States)

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

    2017-07-01

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

  5. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies

    DEFF Research Database (Denmark)

    Vestergaard, Lasse S; Ringwald, Pascal

    2007-01-01

    Reduced sensitivity of Plasmodium falciparum to formerly recommended cheap and well-known antimalarial drugs places an increasing burden on malaria control programs and national health systems in endemic countries. The high costs of the new artemisinin-based combination treatments underline the use...... of rational and updated malaria treatment policies, but defining and updating such policies requires a sufficient volume of high-quality drug-resistance data collected at national and regional levels. Three main tools are used for drug resistance monitoring, including therapeutic efficacy tests, in vitro...... tests, and analyses of molecular markers. Data obtained with the therapeutic efficacy test conducted according to the standard protocol of the World Health Organization are most useful for updating national treatment policies, while the in vitro test and molecular markers can provide important...

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2017-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Mungthin Mathirut

    2005-08-01

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

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

    Science.gov (United States)

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

    2013-11-22

    The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    African Journals Online (AJOL)

    DR. AMINU

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

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

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2011-12-01

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

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

    Science.gov (United States)

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

    1994-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Abong'o Benard

    2010-10-01

    Full Text Available Abstract Background Interventions to reverse trends in malaria-related morbidity and mortality in Kenya focus on preventive strategies and drug efficacy. However, the pattern of use of anti-malarials in malaria-endemic populations, such as in western Kenya, is still poorly understood. It is critical to understand the patterns of anti-malarial drug use to ascertain that the currently applied new combination therapy to malaria treatment, will achieve sustained cure rates and protection against parasite resistance. Therefore, this cross-sectional study was designed to determine the patterns of use of anti-malarial drugs in households (n = 397 in peri-urban location of Manyatta-B sub-location in Kisumu in western Kenya. Methods Household factors, associated with the pattern of anti-malarials use, were evaluated. Using clusters, questionnaire was administered to a particular household member who had the most recent malaria episode (within Results Stratification of the type of anti-malarial drugs taken revealed that 37.0% used sulphadoxine/pyrimethamine (SP, 32.0% artemisinin-based combined therapy (ACT, 11.1% anti-pyretics, 7.3% chloroquine (CQ, 7.1% quinine, 2.5% amodiaquine (AQ, while 3.0% used others which were perceived as anti-malarials (cough syrups and antibiotics. In a regression model, it was demonstrated that age (P = 0.050, household size (P = 0.047, household head (P = 0.049, household source of income (P = 0.015, monthly income (P = 0.020, duration of use (P = 0.029, dosage of drugs taken (P = 0.036, and source of drugs (P = 0.005 significantly influenced anti-malarial drug use. Overall, 38.8% of respondents used drugs as recommended by the Ministry of Health. Conclusion This study demonstrates that consumers require access to correct and comprehensible information associated with use of drugs, including self-prescription. There is potential need by the Kenyan government to improve malaria care and decrease malaria-related morbidity and

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

    Science.gov (United States)

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

    1995-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Samuel Egieyeh

    2016-01-01

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

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

    Science.gov (United States)

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

    2000-01-01

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

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

    Science.gov (United States)

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

    2016-09-20

    More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

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    Giuseppe ePulice

    2016-03-01

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

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

    DEFF Research Database (Denmark)

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

    1987-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

    Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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

    Science.gov (United States)

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

    2014-02-01

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

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

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    Kotaki Hajime

    2010-11-01

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

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

    Science.gov (United States)

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

    2012-08-09

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

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

    Science.gov (United States)

    Evans, Lawrence; Coignez, Veerle; Barojas, Adrian; Bempong, Daniel; Bradby, Sanford; Dijiba, Yanga; James, Makeida; Bretas, Gustavo; Adhin, Malti; Ceron, Nicolas; Hinds-Semple, Alison; Chibwe, Kennedy; Lukulay, Patrick; Pribluda, Victor

    2012-06-15

    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. 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. 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. The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines

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

    Directory of Open Access Journals (Sweden)

    Evans Lawrence

    2012-06-01

    Full Text Available Abstract 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

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

    Science.gov (United States)

    Nevin, Remington L

    2012-10-01

    Recently, evidence has emerged from an unusual form of mass drug administration practised among detainees held at US Naval Station Guantánamo Bay, Cuba ('Guantánamo'), ostensibly as a public health measure. Mefloquine, an antimalarial drug originally developed by the US military, whose use is associated with a range of severe neuropsychiatric adverse effects, was administered at treatment doses to detainees immediately upon their arrival at Guantánamo, prior to laboratory testing for malaria and irrespective of symptoms of disease. In this analysis, the history of mefloquine's development is reviewed and the indications for its administration at treatment doses are discussed. The stated rationale for the use of mefloquine among Guantánamo detainees is then evaluated in the context of accepted forms of population-based malaria control. It is concluded that there was no plausible public health indication for the use of mefloquine at Guantánamo and that based on prevailing standards of care, the clinical indications for its use are decidedly unclear. This analysis suggests the troubling possibility that the use of mefloquine at Guantánamo may have been motivated in part by knowledge of the drug's adverse effects, and points to a critical need for further investigation to resolve unanswered questions regarding the drug's potentially inappropriate use. Published 2012. This article is a US Government work and is in the public domain in the USA.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-03-01

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

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

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    Dorcas Osei-Safo

    2014-01-01

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

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

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    T. A. Klein

    1992-01-01

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

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

    Science.gov (United States)

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

    1993-01-01

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

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

    Science.gov (United States)

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

    2012-12-01

    Antimalarial drug combinations containing artemisinins (ACTs) have become first choice therapies for Plasmodium falciparum malaria. Data on safety of ACTs in pregnancy are limited and no previous study has been conducted on the developmental toxicity of artesunate-mefloquine combinations on the first trimester of gestation. To evaluate the developmental toxicity of an artesunate/mefloquine combination, pregnant rats were treated orally with artesunate (15 and 40 mg/kg bwt/day), mefloquine (30 and 80 mg/kg bwt/day) and artesunate/mefloquine (15/30 and 40/80 mg/kg bwt/day) on gestation days 9-11. Dams were C-sectioned on day 20, and their uteri and fetuses removed and examined for soft tissue and skeleton abnormalities. Artesunate increased embryolethality and the incidence of limb long bone malformations on the absence of overt maternal toxicity. Mefloquine (80 mg/kg bwt/day) was maternally toxic and enhanced fetal variations. Combination of artesunate and mefloquine did not enhance their toxicity compared to the toxicity observed after its separate administration. Embryotoxicity of artesunate was apparently attenuated when it is co-administered with mefloquine. Copyright © 2012 Elsevier Inc. All rights reserved.

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

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    Waleed M. Sweileh

    2017-01-01

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

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

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    Chance Michael L

    2011-08-01

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

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

    Science.gov (United States)

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

    2011-08-21

    This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP). Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt)-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr)-C59R and dihydropteroate synthase (dhps)-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9). The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African) CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum parasites from Yemen. Mutant pfcrtT76 is highly prevalent but it

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

    Science.gov (United States)

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

    2016-11-04

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

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Nain Vikrant

    2010-09-01

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

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

    Science.gov (United States)

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

    2015-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie

    2012-08-01

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

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

    Science.gov (United States)

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

    2014-12-01

    With the emergence of artesunate antimalarial counterfeiting in Southeast Asia and sub-Saharan Africa, we present the production of a rapid, inexpensive and simple colorimetric-based testing kit for the detection of counterfeit artesunate in order to preserve life and prevent the development of multi-drug resistant malaria. The kit works based on paper microfluidics which offer several advantages over conventional microfluidics, and has great potential to generate inexpensive, easy-to-use, rapid and disposable diagnostic devices. Here, we have developed a colorimetric assay that is specific to artesunate and turns yellow upon addition of the sample. The test can be done within minutes, and allows for a semi-quantitative analysis of the artesunate tablets by comparing the developed yellow color on the paper test to a color-coded key chart that comes with the kit. A more accurate and precise analysis is done by utilizing a color analyzer on an iPhone camera that measures the color intensity of the developed color on the paper chip. A digital image of the chip was taken and analyzed by measuring the average gray intensity of the color developed on the paper circle. A plot of the artesunate concentration versus the average gray scale intensity was generated. Results show that the intensity of the yellow color developed on the paper test was consistent and proportional to the amount of artesunate present in the sample. With artesunate concentrations ranging from 0.0 to 20mg/mL, a linear calibration plot was obtained with a detection limit of 0.98 mg/mL. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    López-Antuñano Francisco Javier

    1999-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Krettli Antoniana U

    2001-01-01

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

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

    Science.gov (United States)

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

    2011-05-24

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

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

    International Nuclear Information System (INIS)

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

    2002-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2002-09-01

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

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

    Science.gov (United States)

    2010-01-01

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

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

    Science.gov (United States)

    Emejulu, Jude-Kennedy C; Okwaraoha, Blaise Ogedi

    2011-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-11-30

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2016-08-01

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

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

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Sow, Doudou; Nag, Sidsel

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Shaukat Ayesha M

    2012-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Monica Shah

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

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

    Science.gov (United States)

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

    2014-11-15

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

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

    DEFF Research Database (Denmark)

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

    1987-01-01

    Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic...... levels suppressed the lymphocytes' proliferation, but not their IL-2 production. All three quinolines suppressed the proliferation of lymphocytes, but not equally, with mefloquine having the strongest effect. Quinine suppressed the growth at therapeutic concentrations. The IL-2 production was suppressed...... at concentrations twice as high as those required to suppress lymphocyte proliferation. Addition of exogenous IL-2 only partially reversed the suppressive effect on lymphocyte proliferation. Delayed addition of the quinolines decreased their suppressive effect, but not completely. The mechanisms of action on human...

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

    OpenAIRE

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

    1993-01-01

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

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

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    Reagan M Mogire

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

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

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    Olugbenga O. Oluwagbemi

    2018-04-01

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

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

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    Pradines Bruno

    2011-10-01

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

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

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

    2018-03-01

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

  4. Thiazole Containing Heterocycles With Antimalarial Activity.

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    Kumawat, Mukesh Kumar

    2017-07-25

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

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

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    Francisco Javier López-Antuñano

    1999-10-01

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

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

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

    2018-01-01

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

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

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    Sylla Thiam

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2011-04-06

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

  10. Correlation of in vitro sensitivity of chloroquine and other antimalarials with the partner drug resistance to Plasmodium falciparum malaria in selected sites of India

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    Supriya Sharma

    2017-01-01

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

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

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

    2016-01-01

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

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

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    Nor Azrina Norahmad

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

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

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    Ringsted Frank M

    2011-08-01

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

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

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

    2011-08-05

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

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

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

    2017-01-06

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

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

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

    2015-07-14

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

  17. World Antimalarial Resistance Network (WARN IV: Clinical pharmacology

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    Gbotosho Grace O

    2007-09-01

    Full Text Available Abstract A World Antimalarial Resistance Network (WARN database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics. By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component

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

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    Vreeke Ed

    2007-07-01

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

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

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    Nanang Yunarto

    2016-09-01

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

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

    Science.gov (United States)

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

    2013-12-01

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2016-01-01

    Background The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP) is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ) and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1) and type 1 antifolate antimalarial medicines (Pfdhfr). Methods Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72–76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt) gene by real time polymerase chain reaction (PCR) using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1) gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene. Results Two haplotypes of Pfcrt (n = 54) were observed: CVMNK 13(24.2%) and CVIET 41 (75.9%) of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28) haplotypes were NYSND 15(53.6%), YYSND 5(17.9%), NFSND 6(21.4%) and YFSND 2(7.1%). The Pfdhfr (n = 15) were ACNCSVI 4(26.7%), and ACICNSVI 1(6.7%) and ACIRNVI 10 (66.7%). The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Yand184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024) while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006). The median parasitaemia were similar (P>0.05) in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and

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

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    Silvia Blair-Trujillo

    2002-04-01

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

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

    Science.gov (United States)

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

    2016-02-19

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

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

    Science.gov (United States)

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

    2009-04-01

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

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

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    Malisa Allen

    2012-03-01

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

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

    Science.gov (United States)

    Malisa, Allen Lewis; Kiriba, Deodatus

    2012-03-28

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

  8. A cross-sectional analysis of traditional medicine use for malaria alongside free antimalarial drugs treatment amongst adults in high-risk malaria endemic provinces of Indonesia.

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

    Frosch, Torsten; Popp, Jürgen

    2010-01-01

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

  10. The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.

    Science.gov (United States)

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

    2012-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Barnes Karen I

    2010-12-01

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

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Science.gov (United States)

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

    2004-12-01

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

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

    KAUST Repository

    Lepore, Rosalba

    2011-11-28

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

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

    Science.gov (United States)

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

    2010-09-01

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

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

    Science.gov (United States)

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

    2009-02-01

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

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

    Science.gov (United States)

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

    2017-03-01

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    Science.gov (United States)

    Maaswinkel, Hans; Zhu, Liqun; Weng, Wei

    2015-04-02

    New antimalarial drugs need to be developed because over time resistance against the existing drugs develops. Furthermore, some of the drugs have severe side effects. Here we describe a behavioral small-fish model for early detection of neurotoxic effects of new drugs. As case example we compare the effects of two mefloquine diastereomers on the behavior of goldfish using an automated 3D tracking system. In a preliminary experiment, the overall toxic effects in terms of motor and respiratory impairments were determined during a 3-hour exposure to the drugs at relatively high doses (21.5 and 43 mgL). In the second experiment, behavioral testing was performed 24 h after a 3.5-h drug exposure to a low dose (14.25 mgL) of either drug. For the two high doses, erythro-mefloquine resulted in severe motor problems and respiratory problems occurred. In goldfish treated with threo-mefloquine, at 43 mgL the motor/respiratory impairments were less severe and at 21.5 mgL no such problems were observed. For the lower dose (14.25 mgL), erythro-mefloquine reduced locomotion. There was also a tendency for increased freezing, and the preference for quadrant two of the observation container was increased. No behavioral effects of threo-mefloquine were found. The results demonstrate that in goldfish exposed to the drugs dissolved in the water, threo-mefloquine has less severe toxic effects as compared to erythro-mefloquine. These findings are consistent with other studies and support the usefulness of the small-fish model for predicting adverse effects of new antimalarial drugs during the initial phases of drug development.

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

    Science.gov (United States)

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

    2016-11-01

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

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

    Science.gov (United States)

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

    2004-08-15

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

    1990-08-15

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

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

    DEFF Research Database (Denmark)

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

    1995-01-01

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

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

    International Nuclear Information System (INIS)

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

    2007-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sow Diarietou

    2009-06-01

    Full Text Available Abstract Background The introduction of new anti-malarial treatment that is effective, but more expensive, raises questions about whether the high level of effectiveness observed in clinical trials can be found in a context of family use. The objective of this study was to determine the factors related to adherence, when using the amodiaquine/sulphadoxine-pyrimethamine (AQ/SP association, a transitory strategy before ACT implementation in Senegal. Methods The study was conducted in five rural dispensaries. Children, between two and 10 years of age, who presented mild malaria were recruited at the time of the consultation and were prescribed AQ/SP. The child's primary caretaker was questioned at home on D3 about treatment compliance and factors that could have influenced his or her adherence to treatment. A logistic regression model was used for the analyses. Results The study sample included 289 children. The adherence rate was 64.7%. Two risks factors for non-adherence were identified: the children's age (8–10 years (ORa = 3.07 [1.49–6.29]; p = 0.004; and the profession of the head of household (retailer/employee versus farmer (ORa = 2.71 [1.34–5.48]; p = 0.006. Previously seeking care (ORa = 0.28 [0.105–0.736], p=0.001] satisfaction with received information (ORa = 0.45 [0.24–0.84]; p = 0.013, and the quality of history taking (ORa = 0.38 [0.21–0.69]; p = 0.001 were significantly associated with good compliance. Conclusion The results of the study show the importance of information and communication between caregivers and health center staff. The experience gained from this therapeutic transition emphasizes the importance of information given to the patients at the time of the consultation and drug delivery in order to improve drug use and thus prevent the emergence of rapid drug resistance.

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

    Directory of Open Access Journals (Sweden)

    Mateus Sebastião João Fernandes

    2015-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Gonzalez-Block Miguel A

    2005-10-01

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

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

    Science.gov (United States)

    Mubyazi, Godfrey M; Gonzalez-Block, Miguel A

    2005-10-20

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

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

    Directory of Open Access Journals (Sweden)

    Nambei W.S.

    2005-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Brasseur Philippe

    2012-12-01

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

  13. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies

    DEFF Research Database (Denmark)

    Vestergaard, Lasse S; Ringwald, Pascal

    2007-01-01

    additional information about changing patterns of resistance. However, some of the tests are technically demanding, and thus there is a need for more resources for training and capacity building in endemic countries to be able to adequately respond to the challenge of drug resistance....... of rational and updated malaria treatment policies, but defining and updating such policies requires a sufficient volume of high-quality drug-resistance data collected at national and regional levels. Three main tools are used for drug resistance monitoring, including therapeutic efficacy tests, in vitro...... tests, and analyses of molecular markers. Data obtained with the therapeutic efficacy test conducted according to the standard protocol of the World Health Organization are most useful for updating national treatment policies, while the in vitro test and molecular markers can provide important...

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

    Directory of Open Access Journals (Sweden)

    Brun Reto

    2009-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Valentina Guzmán

    2006-01-01

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

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

    Science.gov (United States)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

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    Ogunwande Isiaka A

    2011-08-01

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

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

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    Ronn Anita

    2011-08-01

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-03-12

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

  2. Quinoline-based antimalarial hybrid compounds.

    Science.gov (United States)

    Vandekerckhove, Stéphanie; D'hooghe, Matthias

    2015-08-15

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

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

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    Yeshwant Singh

    2014-01-01

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

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

    Science.gov (United States)

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

    2016-02-13

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

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

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    Masaninga Freddie

    2012-10-01

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

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

    Science.gov (United States)

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

    2015-03-26

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

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

    Directory of Open Access Journals (Sweden)

    Katherine Kay

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

  8. The anti-malarial drug Mefloquine disrupts central autonomic and respiratory control in the working heart brainstem preparation of the rat

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    Lall Varinder K

    2012-12-01

    Full Text Available Abstract Background Mefloquine is an anti-malarial drug that can have neurological side effects. This study examines how mefloquine (MF influences central nervous control of autonomic and respiratory systems using the arterially perfused working heart brainstem preparation (WHBP of the rat. Recordings of nerve activity were made from the thoracic sympathetic chain and phrenic nerve, while heart rate (HR and perfusion pressure were also monitored in the arterially perfused, decerebrate, rat WHBP. MF was added to the perfusate at 1 μM to examine its effects on baseline parameters as well as baroreceptor and chemoreceptor reflexes. Results MF caused a significant, atropine resistant, bradycardia and increased phrenic nerve discharge frequency. Chemoreceptor mediated sympathoexcitation (elicited by addition of 0.1 ml of 0.03% sodium cyanide to the aortic cannula was significantly attenuated by the application of MF to the perfusate. Furthermore MF significantly decreased rate of return to resting HR following chemoreceptor induced bradycardia. An increase in respiratory frequency and attenuated respiratory-related sympathetic nerve discharge during chemoreceptor stimulation was also elicited with MF compared to control. However, MF did not significantly alter baroreceptor reflex sensitivity. Conclusions These studies indicate that in the WHBP, MF causes profound alterations in autonomic and respiratory control. The possibility that these effects may be mediated through actions on connexin 36 containing gap junctions in central neurones controlling sympathetic nervous outflow is discussed.

  9. On peroxide antimalarials

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    IGOR OPSENICA

    2007-12-01

    Full Text Available Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure–activity relationship of this kind of antimalarials. The tetraoxanes 2–5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

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

    Science.gov (United States)

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

    2014-03-01

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

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

    Science.gov (United States)

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

    2011-10-31

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

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

    Directory of Open Access Journals (Sweden)

    Chapman Steven

    2011-10-01

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

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

    Science.gov (United States)

    2011-01-01

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

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

    Science.gov (United States)

    Gomes, M; Wayling, S; Pang, L

    1998-01-01

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

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

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    Akter Jasmin

    2012-11-01

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

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

    Science.gov (United States)

    Küster, Tatiana; Stadelmann, Britta; Rufener, Reto; Risch, Corina; Müller, Joachim; Hemphill, Andrew

    2015-11-01

    This study investigated the effects of oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine (MEF) and identified proteins that bind to MEF in parasite extracts and human cells by affinity chromatography. In a pilot experiment, MEF treatment was applied 5 days per week and was intensified by increasing the dosage stepwise from 12.5 mg/kg to 200 mg/kg during 4 weeks followed by treatments of 100 mg/kg during the last 7 weeks. This resulted in a highly significant reduction of parasite weight in MEF-treated mice compared with mock-treated mice, but the reduction was significantly less efficacious compared with the standard treatment regimen of albendazole (ABZ). In a second experiment, MEF was applied orally in three different treatment groups at dosages of 25, 50 or 100 mg/kg, but only twice a week, for a period of 12 weeks. Treatment at 100 mg/kg had a profound impact on the parasite, similar to ABZ treatment at 200 mg/kg/day (5 days/week for 12 weeks). No adverse side effects were noted. To identify proteins in E. multilocularis metacestodes that physically interact with MEF, affinity chromatography of metacestode extracts was performed on MEF coupled to epoxy-activated Sepharose(®), followed by SDS-PAGE and in-gel digestion LC-MS/MS. This resulted in the identification of E. multilocularis ferritin and cystatin as MEF-binding proteins. In contrast, when human cells were exposed to MEF affinity chromatography, nicotinamide phosphoribosyltransferase was identified as a MEF-binding protein. This indicates that MEF could potentially interact with different proteins in parasites and human cells. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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

    Science.gov (United States)

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

    2015-12-01

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

  18. Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar

    2013-01-01

    Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children...... on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant...

  19. QSAR modeling and chemical space analysis of antimalarial compounds

    Science.gov (United States)

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

    2017-05-01

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

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

    Science.gov (United States)

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

    2017-05-01

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

  1. Antimalarial natural products: a review

    Directory of Open Access Journals (Sweden)

    Faraz Mojab

    2012-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-07-15

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

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

    Science.gov (United States)

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

    2018-01-01

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

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

    Science.gov (United States)

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

    2016-06-14

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

  5. Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal.

    Science.gov (United States)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar; Ndiaye, Jean L; Diouf, Ibrahima; Lo, Aminata C; Sylla, Khadime; Dieng, Yemou; Hallett, Rachel; Alifrangis, Michael; Gaye, Oumar

    2013-01-01

    Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n=352) were collected from children under 5years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant haplotypes (CNRN and CICN) was stable between years atSenegal according to WHO recommendations. Copyright © 2013 Académie des sciences. Published by Elsevier SAS. All rights reserved.

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

    Science.gov (United States)

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

    2013-01-01

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

  7. Analytical Tools and Strategic Approach to Detect Poor Quality Medicines, Identify Unknown Components, and Timely Alerts for Appropriate Measures: Case Study of Antimalarial Medicines

    OpenAIRE

    Habyalimana, Védaste; Mbinze Kindenge, Jérémie; Kalenda Tshilombo, Nicodème; Dispas, Amandine; Yemoa Loconon, Achille; Sacre, Pierre-Yves; Widart, Joëlle; De Tullio, Pascal; Counerotte, Stéphane; Kadima Ntokamunda, Justin-Léonard; Ziemons, Eric; Hubert, Philippe; Marini Djang'Eing'A, Roland

    2015-01-01

    Nowadays, the circulation of poor quality medicines is becoming an alarming worldwide phenomenon with serious public health and socio-economic concerns. The situation is particularly critical in developing countries where drug quality assurance and regulatory systems for drug manufacturing, importation, distribution and sales are weak. A sustained vigilance on poor quality medicines that regroup counterfeit/falsified, substandard and degraded medicines is therefore required to ensure patient ...

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  9. The Use of Antimalarial Drugs

    African Journals Online (AJOL)

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

  10. Pyrimidines in antimalarial drug design

    CSIR Research Space (South Africa)

    Moleele, SS

    2008-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Birgit Viira

    2016-06-01

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

  12. Mapping the genome of Plasmodium falciparum on the drug-like chemical space reveals novel anti-malarial targets and potential drug leads

    DEFF Research Database (Denmark)

    Jensen, Kasper; Plichta, Damian Rafal; Panagiotou, Gianni

    2012-01-01

    essential proteins and the effect of their perturbations on the metabolic network of P. falciparum, as well as indication of drug resistance emergence. Finally, we predict potential off-target effects on the human host with associations to cancer, neurological and dermatological disorders, based......The parasite Plasmodium falciparum is the main agent responsible for malaria. In this study, we exploited a recently published chemical library from GlaxoSmithKline (GSK) that had previously been confirmed to inhibit parasite growth of the wild type (3D7) and the multi-drug resistance (D2d) strains...... on integration of available chemical-protein and protein-protein interaction data. Our work suggests that a large number of the P. falciparum proteome is potentially druggable and could therefore serve as novel drug targets in the fight against malaria. At the same time, prioritized compounds from the GSK...

  13. In Vivo Antimalarial Activity of Solvent Fractions of the Leaves of ...

    African Journals Online (AJOL)

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

  14. Quinoline-Based Hybrid Compounds with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Xhamla Nqoro

    2017-12-01

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

  15. The antimalarial ferroquine: from bench to clinic

    Directory of Open Access Journals (Sweden)

    Biot C.

    2011-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Diakite Chiaka

    2011-03-01

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

  17. Do anti-malarials in Africa meet quality standards? The market penetration of non quality-assured artemisinin combination therapy in eight African countries.

    Science.gov (United States)

    Newton, Paul N; Hanson, Kara; Goodman, Catherine

    2017-05-25

    Quality of artemisinin-based combination therapy (ACT) is important for ensuring malaria parasite clearance and protecting the efficacy of artemisinin-based therapies. The extent to which non quality-assured ACT (non-QAACT), or those not granted global regulatory approval, are available and used to treat malaria in endemic countries is poorly documented. This paper uses national and sub-national medicine outlet surveys conducted in eight study countries (Benin, Kinshasa and Kantanga [Democratic Republic of the Congo, DRC], Kenya, Madagascar, Nigeria, Tanzania, Uganda and Zambia) between 2009 and 2015 to describe the non-QAACT market and to document trends in availability and distribution of non-QAACT in the public and private sector. In 2014/15, non-QAACT were most commonly available in Kinshasa (83%), followed by Katanga (53%), Nigeria (48%), Kenya (42%), and Uganda (33%). Non-QAACT accounted for 20% of the market share in the private sector in Kenya, followed by Benin and Uganda (19%), Nigeria (12%) and Zambia (8%); this figure was 27% in Katanga and 40% in Kinshasa. Public sector non-QAACT availability and distribution was much lower, with the exception of Zambia (availability, 85%; market share, 32%). Diverse generics and formulations were available, but non-QAACT were most commonly artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHA PPQ), in tablet formulation, imported, and distributed in urban areas at either pharmacies or drug stores. The number of unique manufacturers supplying non-QAACT to each country ranged from 9 in Uganda to 92 in Nigeria. Addressing the availability and distribution of non-QAACT will require effective private sector engagement and evidence-based strategies to address provider and consumer demand for these products. Given the variation in non-QAACT markets observed across the eight study countries, active efforts to limit registration, importation and distribution of non-QAACT must be tailored to the country context

  18. Preparation, characterization and in vitro release kinetics of polyaspartamide-based conjugates containing antimalarial and anticancer agents for combination therapy

    CSIR Research Space (South Africa)

    Aderibigbe, BA

    2016-09-01

    Full Text Available Malaria is treated by combination of two drugs in order to overcome drug resistance. Antimalarials have been found to be more effective by combining them with low doses of anticancer drugs. Polymer-drug conjugates containing aminoquinoline...

  19. Antimalarial properties of imipramine and amitriptyline

    International Nuclear Information System (INIS)

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

    1986-01-01

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

  20. [Historical overview of antimalarials used in Venezuela].

    Science.gov (United States)

    Zerpa de Artiles, N

    1993-06-01

    A historical review of antimalarials used in Venezuela is presented from the time when the bark of quina was used until the massive distribution of quinine and metoquine by the Dirección de Malariología y Saneamiento Ambiental. The utility of chloroquine and primaquine against sensible parasite isolates and of sulfadoxine-pyrimethamine and quinine, currently used against P. falciparum resistant strains, is thoroughly discussed. The author suggests use of artemisimine and its derivatives as a very promising antimalarial drug. She also stresses the possibility of the application of new antimalaria vaccine against P. falciparum blood states, presently assayed in the country as an additional tool in malaria control programs.

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

    Directory of Open Access Journals (Sweden)

    Arise Rotimi Olusanya

    2017-09-01

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

  2. Psychoactive Drugs and Quality of Life

    Directory of Open Access Journals (Sweden)

    Soren Ventegodt

    2003-01-01

    Full Text Available This study was performed on a representative sample of the Danish population in order to investigate the connection to the use of psychoactive drugs and quality of life (QOL by way of a questionnaire-based survey. The questionnaire was mailed in February 1993 to 2,460 persons aged between 18 and 88, randomly selected from the CPR (Danish Central Register, and 7,222 persons from the Copenhagen Perinatal Birth Cohort 1959–61.A total of 1,501 persons between the ages 18 and 88 years and 4,626 persons between the ages 31 and 33 years returned the questionnaire (response rates of 61.0% and 64.1%, respectively. Variables investigated in this study were ten different psychotropic drugs and quality of life.Our study showed that over half the Danish population had used illegal psychotropic drugs. The most commonly used was cannabis (marijuana though experience of this drug appeared not to co-vary with QOL to any significant extent. Cocaine, amphetamine, and psilocybin had been used by 1.2 to 3.3% of the population and this varied with QOL to a clear albeit small extent. LSD has been used by 1.2% of the population and the users had a QOL score 10% lower than those who had never used psychotropic drugs. The group with the lowest quality of life was found to be persons who had used heroin, morphine, methadone, and a mixture of alcohol and tranquilizers (10–20% below the group with the highest quality of life.

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

    Science.gov (United States)

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

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mostafa A Elfawal

    2012-12-01

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

  5. Antimalarial naphthoquinones from Nepenthes thorelii.

    Science.gov (United States)

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

    1998-04-01

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

  6. Metallocene Antimalarials: The Continuing Quest

    OpenAIRE

    Blackie, Margaret A. L.; Chibale, Kelly

    2007-01-01

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

  7. The interaction of x-rays and antimalarials

    International Nuclear Information System (INIS)

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

    2001-01-01

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

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

    African Journals Online (AJOL)

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

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

    NARCIS (Netherlands)

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

    1995-01-01

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2015-06-05

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

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

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    E. O. Ajaiyeoba

    2013-01-01

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  14. Chloroquine in the Ugandan market fails quality test: a ...

    African Journals Online (AJOL)

    Background: Antimalaria treatment failure has been partly attributed to poor quality antimalarials in the drug market. A 1998 survey in Kampala showed that 55 % of tablets and 62 % of injection forms of chloroquine failed the quality test. Objective: This study was carried out as a follow-up to establish the quality of ...

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

    OpenAIRE

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2017-03-03

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

  17. Quality of drug prescription in primary health care facilities in ...

    African Journals Online (AJOL)

    DR Marwa

    Abstract. Background: Drug therapy can improve a patient's quality of life and health outcomes if only used properly. However, data on prescription quality at primary health care facilities in Tanzania is scanty. The objective of this study was to assess the quality of drug prescriptions in selected health care facilities in.

  18. Quality of drug prescription in primary health care facilities in ...

    African Journals Online (AJOL)

    Background: Drug therapy can improve a patient's quality of life and health outcomes if only used properly. However, data on prescription quality at primary health care facilities in Tanzania is scanty. The objective of this study was to assess the quality of drug prescriptions in selected health care facilities in two districts of ...

  19. Antimalarial activity of selected Ethiopian medicinal plants in mice

    Directory of Open Access Journals (Sweden)

    Eshetu M. Bobasa

    2018-02-01

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

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

    Science.gov (United States)

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

    2013-10-30

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

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

    Directory of Open Access Journals (Sweden)

    Karène Urgin

    2017-01-01

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

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

    Science.gov (United States)

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

    2012-12-01

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

  3. 76 FR 50741 - 2011 Parenteral Drug Association/Food and Drug Administration Joint Public Conference; Quality...

    Science.gov (United States)

    2011-08-16

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0002] 2011 Parenteral Drug Association/Food and Drug Administration Joint Public Conference; Quality and...: Notice of public conference. The Food and Drug Administration (FDA), in cosponsorship with Parenteral...

  4. 76 FR 25358 - 2011 Parenteral Drug Association/Food and Drug Administration Glass Quality Conference; Public...

    Science.gov (United States)

    2011-05-04

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0002] 2011 Parenteral Drug Association/Food and Drug Administration Glass Quality Conference; Public Conference AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public conference. SUMMARY: The Food...

  5. A study of the pharmaceutical quality of chloroquine and ...

    African Journals Online (AJOL)

    Malaria is a major public health problem in endemic countries, and the quality of antimalarial products is a concern in the therapeutic management of individual patient. In this study, we have evaluated the pharmaceutical quality of chloroquine and paracetamol oral products obtained from a major Nigerian drug “market” ...

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

    Science.gov (United States)

    Massaquoi, Moses B F; Kennedy, Stephen B

    2003-02-01

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

  7. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

    Directory of Open Access Journals (Sweden)

    Bertocchi Paola

    2007-02-01

    Full Text Available Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. Results The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date; low content of active substance (in one sample; different, non-declared, active substance (in one sample; sub-standard technological properties and very low dissolution profiles (in about 50% of samples. This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. Conclusion This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution

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

    Directory of Open Access Journals (Sweden)

    Ladda Kajeechiwa

    2016-09-01

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

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

    Science.gov (United States)

    Chaijaroenkul, Wanna; Na-Bangchang, Kesara

    2014-03-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Nasir Tajure Wabe

    2012-10-01

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

  12. Quality Performance of Drugs Analyzed in the Drug Analysis and ...

    African Journals Online (AJOL)

    ICT TEAM

    During the period 2006-2010, the Drug Analysis and Research Unit analyzed 583 samples. The samples comprised 50.6% local and 49.4% imported products. Samples were subjected to compendial or in-house specifications. The failure rate was 12.2% for local products and 14.2% for imports. Antibacterial products ...

  13. Metallocene Antimalarials: The Continuing Quest

    Science.gov (United States)

    Blackie, Margaret A. L.; Chibale, Kelly

    2008-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  15. Post-marketing surveillance of anti-malarial medicines used in Malawi

    OpenAIRE

    Chikowe, Ibrahim; Osei-Safo, Dorcas; Harrison, Jerry JEK; Konadu, Daniel Y; Addae-Mensah, Ivan

    2015-01-01

    Background The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers? label...

  16. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

    Directory of Open Access Journals (Sweden)

    Dea Shahinas

    2013-02-01

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

  17. Quality assurance of herbal drug valerian by chemotaxonomic markers

    African Journals Online (AJOL)

    The quality assurance of valerian (Balchur), a traditional herbal drug of global importance mainly used for nervous disorders, was studied. At global, regional, national and local levels the end users of this drug face the problems of adulteration. Two different botanical sources are commercially marketed in the Indo-Pak ...

  18. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    have an effective means of monitoring the quality of generic drug products in the market. This results in widespread ... countries. Marketing of such drugs has been widely reported in Africa, Asia, and Latin America. © CNCS .... three-fourth of the plate. The plate was dried in air for 15 minutes and examined under UV-light,.

  19. Assessing website pharmacy drug quality: safer than you think?

    Directory of Open Access Journals (Sweden)

    Roger Bate

    Full Text Available 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(R 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

  20. Antimalarial interaction of quinine and quinidine with clarithromycin.

    Science.gov (United States)

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

    2013-03-01

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

  1. Poisoning by anti-malarial drugs

    African Journals Online (AJOL)

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

  2. Some Pharmacological Aspects of Antimalarial Drugs

    African Journals Online (AJOL)

    1974-06-15

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

  3. (annonaceae) leaves-a potential antimalarial drug

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

    2010-04-01

    ... 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 quality... actions. (e) Quality assurance. You must establish and follow written quality assurance procedures. ...

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

    Science.gov (United States)

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

    2016-02-04

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

  7. Quality of selected aromatic herbal drugs available on Belgrade's marketplaces

    OpenAIRE

    Drobac, Milica; Arsenijević, Jelena; Stojanović, Danilo; Jančić, Radiša; Kovačević, Nada

    2017-01-01

    Herbal drugs are often administered in the form of monocomponent teas or herbal tea mixtures (tea blends). In order to assess the quality of herbal drugs that are components of the monocomponent teas commercially available on marketplaces in Belgrade, we analyzed 4 samples of Melissa leaf (Melissae folium), 6 samples of Wild thyme, (Serpylli herba), 6 samples of Yarrow (Millefolii herba), 4 samples of Wormwood (Absinthii herba) and 6 samples of Juniper (Juniperi pseudo-fructus), according to ...

  8. Refractometry for quality control of anesthetic drug mixtures.

    Science.gov (United States)

    Stabenow, Jennifer M; Maske, Mindy L; Vogler, George A

    2006-07-01

    Injectable anesthetic drugs used in rodents are often mixed and further diluted to increase the convenience and accuracy of dosing. We evaluated clinical refractometry as a simple and rapid method of quality control and mixing error detection of rodent anesthetic or analgesic mixtures. Dilutions of ketamine, xylazine, acepromazine, and buprenorphine were prepared with reagent-grade water to produce at least 4 concentration levels. The refraction of each concentration then was measured with a clinical refractometer and plotted against the percentage of stock concentration. The resulting graphs were linear and could be used to determine the concentration of single-drug dilutions or to predict the refraction of drug mixtures. We conclude that refractometry can be used to assess the concentration of dilutions of single drugs and can verify the mixing accuracy of drug combinations when the components of the mixture are known and fall within the detection range of the instrument.

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

    Science.gov (United States)

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

    2015-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Jerapan Krungkrai

    2016-05-01

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

  11. Quality of Sulfadoxine-Pyrimethamine Given as Antimalarial Prophylaxis in Pregnant Women in Selected Health Facilities in Central Region of Ghana

    Directory of Open Access Journals (Sweden)

    Danny F. Yeboah

    2016-01-01

    Full Text Available The use of sulfadoxine-pyrimethamine (SP as an intermittent preventive treatment (IPT against malaria during pregnancy has become a policy in most sub-Sahara African countries and crucially depends on the efficacy of SP. This study sets out to evaluate the effectiveness of the SP given to the pregnant women in some selected health facilities in the Central Region of Ghana to prevent maternal malaria in pregnant women. A total of 543 pregnant women recruited from 7 selected health centres in Central Region of Ghana participated in the study. Parasite density of Plasmodium falciparum was determined from peripheral blood of the pregnant women using microscopy. High performance liquid chromatography (HPLC and dissolution tester were used to determine the quality of the SP. Malaria infection was recorded in 11.2% of pregnant women who had a history of SP consumption. SP failed the dissolution test. Pregnant women who did not receive IPT-SP were 44%. Low haemoglobin level was recorded in 73.5% of the pregnant women. The results indicated that SP was substandard. IPT-SP is ineffective in preventing malaria infection.

  12. Human serum albumin binding of certain antimalarials

    Science.gov (United States)

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

    2018-03-01

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

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

    Science.gov (United States)

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

    2011-10-31

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

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

    Directory of Open Access Journals (Sweden)

    Littrell Megan

    2011-10-01

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

  15. Quality of Life and Adherence to Antiretroviral Drugs

    African Journals Online (AJOL)

    Sitwala

    Quality of Life and Adherence to Antiretroviral Drugs. Medical Journal of Zambia, Volume 37 Number 1 (2010). *P. Mweemba, M.K. Makukula, P.K. Mukwato, M.M. Makoleka. Department of Nursing Sciences, School of Medicine, University of Zambia, Lusaka, Zambia. ABSTRACT. Introduction: Antiretroviral therapy has led to ...

  16. Quality of antiretroviral drugs, stavudine and indinavir capsules ...

    African Journals Online (AJOL)

    Background: The number of antiretroviral drugs (ARVs) available to HIV/AIDS patients in Tanzania is increasing due to a number of intervention programs such as PEPFAR and the Clinton Foundation. These ARVs are imported from a number of countries. However, currently there are no reports on the quality of these ...

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

    International Nuclear Information System (INIS)

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

    2007-01-01

    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

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

    Science.gov (United States)

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

    2003-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Mpimbaza Arthur

    2008-06-01

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

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

    OpenAIRE

    Masseno, Victor; Muriithi, Steven; Nzila, Alexis

    2009-01-01

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

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

    Science.gov (United States)

    Masseno, Victor; Muriithi, Steven; Nzila, Alexis

    2009-07-01

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

  2. Drug resistance in malaria

    Directory of Open Access Journals (Sweden)

    S C Parija

    2011-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-05-15

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

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

    Directory of Open Access Journals (Sweden)

    Eberlin Marcos N

    2011-05-01

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

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

    Science.gov (United States)

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

    2017-03-09

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

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

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    Antia R

    2003-02-01

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

  7. Antimalarial work in China: a historical perspective.

    Science.gov (United States)

    Yip, K

    1998-06-01

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

  8. Perception of quality of life of people with drug addiction

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    Ana Célia Santos

    2017-09-01

    Full Text Available Introduction: Drug addiction affects many people’s lives and statistical data demonstrate the extent of the problem, which usually begins at an early age and is maintained throughout life, with implications for health and quality of life (QOL. Objectives: To evaluate the perception of QOL of people with addictive problems; to compare the perception of QOL between the dependents of illicit drugs and alcohol; to evaluate the differences between the perception of QOL in terms of sociodemographic, health and treatment variables. Methods: A quantitative, descriptive and cross-sectional study was carried out with a sample of 108 people, mostly males, with a mean age of 45 years and low schooling, with a long history of substance use, especially in poly-consumption, beginning on early ages and undergoing treatment in the District of Porto. To evaluate the perception of QOL, the Quality of Life Index (QLI, Portuguese version, by Ferrans & Powers was used. Results: Participants perceived their QOL as positive, with no differences according the type of chemical dependence (illicit drugs/alcohol; Female participants (p=0.01, non-active (p=0.006, who lived alone (p=0.002, had previous treatments (p=0.01, and who continued to consume (p=0.001 presented lower values in the global QLI scores. Conclusions: The aim of this study was to evaluate the perception of QOL of people with drug dependence, and to identify groups with greater vulnerability, in order to plan more effective intervention programmes.

  9. Quality of drug interaction alerts in prescribing and dispensing software.

    Science.gov (United States)

    Sweidan, Michelle; Reeve, James F; Brien, Jo-anne E; Jayasuriya, Pradeep; Martin, Jennifer H; Vernon, Graeme M

    2009-03-02

    To investigate the quality of drug interaction decision support in selected prescribing and dispensing software systems, and to compare this information with that found in a range of reference sources. A comparative study, conducted between June 2006 and February 2007, of the support provided for making decisions about 20 major and 20 minor drug interactions in six prescribing and three dispensing software systems used in primary care in Australia. Five electronic reference sources were evaluated for comparison. Sensitivity, specificity and quality of information; for major interactions: whether information on clinical effects, timeframe and pharmacological mechanism was included, whether management advice was helpful, and succinctness. Six of the nine software systems had a sensitivity rate > or = 90%, detecting most of the major interactions. Only 3/9 systems had a specificity rate of > or = 80%, with other systems providing inappropriate or unhelpful alerts for many minor interactions. Only 2/9 systems provided adequate information about clinical effects for more than half the major drug interactions, and 1/9 provided useful management advice for more than half of these. The reference sources had high sensitivity and in general provided more comprehensive clinical information than the software systems. Drug interaction decision support in commonly used prescribing and dispensing software has significant shortcomings.

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

    Science.gov (United States)

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

    2014-10-01

    Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Acute oral toxicity dose at 5000 mg/kg was conducted to evaluate the safety of this extract. Twenty mice were divided into control and experimental group. All the mice were observed for signs of toxicity, mortality, weight changes and histopathological changes. Antimalarial activity of different extract doses of 50, 200, 400 and 1000 mg/kg were tested in vivo against Plasmodium berghei infections in mice (five mice for each group) during early, established and residual infections. The acute oral toxicity test revealed that no mortality or evidence of adverse effects was seen in the treated mice. The extract significantly reduced the parasitemia by the 50 (P = 0.000), 200 (P = 0.000) and 400 mg/kg doses (P = 0.000) in the in vivo prophylactic assay. The percentage chemo-suppression was calculated as 83.33% for 50 mg/kg dose, 75.62% for 200 mg/kg dose and 90.74% for 400 mg/kg dose. Body weight of all treated groups; T1, T2, T3 and T4 also showed enhancement after 7 days posttreatment. Statistically no reduction of parasitemia calculated for curative and suppressive test. Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection.

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

    OpenAIRE

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

    2015-01-01

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

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

    OpenAIRE

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

    2013-01-01

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

  13. Antimalarial properties of South African medicinal plants

    CSIR Research Space (South Africa)

    Pillay, P

    2007-01-01

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

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

    Science.gov (United States)

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

    2016-02-03

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

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

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    Divya Shitlani

    2016-06-01

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

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

    Science.gov (United States)

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

    2017-07-03

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

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

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    Dismas Baza

    2011-02-01

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

  18. Design, Synthesis and Testing of Novel Antimalarial

    Science.gov (United States)

    2006-05-05

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

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

    Science.gov (United States)

    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.

  20. Quality control of drugs. Certification scheme on the quality of pharmaceutical products moving in international commerce.

    Science.gov (United States)

    1979-01-01

    In an effort to ensure a desirable level of quality control of drugs in international commerce, the 28th World Health Assembly recommended, in its resolution WHA28.65, that Member States apply the requirements for "Good Practices in the Manufacture and Quality Control of Drugs" and participate in the Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce. Since the publication of the 1st list 13 countries (Austria, Congo, Denmark, El Salvador, India, Iran, Israel, Liberia, Swaziland, Thailand, Tunisia, United Republic of Tanzania, and Zaire) have informed the World Health Organization of their agreement to participate in the Certification Scheme, and the texts of their replies are included here.

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

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    Noraziah Mohamad Zin

    2017-12-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2012-03-01

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

  4. Therapeutic efficacy of artesunate in the treatment of uncomplicated Plasmodium falciparum malaria and anti-malarial, drug-resistance marker polymorphisms in populations near the China-Myanmar border

    Directory of Open Access Journals (Sweden)

    Huang Fang

    2012-08-01

    Full Text Available Abstract Background The aim of this study was to evaluate the clinical outcome after seven-day artesunate monotherapy for uncomplicated Plasmodium falciparum malaria in Yingjiang County along the China-Myanmar border and investigate genetic polymorphisms in the P. falciparum chloroquine-resistance transporter (pfcrt, multidrug resistance 1 (pfmdr1, dihydrofolate reductase (pfdhfr, dihydropteroate synthase (pfdhps and ATPase (pfatp6 genes. Methods Patients ≥ one year of age with fever (axillary temperature ≥37.5°C or history of fever and P. falciparum mono-infection were included. Patients received anti-malarial treatment with artesunate (total dose of 16 mg/kg over seven days by directly observed therapy. After a 28-day follow-up, treatment efficacy and effectiveness were assessed based on clinical and parasitological outcomes. Treatment failure was defined as recrudescence of the original parasite and distinguished with new infection confirmed by PCR. Analysis of gene mutation and amplification were performed by nested polymerase chain reaction. Results Sixty-five patients were enrolled; 10 withdrew from the study, and six were lost to follow-up. All but two patients demonstrated adequate clinical and parasitological response; 12 had detectable parasitaemia on day 3. These two patients were confirmed to be new infection by PCR. The efficacy of artesunate was 95.9%. The pfcrt mutation in codon 76 was found in all isolates (100%, and mutations in codons 71 and 72 were found in 4.8% of parasite isolates. No mutation of pfmdr1 (codons 86 or 1246 was found. Among all samples, 5.1% were wild type for pfdhfr, whereas the other samples had mutations in four codons (51, 59, 108 and 164, and mutations in pfdhps (codons 436, 437, 540 and 581 were found in all isolates. No samples had mutations in pfatp6 codons 623 or 769, but two new mutations (N683K and R756K were found in 4.6% and 9.2% of parasite isolates, respectively. Conclusion Plasmodium

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

    Science.gov (United States)

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

    2014-09-13

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

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

    Science.gov (United States)

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

    2012-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Misael Chinchilla

    2012-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Mukesh Kumar Kumawat

    2016-09-01

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

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

    Science.gov (United States)

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

    2005-08-12

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

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

    Science.gov (United States)

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

    2013-07-01

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

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

    Science.gov (United States)

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

    2017-05-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Joan N Kalyango

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

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

    Science.gov (United States)

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

    2017-07-18

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

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

    Directory of Open Access Journals (Sweden)

    Alaíde Braga de Oliveira

    2009-08-01

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

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

    Science.gov (United States)

    2014-01-01

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

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

    Science.gov (United States)

    Karunamoorthi, Kaliyaperumal

    2014-06-02

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

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

    African Journals Online (AJOL)

    userpc

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

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

    Science.gov (United States)

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

    2017-01-12

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

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

    Science.gov (United States)

    Bhat, G P; Surolia, N

    2001-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Valter F de Andrade-Neto

    2007-06-01

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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

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

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

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

  5. Antimalarial Activity of Ultra-Short Peptides

    Directory of Open Access Journals (Sweden)

    María Yolanda Rios

    2009-12-01

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

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

    Science.gov (United States)

    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

  7. Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

    Directory of Open Access Journals (Sweden)

    Benjamin Palafox

    Full Text Available 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.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 antimalarial supply sources

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

    Science.gov (United States)

    Kebebe, Dereje; Mulisa, Eshetu; Gashe, Fanta

    2017-01-01

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

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

    Science.gov (United States)

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

    1993-07-01

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

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

    Science.gov (United States)

    Awad, Abdelmoneim I; Eltayeb, Idris B

    2007-07-01

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

  11. Health, perceived quality of life and health services use among homeless illicit drug users.

    Science.gov (United States)

    O'Brien, K K; Schuttke, A; Alhakeem, A; Donnelly-Swift, E; Keogh, C; O'Carroll, A; O'Sullivan, K; Galvin, R; Fahey, T

    2015-09-01

    Drug misuse has been identified as a significant problem in homeless populations. This study examines aspects of physical and mental health, perceived quality of life and health service use among homeless illicit drug users and compares these to non-drug users. Participants were recruited through health clinics across Dublin. A questionnaire assessed participants' drug use, health and well-being, health behaviours and use of health services. Descriptive statistics are presented for the entire cohort and drug users separately. Logistic regression analysis was used to examine the relationship between drug use and (i) multimorbidity, (ii) anxiety and/or depression, (iii) perceived quality of life and (iv) use of health services. Of 105 participants recruited, 35 (33%) were current drug users. Current and previous drug users were significantly more likely to have multimorbidity than those who had never taken drugs (OR 4.86, 95% CI 1.00-23.66). There was no significant difference between drug users and non-drug users in the prevalence of anxiety and/or depression. Drug users were five times more likely than non-drug users to have a low perceived quality of life (OR 5.2, 95% CI 1.7-16.0). Health service utilization was high, although some services were used less by drug users (e.g., dentist and psychiatric outpatient services) while others were used more often (e.g., phoneline services and day care centres). This study highlights the high levels of drug use in this population and the negative impact of drug use on health and perceived quality of life of a homeless population in Dublin. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. How the media do drugs: quality control and the reporting of drug issues in the UK print media.

    Science.gov (United States)

    Coomber; Morris; Dunn

    2000-05-01

    Exaggeration, distortion, inaccuracy, sensationalism; each of these labels has been consistently applied to the reporting of drug related issues in the print and other media over the last 40 years and beyond. This research sought to understand what quality control mechanisms are employed by the UK print media in relation to issues related to illicit drugs to ensure accurate, informed and appropriate reporting. It was found that the print media in the UK employ almost no quality control mechanisms to ensure that such reporting takes place and that they predominately rely on the demonstrably insufficient qualities of the 'good reporting' skills that journalists bring to their research and writing. What concerns did exist regarding accuracy related predominately to protecting the publication from being sued for libel and no specific journalistic expertise of drug issues was considered necessary. A discussion of these issues is undertaken followed by the recommendation for the production of a negotiated media guide.

  13. Quality assurance of herbal drug valerian by chemotaxonomic markers

    African Journals Online (AJOL)

    STORAGESEVER

    2009-03-20

    Mar 20, 2009 ... under 366 nm UV light. This is a very reliable and reproducible method of authentication of a particular herbal drug and differen- tiation of problematic medicinal plants on the basis of TLC fingerprints. Digital photography. A digital camera (Sony, DSC-W50) was used in the photography of the herbal drugs ...

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Science.gov (United States)

    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 paragraphs...

  16. The relationship between guilt and quality of drug experiences.

    Science.gov (United States)

    Evans, R G; Schill, T R; Monroe, S

    1978-10-01

    Consistent with predictions from Mosher's (1966) guilt construct, the present study found that high guilt males, compared with low guilt Ss, reported significantly less use of marijuana, depressant, stimulant and hallucinogenic drugs. Among all Ss who reported at least one use within each drug category, high guilt Ss rated their experiences as less pleasant and reported a higher frequency of "bad trips" than did low guilt individuals. Overall, these results support Mosher's contention that high vs. low guilt Ss are less likely to engage in culturally prohibited activities such as drug use and are more likely to have unpleasant experiences resulting from guilt when such activities are pursued.

  17. Clarithromycin enhances the antimalarial efficacy of mefloquine via its increased bioavailability and disrupting P. falciparum apicoplast.

    Science.gov (United States)

    Gunjan, S; Singh, S K; Chauhan, B S; Pandey, S K; Ahmad, H; Dwivedi, A K; Tripathi, R

    2015-09-01

    Many important drugs like mefloquine are not being used because of the development of resistance and other related issues. In the present study, we aimed to control drug resistance by using combination therapy and tried to understand the mechanism involved. We have explored in vitro interaction of clarithromycin (CLTR), and mefloquine (MQ) against Pf3D7 and PfK1 strains. Bioavailability of MQ in parasitized RBC lysate was checked in the presence/absence of CLTR using HPLC method. Further tufA mRNA/protein expression was investigated to know the effect of both drugs on apicoplast by using qPCR and Western blotting. MQ and CLTR inhibited growth of Pf3D7 and PfK1. CLTR showed its delayed antimalarial effect by its low IC50 values in the second cycle which indicates its effect on apicoplast. Downregulation of tufA expression on both mRNA and protein level supports this hypothesis. MQ and CLTR showed synergism/additiveness (mean ∑FICs = 0.89 and 1.26) against Pf3D7 and PfK1 respectively. It is evidenced from HPLC data that CLTR might have reduced metabolism of MQ in Plasmodium falciparum, leading to increased levels of MQ to produce enhanced antimalarial activity. The metabolism of CLTR is also reduced may be due to competitive metabolism of MQ via CYP3A4. The present study reveals that broad spectrum biological activities (i.e. antimalarial and antiviral) of MQ can be saved by using suitable partner drug like CLTR. This study also shows that CLTR increases the concentration of MQ and disrupts the apicoplast. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Julia Penna-Coutinho

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

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

    Science.gov (United States)

    Cervantes, Serena; Stout, Paige E; Prudhomme, Jacques; Engel, Sebastian; Bruton, Matthew; Cervantes, Michael; Carter, David; Tae-Chang, Young; Hay, Mark E; Aalbersberg, William; Kubanek, Julia; Le Roch, Karine G

    2012-01-03

    The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. © 2011 Cervantes et al; licensee BioMed Central Ltd.

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

    Science.gov (United States)

    Devender, Nalmala; Gunjan, Sarika; Chhabra, Stuti; Singh, Kartikey; Pasam, Venkata Reddy; Shukla, Sanjeev K; Sharma, Abhisheak; Jaiswal, Swati; Singh, Sunil Kumar; Kumar, Yogesh; Lal, Jawahar; Trivedi, Arun Kumar; Tripathi, Renu; Tripathi, Rama Pati

    2016-02-15

    In a quest to discover new drugs, we have synthesized a series of novel β-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 μM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 μM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. Post-marketing surveillance of anti-malarial medicines used in Malawi.

    Science.gov (United States)

    Chikowe, Ibrahim; Osei-Safo, Dorcas; Harrison, Jerry J E K; Konadu, Daniel Y; Addae-Mensah, Ivan

    2015-03-25

    The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers' label claim and pharmacopoeia specifications. Samples of anti-malarial medicines (112) collected from both licensed and unlicensed markets throughout Malawi were subjected to visual inspection of dosage form and packaging, and registration verification with the regulatory body. Basic (colourimetric) tests were employed to establish the presence and identity of the requisite APIs. Semi-quantitative thin layer chromatography (SQ-TLC) was employed as a quick assay for the verification of identity and estimation of the API content while HPLC assays were used to quantify the APIs. The results were compared with pharmacopoeia specifications and manufacturers' label claims. For combination therapies, a sample was considered to have failed if one or more of its component APIs did not meet pharmacopoeia specifications. There was 86.6% registration status and 100% compliance with visual inspection and basic tests confirming the presence of requisite APIs. The identification test was confirmed by the SQ-TLC assay. API quantification by HPLC assay however, showed that 88.4% (99/112) of the samples failed the quality tests due to the presence of either insufficient or excessive API. The results suggest the existence of substandard anti-malarial medicines in Malawi. The presence of both excessive and insufficient artemisinin-based and non-artemisinin-based API, clearly points to poor adherence to GMP and improper handling during storage or distribution. The country relies heavily on imported anti-malarial

  2. Microbial burden of some herbal antimalarials marketed at Elele, Rivers State.

    Science.gov (United States)

    Tatfeng, Y M; Olama, E H; Ojo, T O

    2009-12-30

    Herbal antimalarials still remain an alternative to our traditional communities who can not afford orthodox antimalarials. This study was aimed at investigating the microbial quality of six herbal antimalarials using standard microbiological methods. Of the six preparations analyzed, "schnapps", palm wine and water were the media of preparation; the water base preparations recorded higher microbial load. The mean microbial load was 159.5 × 10(5) cfu/ml and 217.4 × 10(2)cfu/ml in water and alcohol base preparations respectively. The microbial profile of the preparations showed that the schnapps base preparations were predominantly contaminated with Bacillus sp (Aerobic spore bearers) and Mucor spp. The palm wine preparation harboured Bacillus sp, yeasts and Mucor spp while the water base preparations had several isolates such as Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli 0157H7, Proteus mirabilis, Enterococcus feacalis, Serratia marcensces, Staph. aureus, Bacillus spp and Mucor spp. Conclusively, this study underlines the public health importance of these preparations given the high burden of such human pathogen as Ecoli O157H7, Ps aeruginosa, Stahp aureus, etc. in the preparations.

  3. Is the quality of brief motivational interventions for drug use in primary care associated with subsequent drug use?

    Science.gov (United States)

    Palfai, Tibor P; Cheng, Debbie M; Bernstein, Judith A; Palmisano, Joseph; Lloyd-Travaglini, Christine A; Goodness, Tracie; Saitz, Richard

    2016-05-01

    Although a number of brief intervention approaches for drug use are based on motivational interviewing (MI), relatively little is known about whether the quality of motivational interviewing skills is associated with intervention outcomes. The current study examined whether indices of motivational interviewing skill were associated with subsequent drug use outcomes following two different MI-based brief interventions delivered in primary care; a 15 min Brief Negotiated Interview (BNI) and a 45 min adaptation of motivational interviewing (MOTIV). Audio recordings from 351 participants in a randomized controlled trial for drug use in primary care were coded using the Motivational Interviewing Treatment Integrity Scale, (MITI Version 3.1.1). Separate negative binomial regression analyses, stratified by intervention condition, were used to examine the associations between six MITI skill variables and the number of days that the participant used his/her main drug 6 weeks after study entry. Only one of the MITI variables (% reflections to questions) was significantly associated with the frequency of drug use in the MOTIV condition and this was opposite to the hypothesized direction (global p=0.01, adjusted IRR 1.50, 95%CI: 1.03-2.20 for middle vs. lowest tertile [higher skill, more drug use]. None were significantly associated with drug use in the BNI condition. Secondary analyses similarly failed to find consistent predictors of better drug outcomes. Overall, this study provides little evidence to suggest that the level of MI intervention skills are linked with better drug use outcomes among people who use drugs and receive brief interventions in primary care. Findings should be considered in light of the fact that data from the study are from negative trial of SBI and was limited to primary care patients. Future work should consider alternative ways of examining these process variables (i.e., comparing thresholds of proficient versus non-proficient skills) or

  4. Augmentation of the Differentiation Response to Antitumor Antimalarials

    National Research Council Canada - National Science Library

    Rahim, Rayhana

    2003-01-01

    .... We have shown that the quinoline antimalarials chloroquine (CO) and hydroxychioroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-10A cells...

  5. Unambiguous Synthesis and Prophylactic Antimalarial Activities of Imidazolidinedione Derivatives

    National Research Council Canada - National Science Library

    Zhang, Quan; Guan, Jian; Sacci, John; Ager, Arba; Ellis, William; Mihlhous, Wilbur; Kyle, Dennis; Lin, Ai J

    2005-01-01

    .... To search for compounds with good oral efficacy, a series of carbamate derivatives of the active components were prepared by the new procedure, many of which showed profound causal prophylactic antimalarial activity against Plasmodium yoelil in mouse by oral administration.

  6. Pharmacological screening of some traditionally-used antimalarial ...

    African Journals Online (AJOL)

    Pharmacological screening of some traditionally-used antimalarial plants from the Democratic Republic of Congo compared to their ecological taxonomic equivalence in Madagascar. KN Ngbolua, H Rafatro, H Rakotoarimanana, US Ratsimamanga, V Mudogo, PT Mpiana, DST Tshibangu ...

  7. In Vivo Antimalarial Activities of Plants Used in Ethiopian Traditional ...

    African Journals Online (AJOL)

    In Vivo Antimalarial Activities of Plants Used in Ethiopian Traditional Medicine, Delomenna, Southeast Ethiopia. Ashenafi Asefa, Kelbassa Urga, Mulugeta Guta, Waleleng Mekonene, Daniel Melaku, Kise Mudie, Tesgayae Kidanemariam ...

  8. Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

    OpenAIRE

    Avdeef, Alex; Fuguet, Elisabet; Llinàs, Antonio; Ràfols, Clara; Bosch, Elisabeth; Völgyi, Gergely; Verbić, Tatjana; Boldyreva, Elena; Takács-Novák, Krisztina

    2016-01-01

    This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (su...

  9. In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

    Directory of Open Access Journals (Sweden)

    Adeleke Clement Adebajo

    2014-08-01

    Full Text Available Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED50 values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED50 value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED50 of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED50 = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05 more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity.

  10. Drug treatment in the elderly: an intervention in primary care to enhance prescription quality and quality of life.

    Science.gov (United States)

    Olsson, Inger Nordin; Runnamo, Rebecka; Engfeldt, Peter

    2012-03-01

    The aim of the study was to assess the effect on prescription quality and quality of life after intervention with prescription reviews and promotion of patient participation in primary care. A randomized controlled study with three groups: (A) controls, (B) prescription review sent to physician, and (C) as in B and with a current comprehensive medication record sent to the patient. The municipality of Örebro, Sweden (130 000 inhabitants). The study focused on the easiest possible intervention to increase prescription quality and thereby increase quality of life. The intervention should be cost-efficient, focus on colleague-to-colleague advice, and be possible to perform in the primary health care centre without additional resources such as a pharmacist. 150 patients recently discharged from hospital. Inclusion criteria were: ≥ 75 years, ≥ five drugs and living in ordinary homes. Quality of life (EQ-5D index, EQ VAS) and quality of prescriptions. Extreme polypharmacy was common and persistent in all three groups and this was accompanied by an unchanged frequency of drug-risk indicators. There was a low EQ-5D index and EQ VAS in all three groups throughout the study. No statistically significant differences were found anywhere between the groups. The intervention seems to have had no effect on quality of prescriptions or quality of life. This underlines the major challenge of finding new strategies for improving prescription quality to improve patient outcome measures such as quality of life and reduce the known risks of polypharmacy for the elderly.

  11. Formulation, quality control and shelf life of the experimental cytostatic drug cyclopentenyl cytosine

    NARCIS (Netherlands)

    Schimmel, Kirsten; Guchelaar, Henk-Jan; van Kan, Erik

    2006-01-01

    This paper describes the formulation and quality control of an aqueous sterilized formulation of the experimental cytostatic drug cyclopentenyl cytosine (CPEC) to be used in Phase I/II clinical trials. The raw drug substance was extensively tested. A High Pressure Liquid Chromotography (HPLC) method

  12. Microbiological Quality of some Expired Drugs in Sokoto Metropolis ...

    African Journals Online (AJOL)

    5Department of Biological Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria. 6Department of Science ... ABSTRACT: Twenty eight samples of expired drugs were obtained from different medical stores including. Sokoto State Medical Store in .... prevented completely through testing of the final product (Orji, 2003).

  13. Microbiological Quality of some Expired Drugs in Sokoto Metropolis ...

    African Journals Online (AJOL)

    The nutrient agar plates were incubated at 37oC for 24 hours and the Malt Extract plates were incubated at 26oC for 3-7 days After incubation, the organisms were identified using a combination of microscopy and biochemical tests. For each drug, the procedure was repeated four times. The frequency of occurrence of each ...

  14. Quality of drug label information on QT interval prolongation

    DEFF Research Database (Denmark)

    Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H

    2014-01-01

    BACKGROUND: Information regarding QT-prolongation in the drug label may vary between products. This could lead to suboptimal risk minimization strategies. OBJECTIVE: To systematically assess the variation in the extent and content of information on QT prolongation in the summary of product...

  15. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    International Nuclear Information System (INIS)

    Rehman, F.U.; Khan, M.F.; Khan, G.M.; Khan, H.; Khan, I.U.

    2010-01-01

    Metal complexes are famous for a wide array of chemotherapeutic effects. The current study was designed to synthesize and evaluate unexplored chemotherapeutic effects of Cu (II) and Nickel (II) complexes of the non-steroidal anti-inflammatory drug diclofenac. Nickel complex exhibited significant leishmanicidal activity against Lieshmania major, while the copper complex was found to possess low activity against the same pathogen. Both of the complexes revealed low antibacterial activities and were interestingly failed to produce any considerable antimalarial activity against Plasmodium falciparum 3D7. Selective leishmanicidal activities of Nickel (II) complex of diclofenac needs further improvement to be developed as potential new metal-based leishmanicidal agent.(author)

  16. Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp

    OpenAIRE

    Laurent, Dominique; Jullian, Valérie; Parenty, A.; Knibiehler, M.; Dorin, D.; Schmitt, S.; Lozach, O.; Lebouvier, N.; Frostin, M.; Alby, F.; Maurel, Séverine; Doerig, C.; Meijer, L.; Sauvain, Michel

    2006-01-01

    As part of our search for new antimalarial drugs, we have screened for inhibitors of Pfnek-1, a protein kinase of Plasmodium falciparum, in south Pacific marine sponges. On the basis of a preliminary screening, the ethanolic crude extract of a new species of Xestospongia collected in Vanuatu was selected for its promising activity. A bioassay-guided fractionation led us to isolate xestoquinone which inhibits Pfnek-1 with an IC50 around 1 mu M. Among a small panel of plasmodial protein kinases...

  17. Quality of life in children with adverse drug reactions: a narrative and systematic review.

    Science.gov (United States)

    Del Pozzo-Magaña, Blanca R; Rieder, Michael J; Lazo-Langner, Alejandro

    2015-10-01

    Adverse drug reactions are a common problem affecting adults and children. The economic impact of the adverse drug reactions has been widely evaluated; however, studies of the impact on the quality of life of children with adverse drug reactions are scarce. The aim was to evaluate studies assessing the health-related quality of life of children with adverse drug reactions. We conducted a systematic review that included the following electronic databases: MEDLINE, EMBASE and the Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Cochrane Controlled Trials Register and the Health Technology Assessment Databases). Nine studies were included. Four of the studies were conducted in children with epilepsy; the rest of them involved children with chronic viral hepatitis, Crohn's disease, paediatric cancer and multiple adverse drug reactions compared with healthy children. Based on their findings, authors of all studies concluded that adverse drug reactions had a negative impact on the quality of life of children. No meta-analysis was conducted given the heterogeneous nature of the studies. To date, there is no specific instrument that measures quality of life of children with adverse drug reactions, and the information available is poor and variable. In general, adverse drug reactions have a negative impact on the quality of life of affected children. For those interested in this area, more work needs to be done to improve tools that help to evaluate efficiently the health-related quality of life of children with adverse drug reactions and chronic diseases. © 2014 The British Pharmacological Society.

  18. Review of Drug Quality and Security Act of 2013: The Drug Supply Chain Security Act (DSCSA

    Directory of Open Access Journals (Sweden)

    Elona Gjini

    2016-10-01

    Full Text Available The Drug Supply Chain Security Act (DSCSA signed into law in November 27, 2013 by president Obama creates a uniform national standard for tracing drug products through the supply chain. The goal of DQSA is to enhance FDA’s ability to help protect consumers by detecting and removing potential dangerous products from the pharmaceutics distribution supply chain. A new electronic, interoperable system will identify and trace only prescription drugs in the finished form for human use while distributed in the United States. The purpose of this review was to shed light on a complex and complicated process that it will require cooperation between FDA and drug manufactures, wholesale drug distributors, repackagers and dispensers. The implementation of the DSCSA is based on several law requirements and FDA has developed a schedule with time frames for each of them to be executed over a 10-year period. From this review, FDA recommendations are provided through the FDA Guidance on Identifying Suspect Product document to help trading partners and provide information about the risk of suspect drugs entering the supply chain. Moreover, FDA organized on April 5-6, 2016 in Silver Spring, MD a public workshop to gather valuable feedback from stakeholders who shared their input about the implementation of the new electronic system and its requirements. By the end of 2023, a unified system will provide easier data exchange and less errors, and will increase the safety and security of the pharmaceutical distribution supply chain.   Type: Student Project

  19. Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance.

    Science.gov (United States)

    Carey, Maureen A; Papin, Jason A; Guler, Jennifer L

    2017-07-19

    Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. Here, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood. Using this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.

  20. A multiple biomarker assay for quality assessment of botanical drugs using a versatile microfluidic chip.

    Science.gov (United States)

    Li, Zhen-Hao; Ai, Ni; Yu, Lawrence X; Qian, Zhong-Zhi; Cheng, Yi-Yu

    2017-09-25

    Quality control is critical for ensuring the safety and effectiveness of drugs. Current quality control method for botanical drugs is mainly based on chemical testing. However, chemical testing alone may not be sufficient as it may not capture all constituents of botanical drugs. Therefore, it is necessary to establish a bioassay correlating with the drug's known mechanism of action to ensure its potency and activity. Herein we developed a multiple biomarker assay to assess the quality of botanicals using microfluidics, where enzyme inhibition was employed to indicate the drug's activity and thereby evaluate biological consistency. This approach was exemplified on QiShenYiQi Pills using thrombin and angiotensin converting enzyme as "quality biomarkers". Our results demonstrated that there existed variations in potency across different batches of the intermediates and preparations. Compared with chromatographic fingerprinting, the bioassay provided better discrimination ability for some abnormal samples. Moreover, the chip could function as "affinity chromatography" to identify bioactive phytochemicals bound to the enzymes. This work proposed a multiple-biomarker strategy for quality assessment of botanical drugs, while demonstrating for the first time the feasibility of microfluidics in this field.

  1. Quality indicators of preventable adverse drug events in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Thomsen, Linda Aagaard

    population receiving oral antihyperglycaemic treatment (9,791 persons) was set up, and indicator positives identified (Articles no. 2 and 3). The third step in the model consisted of a risk assessment of preventable adverse drug events, including an assessment of clinical areas that need quality improvement...... events are common in primary care, with many resulting in hospitalisation. Projected to a Danish setting, 216,000 patients will experience a preventable adverse drug event each year, and 162,000 of these patients will need hospital admission. Quality improvement interventions should target errors......Summary Background: Preventable adverse drug events are caused by errors in the medication use Preventable adverse drug events are caused by errors in the medication use process, and are of particular interest when designing interventions to improve the quality of medication therapy. Type 2...

  2. Drug policy and administration affecting quality of life of the poor in Thailand.

    Science.gov (United States)

    Prutipinyo, Chardsumon; Sirichotiratana, Nithat

    2011-09-01

    This study aims to analyze drug policy and administration affecting quality of life of the poor in Thailand. Review of official reports and related documents, for the past 10 years (from 2000-2010). By imposing compulsory licensing, the Thai government maintains negotiating power over the price of pharmaceutical products with the patent holders of the original drugs. This gives an opportunity for relevant government agencies to produce or import patented drugs. At present, there are many problems and obstacles. The findings show that developing countries need to strengthen their negotiating power so that the pharmaceutical manufacturers cannot take advantage through mechanisms provided for such as compulsory licensing and provisions for flexibility in Trade-Related Intellectual Property Rights (TRIPS) agreement. Furthermore, these countries must support and empower the local pharmaceutical manufacturers to produce generic drugs. Developing countries should ensure that their populations have confidence in universal coverage service and medical systems regarding the quality of generic drugs.

  3. Quality indicators of preventable adverse drug events in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Thomsen, Linda Aagaard

    interventions against medication errors. Methods: A systematic literature review of the available literature on preventable adverse A systematic literature review of the available literature on preventable adverse drug events was conducted to describe the incidence and characteristics of preventable adverse......Summary Background: Preventable adverse drug events are caused by errors in the medication use Preventable adverse drug events are caused by errors in the medication use process, and are of particular interest when designing interventions to improve the quality of medication therapy. Type 2...... diabetes became the case because a large proportion of patients are undertreated and not monitored as recommended; yet, the epidemiology of preventable adverse drug events in type 2 diabetes is largely unknown. The aims of the studies were to develop quality indicators for preventable adverse drug events...

  4. Prescription drugs in nursing homes: managing costs and quality in a complex environment.

    Science.gov (United States)

    Mendelson, Dan; Ramchand, Rajeev; Abramson, Richard; Tumlinson, Anne

    2002-11-12

    This brief provides a description of prescription drug use in nursing homes and a summary of current policy issues in this area. The brief first profiles the nursing home pharmaceutical market, outlining the major trends in demographics and drug utilization, the supply chain by which drugs go from manufacturers to pharmacies to nursing home residents, and the alternative arrangements by which prescription drugs in nursing homes are financed. The brief then provides a synopsis of current policy issues, focusing in turn on cost containment and quality improvement initiatives.

  5. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    requirements for the registration, assessment, marketing, authorization, and quality control of .... The mobile phase was consisted of a mixture of methanol, dichloromethane, ammonia and acetonitrile. (40:40:20:10) as stated in BP 2004. A test solution of 0.05% w/v was prepared by mixing 750 ml of water with powdered ...

  6. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    ABSTRACT. An attempt was made to assess the quality and compare the physicochemical equivalence of six brands of ciprofloxacin tablets marketed in Tigray, Ethiopia. Six brands of ciprofloxacin tablets were used in the study. Identity, weight uniformity test, disintegration test, dissolution test and assay for the content of ...

  7. Quality of Life and Adherence to Antiretroviral Drugs | Mweemba ...

    African Journals Online (AJOL)

    Quality of life is a complex broad ranging multidimensional concept defined in terms of individual's subjective experiences. The definition by the ... Antiretroviral regimens are demanding and difficult, with numerous possible side effects and patients need to take the pills for indefinite periods of time. Efficacy of antiretroviral ...

  8. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    An attempt was made to assess the quality and compare the physicochemical equivalence of six brands of ciprofloxacin tablets marketed in Tigray, Ethiopia. Six brands of ciprofloxacin tablets were used in the study. Identity, weight uniformity test, disintegration test, dissolution test and assay for the content of active ...

  9. Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

    International Nuclear Information System (INIS)

    Ofulla, A.V.O.

    1995-01-01

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3 H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC 50 s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC 50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC 50 73.36 ± 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 (± 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs

  10. A Survey of Antimalarial Drug Use Practices among Urban Dwellers ...

    African Journals Online (AJOL)

    One hundred and twenty five (125) (35.71) of the respondents frequently experienced malaria attack and practiced self-medication. One hundred and fifteen (115) (32.86%) of the respondents treated their malaria episode with Sulphadoxine-Pyrimethamine (SP) combination while 90 (25.71%) of the respondents frequently ...

  11. EVALUATION OF ANTIMALARIAL DRUGS IN INDONESIA, 1981 - 1995

    Directory of Open Access Journals (Sweden)

    Emiliana Tjitra

    2012-09-01

    Full Text Available Telah dilakukan evaluasi obat-obat antimalaria in-vitro dan in-vivo untuk menentukan pola resistensi dan memanfaatkan data ini untuk melakukan sistem pengamatan yang efektif. Semua penelitian pengobatan dan pencegahan malaria di lapangan dan rumah sakit dalam kurun waktu 1981 - 1995 ditelaah. Pertama kali kasus resistensi P. falciparum terhadap klorokuin ditemukan di Kalimantan Timur pada tahun 1973, dan telah menyebar ke seluruh (27 propinsi Indonesia dengan derajat RI - RIIL Pada saat ini, resistensi Riil telah didapatkan di 20 propinsi, sedangkan pada tahun 1981-1985 hanya di 4 propinsi. Kasus malaria vivaks resisten klorokuin dilaporkan pertama kali dari Sumatera Utara (P. Nias pada tahun 1991, dan kemudian ditemukan di Irian Jaya (41%, Sumatera Utara (13%, Nusa Tenggara Timur (8%, Sulawesi Utara (2% dan Jakarta (laporan kasus yang didapatkan dari transfusi darah. Malaria falsiparum yang tercatat resisten sulfadoksin-pirimetamin didapatkan di 11 propinsi dengan derajat RI - RII. P. falciparum resisten in-vitro juga didapatkan terhadap kina (6 propinsi, meflokuin (5 propinsi dan amodiakuin (4 propinsi. Beberapa obat antimalaria baru (meflokuin, halofantrin dan derivat artemisinin telah diteliti dan ternyata efektif untuk pengobatan malaria tanpa komplikasi. Penelitian pencegahan menunjukkan angka pencegahan untuk klorokuin 41-92%, sulfadoksin- pirimetamin 98%, primakuin 89-92%, doksisiklin 99% dan meflokuin 100 %. Efek samping obat-obat antimalaria tersebut umumnya ringan. Di Indonesia, penyebaran malaria falsiparum resisten klorokuin R1II dan malaria falsiparum resisten multidrug merupakan masalah kesehatan masyarakat yang serius dan tantangan dalam pengobatan. Demikian pula kehadiran malaria vivaks resisten klorokuin menimbulkan masalah baru yang lain. Oleh sebab itu obat-obat antimalaria yang didistribusikan sebaiknya dikemas per paket untuk dosis obat pengobatan yang lengkap dengan keterangan cara minum obat yang jelas. Dengan demikian dapat dicegah pemberian dosis pengobatan yang tidak cukup dan berkembangnya resistensi obat. Selama obat antimalaria baru belum tersedia di Indonesia, perlu dilakukan penelitian perbaikan efikasi obat antimalaria yang sudah ada. Obat pencegahan alternatif yang aman dan efektif untuk anak-anak, ibu hamil dan menyusui juga perlu diteliti.

  12. Research Article Antimalarial Drugs for Pediatrics - Prescribing and ...

    African Journals Online (AJOL)

    Erah

    2011-03-23

    Mar 23, 2011 ... parents of children seeking malaria treatment were also interviewed at the public hospitals. Results: A ... The annual incidence rate is 400–500/1,000 people, and this number doubles for children less than five years of age [1]. It is estimated that over 1% .... remaining 78 (39%) refused to dispense the.

  13. Evaluation of French Guiana traditional antimalarial remedies.

    Science.gov (United States)

    Bertani, S; Bourdy, G; Landau, I; Robinson, J C; Esterre, Ph; Deharo, E

    2005-04-08

    In order to evaluate the antimalarial potential of traditional remedies used in French Guiana, 35 remedies were prepared in their traditional form and screened for blood schizonticidal activity in vitro on Plasmodium falciparum chloroquine re4sistant strain (W2). Some of these extracts were screened in vivo against Plasmodium yoelii rodent malaria. Ferriprotoporphyrin inhibition test was also performed. Four remedies, widely used among the population as preventives, were able to inhibit more than 50% of the parasite growth in vivo at around 100 mg/kg: Irlbachia alata (Gentiananceae), Picrolemma pseudocoffea (Simaroubaceae), Quassia amara (Simaroubaceae), Tinospora crispa (Menispermaceae) and Zanthoxylum rhoifolium (Rutaceae). Five remedies displayed an IC50 in vitro < 10 microg/ml: Picrolemma pseudocoffea, Pseudoxandra cuspidata (Annonaceae) and Quassia amara leaves and stem, together with a multi-ingredient recipe. Two remedies were more active than a Cinchona preparation on the ferriprotoporphyrin inhibition test: Picrolemma pseudocoffea and Quassia amara. We also showed that a traditional preventive remedy, made from Geissospermum argenteum bark macerated in rum, was able to impair the intrahepatic cycle of the parasite. For the first time, traditional remedies from French Guiana have been directly tested on malarial pharmacological assays and some have been shown to be active.

  14. The method of quality marker research and quality evaluation of traditional Chinese medicine based on drug properties and effect characteristics.

    Science.gov (United States)

    Zhang, Tiejun; Bai, Gang; Han, Yanqi; Xu, Jun; Gong, Suxiao; Li, Yazhuo; Zhang, Hongbing; Liu, Changxiao

    2018-03-01

    Quality of traditional Chinese medicine (TCM) plays a critical role in industry of TCM. Rapid development of TCM pharmaceutical areas is, however, greatly limited, since there are many issues not been resolved, concerning the quality study of TCM. Core concept of TCM quality as well as the characteristics of TCM was discussed, in order to guide the quality research and evaluation of TCM, further improve the level of TCM quality control. In this review, on the basis of systematic analysis of fundamental property and features of TCM in clinical application, the approaches and methods of quality marker (Q-marker) study were proposed through combination of transitivity and traceability of essentials of quality, correlation between chemical ingredients and drug property/efficacy, as well as analysis of endemicity of ingredients sharing similar pharmacophylogenetic and biosynthetic approaches. The approaches and methods of Q-marker study were proposed and the novel integrated pattern for quality assessment and control of TCM was established. The core concept of Q-marker has helped to break through the bottleneck of the current fragmented quality research of TCM and improved the scientificity, integrity and systematicness of quality control. Copyright © 2018 Elsevier GmbH. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Elizabeth Pisani

    2017-08-01

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

  16. Report of the WHO Collaborating Centre for Quality Assurance of Essential Drugs

    Directory of Open Access Journals (Sweden)

    Drs. R. Pandjaitan

    2012-09-01

    Full Text Available National Quality Control Laboratory of Drugs and Food (NQCL DF is a central quality control laboratory for pharmaceuticals and food commodities under the supervision of the Director General of Drug and Food Control, Ministry of Health.Based on the Ministry of Health Act.No. 145/Menkes/SK/IV/1978, in 1978, NQCL DF was established. In the same year 27 Provincial Quality Control Laboratory of Drug and Food (PQCL DF, in each province in Indonesia were also established based on the Ministry of Health Act.No. 146/Menkes/ SK/IV/1978. The objective of NQCL DF are: To protect the consumers from adulterated or misbranded pharmaceutical and food commodities.To evaluated and to accrediate the quality control laboratories of pharmaceuticals and food commoditities.To control and give guidance to all quality control laboratories of drug and food.To stimulate the quality of domestic pro­ducts of pharmaceuticals and food com­modities to promote the volume of exports.

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

    Directory of Open Access Journals (Sweden)

    Khodakarim Nastaran

    2010-05-01

    Full Text Available Abstract Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain and CY27 (chloroquine-sensitive strain, using the parasite lactate dehydrogenase (pLDH assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain. Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy, Solanum surattense (Burm.f. and Prosopis juliflora (Sw. showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time.

  18. Quinoline hybrids and their antiplasmodial and antimalarial activities.

    Science.gov (United States)

    Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

    2017-10-20

    Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Drug management in acute kidney disease - Report of the Acute Disease Quality Initiative XVI meeting.

    Science.gov (United States)

    Ostermann, Marlies; Chawla, Lakhmir S; Forni, Lui G; Kane-Gill, Sandra L; Kellum, John A; Koyner, Jay; Murray, Patrick T; Ronco, Claudio; Goldstein, Stuart L

    2018-02-01

    To summarize and extend the main conclusions and recommendations relevant to drug management during acute kidney disease (AKD) as agreed at the 16 th Acute Disease Quality Initiative (ADQI) consensus conference. Using a modified Delphi method to achieve consensus, experts attending the 16 th ADQI consensus conference reviewed and appraised the existing literature on drug management during AKD and identified recommendations for clinical practice and future research. The group focussed on drugs with one of the following characteristics: (i) predominant renal excretion; (ii) nephrotoxicity; (iii) potential to alter glomerular function; and (iv) presence of metabolites that are modified in AKD and may affect other organs. We recommend that medication reconciliation should occur at admission and discharge, at AKD diagnosis and change in AKD phase, and when the patient's condition changes. Strategies to avoid adverse drug reactions in AKD should seek to minimize adverse events from overdosing and nephrotoxicity and therapeutic failure from under-dosing or incorrect drug selection. Medication regimen assessment or introduction of medications during the AKD period should consider the nephrotoxic potential, altered renal and nonrenal elimination, the effects of toxic metabolites and drug interactions and altered pharmacodynamics in AKD. A dynamic monitoring plan including repeated serial assessment of clinical features, utilization of renal diagnostic tests and therapeutic drug monitoring should be used to guide medication regimen assessment. Drug management during different phases of AKD requires an individualized approach and frequent re-assessment. More research is needed to avoid drug associated harm and therapeutic failure. © 2017 The British Pharmacological Society.

  20. Quality assurance of chemical ingredient classification for the National Drug File - Reference Terminology.

    Science.gov (United States)

    Zheng, Ling; Yumak, Hasan; Chen, Ling; Ochs, Christopher; Geller, James; Kapusnik-Uner, Joan; Perl, Yehoshua

    2017-09-01

    The National Drug File - Reference Terminology (NDF-RT) is a large and complex drug terminology consisting of several classification hierarchies on top of an extensive collection of drug concepts. These hierarchies provide important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles connecting drugs to classifications. In previous studies, we have introduced various kinds of Abstraction Networks to summarize the content and structure of terminologies in order to facilitate their visual comprehension, and support quality assurance of terminologies. However, these previous kinds of Abstraction Networks are not appropriate for summarizing the NDF-RT classification hierarchies, due to its unique structure. In this paper, we present the novel Ingredient Abstraction Network (IAbN) to summarize, visualize and support the audit of NDF-RT's Chemical Ingredients hierarchy and its associated drugs. A common theme in our quality assurance framework is to use characterizations of sets of concepts, revealed by the Abstraction Network structure, to capture concepts, the modeling of which is more complex than for other concepts. For the IAbN, we characterize drug ingredient concepts as more complex if they belong to IAbN groups with multiple parent groups. We show that such concepts have a statistically significantly higher rate of errors than a control sample and identify two especially common patterns of errors. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. ANTIMICROBIAL, PHYSICAL AND CHEMICAL QUALITIES OF MEDICINAL ANTISEPTIC DRUGS

    Directory of Open Access Journals (Sweden)

    Paliy D. V.

    2014-12-01

    Full Text Available In our research results of the study of antimicrobial, physical and chemical qualities of antiseptic medicines of decamethoxin (DCM. Antimicrobial activity of DCM, palisan, decasan, deseptol against srains of S.aureus (n 56, S.epidermidis (n 26, E.coli (n 24, P.mirabilis (n 11, P.vulgaris (n 8 was studied by means of method of serial dilutions. Obtained data of mass spectrometry study of antimicrobial compositions with constant concentrations of DCM have shown that medicinal forms of DCM are complex physical and chemical systems, because of different origin and number of adjuvant ingredients used during their fabrication. Among synthetic quaternary ammonium agents there have been found the substance (commercial name of medicine is decamethoxin to have high antimicrobial activity against strains of grampositive and gram-negative microorganisms, an also C.albicans. There was found that antimicrobial activity of antiseptic palisan had been higher comparably to DCM in equivalent concentration. The composition and concentrations of acting agents and the methodology of preparation of palisan have been substantiated on the basis of microbiological, mass spectrometry characteristics of antiseptics DCM, palisan.

  2. Risky drug use and effects on sleep quality and daytime sleepiness.

    Science.gov (United States)

    Ogeil, Rowan P; Phillips, James G; Rajaratnam, Shantha M W; Broadbear, Jillian H

    2015-09-01

    Sleep problems are commonly reported following alcohol and cannabis abuse, but our understanding of sleep in non-clinical drug using populations is limited. The present study examined the sleep characteristics of alcohol and cannabis users recruited from the wider community. Two hundred forty-eight self-identified alcohol and/or cannabis users (131 women and 117 men) with a mean age of 26.41 years completed an online study that was advertised via online forums, print media and flyers. As part of the study, participants completed validated sleep scales assessing sleep quality (Pittsburgh Sleep Quality Index) and excessive daytime sleepiness (Epworth Sleepiness Scale) in addition to validated drug scales assessing alcohol (Alcohol Use Disorders Identification Test) and cannabis (Marijuana Screening Inventory) use. Problems with sleep quality were more commonly reported than were complaints of excessive daytime sleepiness. Clinically significant poor sleep quality was associated with comorbid problem alcohol and cannabis use. Women reporting problem alcohol and cannabis use had poorer sleep outcomes than men. Social drug users who report risky alcohol and cannabis use also report poor sleep. Poor sleep quality likely exacerbates any drug-associated problems in non-clinical populations. Copyright © 2015 John Wiley & Sons, Ltd.

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

    Science.gov (United States)

    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 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. © The American Society of Tropical Medicine and Hygiene.

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

    Science.gov (United States)

    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. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Murtihapsari Murtihapsari

    2013-12-01

    Full Text Available Plasmodium falciparum, the agent of malignant malaria, is one of mankind's most severe scourges, mainly in the tropic world. Efforts to develop preventive vaccines or remedial drugs are handicapped by the parasite's rapid evolution of drug resistance. Here, we presented an advance work on examination of antimalarial component from marine life of Xestospongia sp., the study is based on hexane extraction method. The premier result, we obtained five fractions. Among these five fractions, the fourth has the most potent inhibitory against the growth of P. falciparum 3D7 with an IC50: 7.13 µg/mL. A compiled spectrum analysis, FTIR, 1H-NMR and GC-MS, revealed that the fourth fraction consisted abundantly of two secondary metabolites such as flavonoids and triterpenoids. Finally, our results suggest a plausible structure rooted to the base of ibuprofen.

  6. Do advertisements for antihypertensive drugs in Australia promote quality prescribing? A cross-sectional study.

    Science.gov (United States)

    Montgomery, Brett D; Mansfield, Peter R; Spurling, Geoffrey K; Ward, Alison M

    2008-05-20

    Antihypertensive medications are widely prescribed by doctors and heavily promoted by the pharmaceutical industry. Despite strong evidence of the effectiveness and cost-effectiveness of thiazide diuretics, trends in both promotion and prescription of antihypertensive drugs favour newer, less cost-effective agents. Observational evidence shows correlations between exposure to pharmaceutical promotion and less ideal prescribing. Our study therefore aimed to determine whether print advertisements for antihypertensive medications promote quality prescribing in hypertension. We performed a cross-sectional study of 113 advertisements for antihypertensive drugs from 4 general practice-oriented Australian medical publications in 2004. Advertisements were evaluated using a quality checklist based on a review of hypertension management guidelines. Main outcome measures included: frequency with which antihypertensive classes were advertised, promotion of thiazide class drugs as first line agents, use of statistical claims in advertisements, mention of harms and prices in the advertisements, promotion of assessment and treatment of cardiovascular risk, promotion of lifestyle modification, and targeting of particular patient subgroups. Thiazides were the most frequently advertised drug class (48.7% of advertisements), but were largely promoted in combination preparations. The only thiazide advertised as a single agent was the most expensive, indapamide. No advertisement specifically promoted any thiazide as a better first-line drug. Statistics in the advertisements tended to be expressed in relative rather than absolute terms. Drug costs were often reported, but without cost comparisons between drugs. Adverse effects were usually reported but largely confined to the advertisements' small print. Other than mentioning drug interactions with alcohol and salt, no advertisements promoted lifestyle modification. Few advertisements (2.7%) promoted the assessment of cardiovascular risk

  7. Do advertisements for antihypertensive drugs in Australia promote quality prescribing? A cross-sectional study

    Directory of Open Access Journals (Sweden)

    Spurling Geoffrey K

    2008-05-01

    Full Text Available Abstract Background Antihypertensive medications are widely prescribed by doctors and heavily promoted by the pharmaceutical industry. Despite strong evidence of the effectiveness and cost-effectiveness of thiazide diuretics, trends in both promotion and prescription of antihypertensive drugs favour newer, less cost-effective agents. Observational evidence shows correlations between exposure to pharmaceutical promotion and less ideal prescribing. Our study therefore aimed to determine whether print advertisements for antihypertensive medications promote quality prescribing in hypertension. Methods We performed a cross-sectional study of 113 advertisements for antihypertensive drugs from 4 general practice-oriented Australian medical publications in 2004. Advertisements were evaluated using a quality checklist based on a review of hypertension management guidelines. Main outcome measures included: frequency with which antihypertensive classes were advertised, promotion of thiazide class drugs as first line agents, use of statistical claims in advertisements, mention of harms and prices in the advertisements, promotion of assessment and treatment of cardiovascular risk, promotion of lifestyle modification, and targeting of particular patient subgroups. Results Thiazides were the most frequently advertised drug class (48.7% of advertisements, but were largely promoted in combination preparations. The only thiazide advertised as a single agent was the most expensive, indapamide. No advertisement specifically promoted any thiazide as a better first-line drug. Statistics in the advertisements tended to be expressed in relative rather than absolute terms. Drug costs were often reported, but without cost comparisons between drugs. Adverse effects were usually reported but largely confined to the advertisements' small print. Other than mentioning drug interactions with alcohol and salt, no advertisements promoted lifestyle modification. Few

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

    Science.gov (United States)

    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. Copyright © 2011 Wiley-Liss, Inc.

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

    Directory of Open Access Journals (Sweden)

    Gabra Michael

    2011-06-01

    in Kilombero to 47% in Morogoro Rural. Conclusions The intervention increased access to affordable ACTs for underserved populations. Indications are that antimalarial monotherapies are being "crowded out" of the market. Importantly, the transition to ACTs has been accomplished in an environment where the safety and efficacy of the drugs and the quality of services are being monitored and regulated. This paper presents a description of the pilot program implementation, results of the program evaluation, and a discussion of the challenges and recommendations that will be used to guide rollout of subsidized ACT in ADDOs in the rest of Tanzania and possibly in other countries.

  10. Low quality of reporting adverse drug reactions in paediatric randomised controlled trials

    NARCIS (Netherlands)

    de Vries, Tjalling W; van Roon, Eric N

    2010-01-01

    OBJECTIVE: Randomised controlled trials (RCT) offer an opportunity to learn about frequency and character of adverse drug reactions. To improve the quality of reporting adverse effects, the Consort group published recommendations. The authors studied the application of these recommendations in RCTs

  11. Assessment of drug treatment quality in two Danish health-care centres

    DEFF Research Database (Denmark)

    Andersen, Stig Ejdrup; Edfors, Kajsa

    2011-01-01

    Bridging the primary and secondary sector, health-care centres aim to reduce morbidity and prevent further hospitalization in patients with chronic heart diseases. The aim of this study was to describe the quality of drug treatment in patients with chronic heart diseases in two Copenhagen health-care...

  12. Comparison of indicators assessing the quality of drug prescribing for asthma

    NARCIS (Netherlands)

    Veninga, C.C.M.; Denig, P.; Pont, L.G.; Haaijer-Ruskamp, F.M.

    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

  13. Evaluation of the quality of anti Tuberculosis drugs in Lusaka, Zambia

    African Journals Online (AJOL)

    Methodology: This was a cross sectional study whose objective was to determine the quality of 3 types of fixed dose combination (FDC) anti TB drugs namely 4FDC, 3FDC and 2FDC tablets available in Lusaka District by assessing the presence of active ingredients and the percentage content of these active ingredients ...

  14. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries.

    Science.gov (United States)

    O'Connell, Kathryn A; Gatakaa, Hellen; Poyer, Stephen; Njogu, Julius; Evance, Illah; Munroe, Erik; Solomon, Tsione; Goodman, Catherine; Hanson, Kara; Zinsou, Cyprien; Akulayi, Louis; Raharinjatovo, Jacky; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Adjibabi, Chérifatou Bello; Agbango, Jean Angbalu; Ramarosandratana, Benjamin Fanomezana; Coker, Babajide; Rubahika, Denis; Hamainza, Busiku; Chapman, Steven; Shewchuk, Tanya; Chavasse, Desmond

    2011-10-31

    Artemisinin-based combination therapy (ACT) is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia. Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets) as compared to first-line quality-assured ACT (price of first-line quality-assured ACT ($0.14 [IQR: $0.10, $0.57]) was significantly lower than the most popular treatment (chloroquine, $0.36 [IQR: $0.36, $0.36]). Quality-assured ACT accounted for less than 25% of total anti-malarial volumes; private-sector quality-assured ACT volumes represented less than 6% of the total market share. Most anti-malarials were distributed through the private sector, but often comprised non-artemisinin therapies, and in the DRC and Nigeria, oral artemisinin monotherapies. Provider knowledge of the first-line treatment was significantly lower in the private sector than in the public/not-for-profit sector. These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials

  15. Evaluation of the use of Cocos nucifera as antimalarial remedy in Malaysian folk medicine.

    Science.gov (United States)

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

    2011-04-12

    White flesh extract of Cocos nucifera (coconut) was studied to ascertain the ethnopharmacological standing of its antimalarial usage in Malaysian folk medicine. The crude methanol extract was investigated for phytochemical constituents and acute oral toxicity. Antimalarial activity of different extract doses of 50, 100, 200 and 400mg/kg were investigated in vivo against Plasmodium berghei (NK65) infections in mice during early, established and residual infections. Chloroquine (20mg/kg) and pyrimethamine (1.2mg/kg) were used as reference drugs. The results revealed that the extract contained some phytochemical constituents and is toxicologically safe by oral administration. The extract significantly reduced the parasitaemia by the 200 and 400mg/kg doses in the all three in vivo assessment assays. However, the extract did not significantly increase the survival time of the infected mice. The observed pharmacological activities suggest that the Malaysian folkloric medicinal application of Cocos nucifera has a pharmacological basis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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

    Science.gov (United States)

    Bamunuarachchi, Gayan S; Ratnasooriya, Wanigasekara D; Premakumara, Sirimal; Udagama, Preethi V

    2013-12-01

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

  17. Concepts of illicit drug quality among darknet market users: Purity, embodied experience, craft and chemical knowledge.

    Science.gov (United States)

    Bancroft, Angus; Scott Reid, Peter

    2016-09-01

    Users of darknet markets refer to product quality as one of the motivations for buying drugs there, and vendors present quality as a selling point. However, what users understand by quality and how they evaluate it is not clear. This article investigates how users established and compared drug quality. We used a two-stage method for investigating users' assessments. The user forum of a darknet market that we called 'Merkat' was analysed to develop emergent themes. Qualitative interviews with darknet users were conducted, then forum data was analysed again. To enhance the applicability of the findings, the forum was sampled for users who presented as dependent as well as recreational. Quality could mean reliability, purity, potency, and predictability of effect. We focused on the different kinds of knowledge users drew on to assess quality. These were: embodied; craft; and chemical. Users' evaluations of quality depended on their experience, the purpose of use, and its context. Market forums are a case of indigenous harm reduction where users share advise and experiences and can be usefully engaged with on these terms. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Daria Van Tyne

    2011-04-01

    Full Text Available The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb, and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS, searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

  19. Bioguided investigation of the antimalarial activities of Trema ...

    African Journals Online (AJOL)

    Acetone extract of T. orientalis leaves was investigated for its antimalarial activity in a mouse model of Plasmodium berghei using the 4 day suppressive test. Bioguided investigation was carried out by using column chromatographic fractions for in-vivo antiplasmodial screening. Preliminary spectroscopic profile of the most ...

  20. Safety and Tolerability Profile of Artemisinin-Based Antimalarial ...

    African Journals Online (AJOL)

    The WHO in 2001 advocated artemisinin- based antimalarial combination therapy (ACT), which was adopted by Nigeria in 2005. The objective of this study was to characterize the safety and tolerability profile of the ACTs in adult patients with uncomplicated malaria. A descriptive longitudinal study was conducted in the ...

  1. Comparative antimalarial and cytotoxic activities of two Vernonia ...

    African Journals Online (AJOL)

    Comparative antimalarial and cytotoxic activities of two Vernonia species: V. amygdalina from the Democratic Republic of Congo and V. cinerea subsp vialis endemic to Madagascar. KN Ngbolua, H Rakotoarimanana, H Rafatro, US Ratsimamanga, V Mudogo, PT Mpiana, DST Tshibangu ...

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

    African Journals Online (AJOL)

    Purpose: To investigate the in vivo antimalarial effect of Eryngium thorifolium, an endemic plant in. Turkey. Methods: The methanol and water extracts were prepared and phytochemical analysis conducted on the extracts. Twenty four healthy Balb/c male mice, divided into 4 groups (n = 6), were infected intravenously with ...

  3. Drug-Resistant Malaria Parasites Introduced into Madagascar from Comoros Islands

    Science.gov (United States)

    Randrianarivo-Solofoniaina, Armand Eugène; Ahmed, Bedja Said; Jahevitra, Martial; Andriantsoanirina, Landy Valérie; Rasolofomanana, Justin Ranjalahy; Rabarijaona, Léon Paul

    2007-01-01

    To determine risk for drug-resistant malaria parasites entering Madagascar from Comoros Islands, we screened travelers. For the 141 Plasmodium falciparum isolates detected by real-time PCR, frequency of mutant alleles of genes associated with resistance to chloroquine and pyrimethamine was high. International-level antimalarial policy and a regional antimalarial forum are needed. PMID:18217565

  4. A review on the status of quality control and standardization of herbal drugs in India

    Directory of Open Access Journals (Sweden)

    Anju Dhiman

    2016-01-01

    Full Text Available Background: Most of the herbal medicines in the world originate from the developing countries. There are ample opportunities for these countries to expand their global export. The world market for botanical medicines including drug products and raw materials has been estimated to have an annual growth rate between 5% and 15%. Total global botanical drug market is estimated at US$62 billion and is expected to grow to the tune of US$5 trillion by the year 2050. In the USA alone, the usage of botanicals has been increased by 380% between the years 1990 and 1997. Materials and Methods: Ayurveda, the Indian system of medicine, is one of the ancient, yet living traditions that face a typical Western bias. Widespread and growing use of botanicals has created public health challenges globally in terms of quality, safety, and efficacy. Results and Discussion: The development of parameters for standardization and quality control of botanicals is a challenging task. Various regulatory authorities, research organizations, and botanical drug manufacturers have contributed in developing guiding principles and addressing issues related to the quality, safety, and efficacy. Conclusions: The present review describes the regulatory aspects of herbal drugs in India and various other countries.

  5. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure.

    Science.gov (United States)

    Mishra, Neelima; Srivastava, Bina; Bharti, Ram Suresh; Rana, Roma; Kaitholia, Kamlesh; Anvikar, Anupkumar R; Das, Manoj Kumar; Ghosh, Susanta K; Bhatt, Rajendra M; Tyagi, Prajesh K; Dev, Vas; Phookan, Sobhan; Wattal, Suman Lata; Sonal, Gagan Singh; Dhariwal, Akshay Chand; Valecha, Neena

    2016-01-01

    To combat the problem of antimalarial drug resistance, monitoring the changes in drug efficacy over time through periodic surveillance is essential. Since 2009, systematic and continuous monitoring is being done through nationwide sentinel site system. Potential early warning signs like partner drug resistance markers were also monitored in the clinical samples from the study areas. A total of 1864 patients with acute uncomplicated malaria were enrolled in therapeutic efficacy studies of artesunate plus sulphadoxine-pyrimethamine (AS+SP) for Plasmodium falciparum; those infected with P. vivax were given chloroquine (CQ). Polymerase chain reaction (PCR) was used to distinguish post-treatment reinfection from treatment failures. Isolates of P. falciparum were also analysed for dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) gene mutations. Overall, 1687 (91.7%) patients completed the follow-up. In most of the falciparum patients the parasitaemia was cleared within 24 h of treatment, except 12 patients who remained parasite positive after 72 h. Presence of dhfr and dhps quintuple mutation was observed predominantly in treatment failure samples. A daily dose of artesunate of 95% cases in all the sentinel sites except in Northeastern region (NE). Chloroquine remained 100% efficacious in case of P. vivax infections. Till 2012, India's national antimalarial drug resistance monitoring system proved highly efficacious and safe towards first-line antimalarials used in the country, except in Northeastern region where a decline in efficacy of AS+SP has been observed. This led to change in first-line treatment for P. falciparum to artemether-lumefantrine in Northeastern region.

  6. Comparison quality of life patients treated with insulin and oral hypoglycemic drugs

    Science.gov (United States)

    Harahap, A. W.; Nasution, M. S.

    2018-03-01

    Diabetes mellitus (DM) is a group of chronic metabolic diseases with characteristic hyperglycemia that occurs due to abnormalities in insulin secretion, insulin action or both. Improved quality of life is one of the goals of DM management. This study aims to compare thequality of life in40 patients with type 2 diabetes using insulin therapy and 40 patients using oral hypoglycemic drugs in H. Adam Malik Hospital year 2015. This study is an observational study with cross-sectionalstudy designand consecutive sampling method. Evaluation of the patient’s quality of life taken through interviews and questionnaires using the Short Form-36 questionnaire consistingof8 domains of quality of life. Statistical analysis using unpaired t-test and Mann-Whitney test. Results of the quality of life-based on patient characteristics showed significant differences in education factor (p=0.005) and employment factor (p=0.001). Quality of life-based on therapy showed significant differences in domain role of physical (p=0.005) and domain role of emotional (p=0.038).The quality of life of patients with type 2 diabetes using insulin better than using hypoglycemic drug significantly in domain role of physical and domain role of emotions.

  7. FABRICATION AND EVALUATION OF SMART NANOCRYSTALS OF ARTEMISININ FOR ANTIMALARIAL AND ANTIBACTERIAL EFFICACY.

    Science.gov (United States)

    Shah, Syed Muhammad Hassan; Ullah, Farhat; Khan, Shahzeb; Shah, Syed Muhammad Mukarram; Isreb, Mohamad

    2017-01-01

    Background: Nanocrystals have the potential to substantially increase dissolution rate, solubility with subsequent enhanced bioavailability via the oral route of a range of poor water soluble drugs. Regardless of other issues, scale up of the batch size is the main issue associated with bottom up approach. Material and Methods: Smart nanocrystals of artemisinin (ARM) was produced relatively at large batch sizes (100, 200, 300 and 400ml) compared to our previously reported study by (Shah, et al., 2016). ARM nanosuspensions/nanocrystals were characterised using zeta sizer, SEM, TEM, DSC, PXRD and RP-HPLC. The nanosuspensions were finally subjected to in vitro antimalarial and antimicrobial activity. Results: The average particle size (PS) for 400 ml batches was 126.5 ±1.02 nm, and the polydispersity index (PI) was 0.194 ± 0.04. The saturation solubility of the ARM nanocrystals was substantially increased to (725.4± 2.0 μg/ml) compared to the raw ARM in water 177.4± 1.3 μg/ml and stabilizer solution (385.3± 2.0 μg/ml). The IC50 value of ARM nanosuspension against P. vivax was 65 and 21 folds lower than micronized 19.5 ng/mL and unprocessed drug (6.4 ng/mL) respectively. The ARM nanosuspension was found highly effective compared to unprocessed drug against all the tested microorganism except E. coli, Shigella and C. albican. Conclusion: The simple precipitation-ultrasonication approach was efficiently employed for fabrication of ARM nanosuspension to scale up the batch size. Similarly, the solubility, antimalarial potential and antimicrobial efficacy of ARM in the form of nanosuspension were significantly enhanced. Findings from this study can persuade research interest for further comprehensive studies using animals model. PMID:28480403

  8. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    Science.gov (United States)

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Wells Timothy NC

    2011-03-01

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

  11. [Drug users' quality of life, self-esteem and self-image].

    Science.gov (United States)

    Silveira, Camila da; Meyer, Carolina; Souza, Gabriel Renaldo de; Ramos, Manoella de Oliveira; Souza, Melissa de Carvalho; Monte, Fernanda Guidarini; Guimarães, Adriana Coutinho de Azevedo; Parcias, Sílvia Rosane

    2013-07-01

    This cross-sectional study aimed to investigate the quality of life, self-esteem and self-image among drug users of São José Institute in São José in the State of Santa Catarina. The accessibility sample was comprised of 100 male patients with a mean age of 43.0 ± 10.7, who had studied for a mean period of 8.4 ± 3.7 years. 48% of them were married and had been hospitalized or treated for a minimum period of seven days. When the participants were not hospitalized they lived with wives and children (23%), were married (48%), employed (72%), were part of income level B (58%), had done something they regret in their lives (57%) and perceived their health as good (57%). Regarding quality of life, the highest scores were found in the environmental domain (65%) and the lowest scores were in the psychological domain (58%). All patients were taking medication and had low self-esteem and self-image (77% and 96% respectively). The absence of interference of the quality of life on self-esteem and self-image of the drug users was observed by means of logistic regression. Positive quality of life did not interfere in changes in low self-esteem and self-image of drug users.

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

    Science.gov (United States)

    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.

  13. Implications of the Food, Drug, and Cosmetic Act on the quality assurance of radiopharmaceuticals used in the United States

    International Nuclear Information System (INIS)

    Kishore, R.; Sheinin, E.B.

    1990-01-01

    The drug sections of the Federal Food, Drug, and Cosmetic Act (Title 21 U.S.C.) are intended to assure the consumer that drugs are safe and effective for their intended use. The Act requires that new drugs be approved by the FDA before they go on the market. The regulations for the new drug review process, are contained in the Code of Federal Regulations (CFR) Title 21, sections 312 for Investigational New Drugs (INDs), 314 for New Drug Applications (NDAs). Section 361 deals with radioactive drugs for certain research (RDR) uses. The regulations require that sufficient information be provided on the acceptable limits and the analytical methods used for the assurance of the identity, strength, quality, purity and the stability of the new drug as well as the raw materials used in the preparation of the new drug. The impact of the Act on the control of radiopharmaceutical products will be discussed

  14. Malaria medicines to address drug resistance and support malaria elimination efforts.

    Science.gov (United States)

    Achan, Jane; Mwesigwa, Julia; Edwin, Chinagozi Precious; D'alessandro, Umberto

    2018-01-01

    Antimalarial drugs are essential weapons to fight malaria and have been used effectively since the 17 th century. However, P.falciparum resistance has been reported to almost all available antimalarial drugs, including artemisinin derivatives, raising concerns that this could jeopardize malaria elimination. Areas covered: In this article, we present a historical perspective of antimalarial drug resistance, review current evidence of resistance to available antimalarial drugs and discuss possible mitigating strategies to address this challenge. Expert commentary: The historical approach to drug resistance has been to change the national treatment policy to an alternative treatment. However, alternatives to artemisinin-based combination treatment are currently extremely limited. Innovative approaches utilizing available schizonticidal drugs such as triple combination therapies or multiple first line treatments could delay the emergence and spread of drug resistance. Transmission blocking drugs like primaquine may play a key role if given to a substantial proportion of malaria infected persons. Deploying antimalarial medicines in mass drug administration or mass screening and treatment campaigns could also contribute to containment efforts by eliminating resistant parasites in some settings. Ultimately, response to drug resistance should also include further investment in the development of new antimalarial drugs.

  15. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

    Directory of Open Access Journals (Sweden)

    O'Connell Kathryn A

    2011-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.

  16. The application of the drug user quality of life scale (DUQOL in Australia

    Directory of Open Access Journals (Sweden)

    Zubaran Carlos

    2012-03-01

    Full Text Available Abstract Background The concept of quality of life relates to the perceptions of individuals about their mental and physical health as well as non-health related areas. The evaluation of quality of life in the context of substance abuse has been conducted using generic instruments. The Drug Users Quality of Life Scale (DUQOL is a specific assessment tool in which the most pertinent and salient areas to drug abusers are taken into consideration. In this study, the authors report the results of a validation study in which the DUQOL was used for the first time in Australia. Methods A sample of 120 participants from inpatient and outpatient treatment facilities completed a series of questionnaires, including the DUQOL and the World Health Organization Quality of Life Assessment-BREF (WHOQOL-BREF. Parameters investigated in this study included the demographic characteristics of the sample, internal structure, and convergent validity. Correlations between the DUQOL scale scores and the scores of the WHOQOL-Bref test were investigated via Pearson product-moment correlation analyses. Results The English version of the DUQOL attained a significant overall Cronbach's alpha of 0.868. The factorial analysis of the DUQOL identified one principal factor that accounted for 28.499% of the variance. Convergent validity analyses demonstrate significant correlations (p Conclusions This study demonstrates that the DUQOL constitutes a reliable research instrument for evaluating quality of life of substance users in Australia.

  17. Batch-to-Batch Quality Consistency Evaluation of Botanical Drug Products Using Multivariate Statistical Analysis of the Chromatographic Fingerprint

    OpenAIRE

    Xiong, Haoshu; Yu, Lawrence X.; Qu, Haibin

    2013-01-01

    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 ...

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

    Science.gov (United States)

    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

  19. Milk quality parameters associated with the occurrence of veterinary drug residues in bulk tank milk

    Directory of Open Access Journals (Sweden)

    Lidia Cristina Almeida Picinin

    Full Text Available ABSTRACT Veterinary drug residues in bulk tank milk are important to all sectors of the dairy chain because they are one of the major factors which determine the safety of the final product. This study attempted to identify milk quality parameters that are associated with the occurrence of veterinary drug residues using multivariate principal component analysis (PCA. A total of 132 raw milk samples were collected from 45 dairy farms in the state of Minas Gerais - Brazil and analyzed for 42 analytes, including pyrethroids, macrocyclic lactones and antibacterials, using liquid chromatography coupled with mass spectrometry in tandem mode and gas chromatography with electron capture detection. Out of the 132 milk samples, 40 samples tested positive for at least one analyte (above the detection limit. The milk parameters associated with the antimicrobial residues by confirmatory tests were lactose and nonfat concentrations, as revealed by PCA. This analysis showed that fat and total solid concentrations, as well as the somatic cell and total bacteria counts were associated with macrocyclic lactone residues in bulk tank milk. A PCA assessing pyrethroid residues in bulk tank milk revealed that the lactose and nonfat solid concentrations and titratable acidity were inversely associated with these residues. Thus, the data analysis indicated that the veterinary drug residues were associated with certain milk quality parameters that can be used to target farms at higher risk of veterinary drug residue contamination for testing programs in combination with incentives, education and training programs to improve mammary health, milk hygiene and safety.

  20. Analyses of marketplace tacrolimus drug product quality: bioactivity, NMR and LC-MS.

    Science.gov (United States)

    Sommers, Cynthia D; Pang, Eric S; Ghasriani, Houman; Berendt, Robert T; Vilker, Vincent L; Keire, David A; Boyne, Michael T

    2013-11-01

    Tacrolimus (FK506) is a potent, narrow therapeutic index, immunosuppressive drug used to avoid organ rejection in patients that have undergone organ transplantation. Recent clinical reports suggested a significant reduction in the tacrolimus concentration/dose ratio in the plasma of liver and kidney recipients when the reference listed drug was substituted with a generic drug. In response to these concerns about switching between tacrolimus from different approved manufacturers during treatment, the FDA initiated purity, potency and quality studies of the innovator and generic tacrolimus products available in the US marketplace. A combination of analytical methods, including mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) and bioactivity assay were developed and validated to assess the quality of tacrolimus. These tests measured the identity, impurities and activity of tacrolimus from active pharmaceutical ingredient (API) sources and with formulated drug product from five different approved manufactures. In addition, some testing was performed on tacrolimus capsules obtained from a non US approved Indian source. The data obtained showed no discernible difference in the impurity profiles and potency between the generic and innovator tacrolimus products. Copyright © 2013. Published by Elsevier B.V.

  1. Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

    Directory of Open Access Journals (Sweden)

    Alex Avdeef

    2016-06-01

    Full Text Available This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation, use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method, solubility type (water, buffer, intrinsic, temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pKa, equilibration time (stirring and sedimentation, separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.

  2. The in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine

    Directory of Open Access Journals (Sweden)

    Giovanny Garavito

    2012-09-01

    Full Text Available The effectiveness of methylene blue (MB combined with pyrimethamine (PYR, chloroquine (CQ or quinine (Q was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. A marked potentiation was observed when MB was administered at a non-curative dose of 15 mg/kg/day in combination with PYR (0.19 mg/kg/day or Q (25 mg/kg/day. No synergy was found between MB (15 mg/Kg and CQ (0.75 mg/Kg. Our results suggest that the combination of MB with PYR or Q may improve the efficacy of these currently used antimalarial drugs.

  3. Antitheilerial Chemical Drugs: A Review | Hayat | Bulletin of Animal ...

    African Journals Online (AJOL)

    Synthetic or semi synthetic chemical drugs were used for treatment of Theileria species. These drugs include antimalarial, trypanocides and antibiotics, antiviral, etc. The aim of this study was to over-view chemical drugs tested for treatment of theileriosis. Keywords: Theileria, treatment, chemical drug ...

  4. Malaria: Antimalarial resistance and policy ramificationsand challenges

    Directory of Open Access Journals (Sweden)

    Kshirsagar N

    2006-01-01

    Full Text Available ′The National health Policy 2002" of India and the "Roll Back Malaria" policy makers have set up an ambitious goal of reducing malaria mortality and morbidity by 25% by 2007, and by 50% by 2010. To achieve these goals, problems should be identified, available evidence analyzed and policy should be changed early. Infection with drug resistant malarial parasites has a tremendous impact on health (prolonged recurrent illness, increased hospital admissions and death, health system (higher cost of treatment and socioeconomics of the region. In view of the evidence of the economic burden of malaria, it has been suggested that second line treatment could be considered at 10% failure instead of 25%. Effective schizonticidal drugs will not only reduce morbidity and mortality but will also reduce transmission. Studies have shown that prevalence of viable (as tested by exflagellation test gametocytes is considerably more after the Chloroquine or Chloroquine + Sulphadoxine-Pyrimethamine treatment compared to Quinine. Unfortunately, the only gametocytocidal drug for Plasmodium falciparum, primaquine, is also loosing its efficacy. 45 mg Primaquine reduces gametocyte prevalence by 50% while a new drug, 75 mg bulaquine or 60 mg primaquine reduces it by 90%. Plasmodium vivax forms 60-70% of malaria cases in India. Relapses which occur in 10-20% of cases adds to the burden. Efficacy, as confirmed by Polymerase Chain Reaction-Single Strand Conformational Polymorphism (PCRSSCP to differentiate relapse and re-infection, of standard dose of primaquine (15 mg/day for 5 days, even 15 mg/day for 14 days for vivax malaria is reducing. Fourteen day treatment is also impractical as compliance is poor. Newer drugs, newer drug delivery systems are thus needed. Slow release formulations with blood levels maintained for one week may be useful. Rationale of giving primaquine in higher doses and different timing need to be considered. The genome of Plasmodium falciparum and

  5. Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety.

    Science.gov (United States)

    Ozdemir, Pinar Guzel; Karadag, Ayşe Serap; Selvi, Yavuz; Boysan, Murat; Bilgili, Serap Gunes; Aydin, Adem; Onder, Sevda

    2014-08-01

    There are limited comparative studies on classic and new-generation antihistamines that affect sleep quality and mood. The purpose of this study was to determine and compare the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood. Ninety-two patients with chronic pruritus completed study in the dermatology outpatient clinic. Treatments with regular recommended therapeutic doses were administered. The effects of antihistaminic drugs on mood, daytime sleepiness, dream anxiety, and sleep quality were assessed on the first day and 1 month after. Outpatients who received cetirizine and hydroxyzine treatments reported higher scores on the depression, anxiety, and fatigue sub-scales than those who received desloratadine, levocetirizine, and rupatadine. Pheniramine and rupatadine were found to be associated with daytime sleepiness and better sleep quality. UKU side effects scale scores were significantly elevated among outpatients receiving pheniramine. Classic antihistamines increased daytime sleepiness and decreased the sleep quality scores. New-generation antihistamines reduced sleep latency and dream anxiety, and increased daytime sleepiness and sleep quality. Both antihistamines, significantly increased daytime sleepiness and nocturnal sleep quality. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Cetirizine and hydroxyzine, seem to have negative influences on mood states. Given the extensive use of antihistamines in clinical settings, these results should be more elaborately examined in further studies.

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

    Directory of Open Access Journals (Sweden)

    Misael Chinchilla

    2012-06-01

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

  7. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Science.gov (United States)

    Jezmir, Julia; Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E Jane

    2016-01-01

    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. 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. 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. 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.

  8. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Julia Jezmir

    Full Text Available 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.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.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.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.

  9. In Vivo Antimalarial Activity of Annona muricata Leaf Extract in Mice Infected with Plasmodium berghei.

    Science.gov (United States)

    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 10(7) 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.

  10. Nurses' perception of the quality of care they provide to hospitalized drug addicts: testing the theory of reasoned action.

    Science.gov (United States)

    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.

  11. Drug-related problems and quality of life in arthritis and low back pain sufferers.

    Science.gov (United States)

    Ernst, Michael E; Iyer, Shrividya S; Doucette, William R

    2003-01-01

    The objective of this study was to determine the relationship between drug-related problems (DRPs) and health-related quality-of-life (HRQoL) in ambulatory, community-dwelling patients with musculoskeletal disorders. A 12-month, prospective, observational study was conducted in 12 independent community pharmacies in eastern Iowa. Ambulatory patients with self-reported diagnoses of osteoarthritis, rheumatoid arthritis, or low back pain were invited to participate. During quarterly visits to the pharmacy, patients used touch-screen computers to fill out the Short Form-36 (SF-36) general health survey. Using the results of these point-of-service health status assessments, community pharmacists interviewed patients to assess for DRPs. To examine the influences of different DRP characteristics on HRQoL and controlling for potential confounders, both univariate and multivariate analyses were performed using the change in physical component summary (PCS) score and mental component summary (MCS) score of the SF-36 from baseline to 12 months as the dependent variables. In each regression, the independent variables were those significant variables from the univariate analyses, as well as the types of DRPs and their outcomes. A total of 461 patients were enrolled in the study. Through 12 months, 926 cumulative DRPs were identified. Overall regression models were significant for the PCS and MCS scores, respectively. Two types of DRPs showed significant negative associations with change in PCS: wrong drug and needs additional drug therapy. One type of DRP showed significant negative association with change in MCS: needs additional drug therapy. Resolution or improvement in DRPs showed a significant positive correlation with change in MCS but not PCS. Two DRPs, needs additional drug therapy and wrong drug, are associated with reduced self-reported physical health in arthritis and low back pain, while the DRP needs additional drug therapy is also associated with reduced self

  12. Injection Drug Use Quality of Life scale (IDUQOL: A validation study

    Directory of Open Access Journals (Sweden)

    Palepu Anita

    2005-07-01

    Full Text Available Abstract Background Existing measures of injection drug users' quality of life have focused primarily on health and health-related factors. Clearly, however, quality of life among injection drug users is impacted by a range of unique cultural, socioeconomic, medical, and geographic factors that must also be considered in any measure. The Injection Drug User Quality of Life (IDUQOL scale was designed to capture the unique and individual circumstances that determine quality of life among injection drug users. The overall purpose of the present study was to examine the validity of inferences made from the IDUQOL by examining the (a dimensionality, (b reliability of scores, (c criterion-related validity evidence, and (d both convergent and discriminant validity evidence. Methods An exploratory factor analysis using principal axis factoring in SPSS 12.0 was conducted to determine whether the use of a total score on the IDUQOL was advisable. Reliability of scores from the IDUQOL was obtained using internal consistency and one-week test-retest reliability estimates. Criterion-related validity evidence was gathered using variables such as stability of housing, sex trade involvement, high-risk injection behaviours, involvement in treatment programs, emergency treatment or overdose over the previous six months, hospitalization and emergency treatment over the subsequent six month period post data collection. Convergent and discriminant validity evidence was gathered using measures of life satisfaction, self-esteem, and social desirability. Results The sample consisted of 241 injection drug users ranging in age from 19 to 61 years. Factor analysis supports the use of a total score. Both internal consistency (alpha = .88 and one-week test-retest reliability (r = .78 for IDUQOL total scores were good. Criterion-related, convergent, and discriminant validity evidence supports the interpretation of IDUQOL total scores as measuring a construct consistent with

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

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    Vincent Thomas

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

  14. Evidence on anti-malarial and diagnostic markets in Cambodia to guide malaria elimination strategies and policies.

    Science.gov (United States)

    Phok, Sochea; Lek, Dysoley

    2017-04-25

    Understanding Cambodia's anti-malarial and diagnostic landscape in 2015 is critical for informing and monitoring strategies and policies as Cambodia moves forward with national efforts to eliminate malaria. The aim of this paper is to present timely and key findings on the public and private sector anti-malarial and diagnostic landscape in Cambodia. This evidence can serve as a baseline benchmark for guiding implementation of national strategies as well as other regional initiatives to address malaria elimination activities. From August 17th to October 1st, 2015, a cross sectional, nationally-representative malaria outlet survey was conducted in Cambodia. A census of all public and private outlets with potential to distribute malaria testing and/or treatment was conducted among 180 communes. An audit was completed for all anti-malarials, malaria rapid diagnostic tests (RDT) and microscopy. A total of 26,664 outlets were screened, and 1303 outlets were eligible and interviewed. Among all screened outlets in the public sector, 75.9% of public health facilities and 67.7% of community health workers stocked both malaria diagnostic testing and a first-line artemisinin-based combination therapy (ACT). Among anti-malarial-stocking private sector outlets, 64.7% had malaria blood testing available, and 70.9% were stocking a first-line ACT. Market share data illustrate that most of the anti-malarials were sold or distributed through the private sector (58.4%), including itinerant drug vendors (23.4%). First-line ACT accounted for the majority of the market share across the public and private sectors (90.3%). Among private sector outlets stocking any anti-malarial, the proportion of outlets with a first-line ACT or RDT was higher among outlets that had reportedly received one or more forms of 'support' (e.g. reportedly received training in the previous year on malaria diagnosis [RDT and/or microscopy] and/or the national treatment guidelines for malaria) compared to outlets

  15. Data quality in drug discovery: the role of analytical performance in ligand binding assays.

    Science.gov (United States)

    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 data quality are still advancing and will further advance the progress in drug development.

  16. Cytotoxic Drugs Departments as a precondition for high-quality product

    Directory of Open Access Journals (Sweden)

    Katarzyna Głuszek

    2014-06-01

    a pharmacy becomes the producer and distributor of oncologic drugs. This is related with high requirements concerning the production of drugs (high quality, safety of the engaged staff, as well as participation in a rational management of medicines. According to the FIP, a pharmacy is a public health care facility where work is performed by authorised persons: Masters of Pharmacy and pharmacy technicians. At present the task of a clinical pharmacist also includes the supervision of activities in the area of clinical pharmacy. This is a new task for pharmacists, who are obliged to constantly expand their knowledge and actively participate in the activities of the medical team.

  17. Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

    OpenAIRE

    Calcul, Laurent; Waterman, Carrie; Ma, Wai Sheung; Lebar, Matthew D.; Harter, Charles; Mutka, Tina; Morton, Lindsay; Maignan, Patrick; Van Olphen, Alberto; Kyle, Dennis E.; Vrijmoed, Lilian; Pang, Ka-Lai; Pearce, Cedric; Baker, Bill J.

    2013-01-01

    We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fr...

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

    Science.gov (United States)

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

    2017-01-01

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

  19. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Directory of Open Access Journals (Sweden)

    Phitsinee Thipubon

    2015-11-01

    Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron cstitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

  20. Antimalarial Activity of Cocos nucifera Husk Fibre: Further Studies

    Science.gov (United States)

    Adebayo, J. O.; Balogun, E. A.; Malomo, S. O.; Soladoye, A. O.; Olatunji, L. A.; Kolawole, O. M.; Oguntoye, O. S.; Babatunde, A. S.; Akinola, O. B.; Aguiar, A. C. C.; Andrade, I. M.; Souza, N. B.; Krettli, A. U.

    2013-01-01

    In this study, the antimalarial and toxicity potentials of husk fibre extracts of five Nigerian varieties of Cocos nucifera were evaluated in vitro. The only active extract fraction, West African Tall (WAT) ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25–500 mg/kg body weight) using various organ function indices. The results revealed that WAT ethyl acetate extract fraction (WATEAEF) contained alkaloids, tannins, and flavonoids and was active against Plasmodium falciparum W2 strain maintained in continuous culture, with a selectivity index of 30.3. The same extract fraction was active in vivo against Plasmodium berghei NK65, causing more than 50% reduction in parasitaemia on days 4 and 6 after inoculation at various doses administered. WATEAEF did not significantly alter (P > 0.05) function indices of the liver and cardiovascular system at all doses administered but significantly increased (P < 0.05) plasma creatinine concentration at 250 and 500 mg/Kg body weight compared to controls. The results of this study suggest that WATEAEF possesses antimalarial activity and may not adversely affect normal liver function nor predispose subjects to cardiovascular diseases but may impair normal kidney function at higher doses. Further studies are underway to isolate the active principles. PMID:23983800

  1. In Vitro Susceptibility of Plasmodium vivax to Antimalarials in Colombia

    Science.gov (United States)

    Fernández, Diana; Segura, César; Arboleda, Margarita; Garavito, Giovanny; Blair, Silvia

    2014-01-01

    The in vitro susceptibilities of 30 isolates of Plasmodium vivax to a number of antimalarials (chloroquine [CQ], mefloquine, amodiaquine, quinine, and artesunate [AS]) were evaluated. The isolates came from the region of Urabá in Colombia, in which malaria is endemic, and were evaluated by the schizont maturation test. The 50% inhibitory concentration (IC50) was 0.6 nM (95% confidence interval [CI], 0.3 to 1.0 nM) for artesunate, 8.5 nM (95% CI, 5.6 to 13.0 nM) for amodiaquine, 23.3 nM (95% CI, 12.4 to 44.1 nM) for chloroquine, 55.6 nM (95% CI, 36.8 to 84.1 nM) for mefloquine, and 115.3 nM (95% CI, 57.7 to 230.5 nM) for quinine. The isolates were classified according to whether the initial parasites were mature or immature trophozoites (Tfz). It was found that the IC50s for chloroquine and artesunate were significantly different in the two aforementioned groups (P Colombia, P. vivax continues to be susceptible to antimalarials. This is the first report, to our knowledge, showing in vitro susceptibilities of P. vivax isolates to antimalarials in Colombia. PMID:25114141

  2. Fingerprinting and validation of a LC-DAD method for the analysis of biflavanones in Garcinia kola-based antimalarial improved traditional medicines.

    Science.gov (United States)

    Tshibangu, P Tshisekedi; Kapepula, P Mutwale; Kapinga, M J Kabongo; Lupona, H Kabika; Ngombe, N Kabamba; Kalenda, Dibungi T; Jansen, O; Wauters, J N; Tits, M; Angenot, L; Rozet, E; Hubert, Ph; Marini, R D; Frédérich, M

    2016-09-05

    African populations use traditional medicines in their initial attempt to treat a range of diseases. Nevertheless, accurate knowledge of the composition of these drugs remains a challenge in terms of ensuring the health of population and in order to advance towards improved traditional medicines (ITMs). In this paper chromatographic methods were developed for qualitative and quantitative analyses of a per os antimalarial ITM containing Garcinia kola. The identified analytical markers were used to establish TLC and HPLC fingerprints. G. kola seeds were analysed by HPLC to confirm the identity of the extract used by the Congolese manufacturer in the ITM. The main compounds (GB1, GB2, GB-1a and Kolaflavanone) were isolated by preparative TLC and identified by UPLC-MS and NMR. For the quantification of the major compound GB1, a simple and rapid experimental design was applied to develop an LC method, and then its validation was demonstrated using the total error strategy with the accuracy profile as a decision tool. The accurate results were observed within 0.14-0.45mg/mL range of GB1 expressed as naringenin. The extracts used in several batches of the analysed oral solutions contained GB1 (expressed as naringenin) within 2.04-2.43%. Both the fingerprints and the validated LC-DAD were found suitable for the quality control of G. kola-based raw material and finished products, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Assessment of the quality and quantity of drug-drug interaction studies in recent NDA submissions: study design and data analysis issues.

    Science.gov (United States)

    Huang, S M; Lesko, L J; Williams, R L

    1999-10-01

    This report investigates the quality and quantity of drug-drug interaction studies in recent new drug applications (NDAs). Eighty-nine studies contained in 14 NDAs submitted between December 1995 and November 1996 to the U.S. Food and Drug Administration (FDA) were reviewed. The results indicated that the median number of clinical drug-drug interaction studies per NDA was 6, almost double that of a 1994-1995 survey. In vitro metabolism data were present in 70% of the submissions. More than 50% of the submissions contained interaction studies using a battery of drugs (cimetidine, digoxin, or warfarin) without optimal use of the in vitro metabolism or in vivo mass balance data. Various study designs using a median number of 12 subjects were employed in the evaluation of drug-drug interactions. Some of the important study design factors such as dose size, dosing regimen, dosing duration, and timing of coadministration were considered, although not consistently, by the sponsors in their study design. Seventy-five percent of the studies used normal, healthy male subjects, and 25% used patients for whom the new molecular entities were intended. In 33% of the studies, female subjects were also recruited. Although the majority (80%) of the submissions still used p-values to determine the significance of drug interactions, 30% used a more relevant equivalence approach with 90% confidence intervals for key pharmacokinetic and/or pharmacodynamic parameter ratios to assess the extent of drug interactions. Overall, 82% of the studies concluded no interaction. Although population pharmacokinetic analysis can be a useful tool in studying drug-drug interactions, only 21% of the submissions used this approach. In summary, this assessment reveals that the quantity and quality of drug-drug interaction studies in NDAs have improved over the years. These improvements, as well as others that can be implemented, should result in more informative labeling and better patient care. FDA

  4. Quality of online pharmacies and websites selling prescription drugs: a systematic review.

    Science.gov (United States)

    Orizio, Grazia; Merla, Anna; Schulz, Peter J; Gelatti, Umberto

    2011-09-30

    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. 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. 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. 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, researchers very often found

  5. Methods for implementing a medicine outlet survey: lessons from the anti-malarial market

    Science.gov (United States)

    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

  6. Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

    Science.gov (United States)

    Court, R; Chirehwa, M T; Wiesner, L; Wright, B; Smythe, W; Kramer, N; McIlleron, H

    2018-05-01

    Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure. We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0-12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings. Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0-12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69-89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97-111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients. Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.

  7. A pilot study on quality of artesunate and amodiaquine tablets used in the fishing community of Tema, Ghana.

    Science.gov (United States)

    Affum, Andrews O; Lowor, Samuel; Osae, Shiloh D; Dickson, Adomako; Gyan, Benjamin A; Tulasi, Delali

    2013-06-28

    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. 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. 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 110% for genuine amodiaquine in

  8. The lay user perspective on the quality of pharmaceuticals, drug therapy and pharmacy services--results of focus group discussions

    DEFF Research Database (Denmark)

    Traulsen, Janine Marie; Almarsdóttir, Anna Birna; Björnsdóttir, Ingunn

    2002-01-01

    This article presents the results of a study on quality of pharmacy services and perceived risk of pharmaceuticals. The results presented here are part of a multi-study evaluation of major changes in drug distribution in Iceland.......This article presents the results of a study on quality of pharmacy services and perceived risk of pharmaceuticals. The results presented here are part of a multi-study evaluation of major changes in drug distribution in Iceland....

  9. The role of private drug vendors as malaria treatment providers in selected malaria endemic areas of Sri Lanka

    DEFF Research Database (Denmark)

    Rajakaruna, R S; Weerasinghe, M; Alifrangis, M

    2006-01-01

    BACKGROUND AND OBJECTIVES: The involvement of private drug vendors in malaria treatment is particularly high in developing countries and understanding their practices and knowledge about antimalarials and malaria treatment will aid in devising strategies to increase the correct use of antimalarials...... and improve adherence to the government's malaria drug policy. Results of a study on the knowledge and practices of the private drug vendors conducted in seven districts in Sri Lanka, mostly in malarious areas are presented. METHODS: Data on awareness of government's malaria drug policy, practice of issuing...... antimalarials, knowledge about malaria and antimalarial drugs were collected from the drug vendors using pre-tested questionnaire in vernacular language. Data were statistically analysed using Stata 8.2. Chi-square test was carried out for individual explanatory variables and a logistic regression model...

  10. The quality of drugs in private pharmacies in Lao PDR: a repeat study in 1997 and 1999.

    Science.gov (United States)

    Syhakhang, Lamphone; Lundborg, Cecilia Stålsby; Lindgren, Björn; Tomson, Göran

    2004-12-01

    To present a repeated test of the quality of ampicillin, tetracycline, chloroquine and ASA from private pharmacies in Laos in 1997 and 1999, and to discuss the quality in relation to the National Drug Policy Programme. A total of 115 of 214 licensed private pharmacies were selected in Savannakhet province, a pilot province in the Lao National Drug Policy Programme. The four drugs, if available, were collected at each pharmacy. Thirty tablets of each drug were taken from a selected container. In 1997, 366 samples were analysed and three hundred in 1999. Identity, assay (content of active component) and measurement of weight variation tests were performed. Drug quality was compared mainly according to the standards of the British and United States' pharmacopoeias. The percentage of substandard drugs decreased significantly from 46% to 22% between 1997 and 1999 (PSubstandard ampicillin and tetracycline were reduced significantly from 67% to 9% and from 38% to 12%, respectively (P active ingredient, 12% vs 4% had too little or too much active ingredient, and 35% vs 14% had weight variation outside pharmacopoeial limits. Drug quality was improved. However, the prevalence of substandard drugs was still unacceptably high, which may result in adverse clinical effect or treatment failure for individual patients.

  11. Injection Drug User Quality of Life Scale (IDUQOL: Findings from a content validation study

    Directory of Open Access Journals (Sweden)

    Palepu Anita

    2007-07-01

    Full Text Available Abstract 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.

  12. Prophylactic use of antimalarials during pregnancy.

    Science.gov (United States)

    Irvine, Marie-Hélène; Einarson, Adrienne; Bozzo, Pina

    2011-11-01

    Some of my pregnant patients wish to travel to malaria-endemic regions. Are there medications that can be used safely during pregnancy for malaria prophylaxis? Pregnant women should avoid travel to malaria-endemic areas if possible. However, if travel cannot be avoided, measures to prevent mosquito bites, along with an effective chemoprophylaxis regimen, should be implemented. Chloroquine or hydroxychloroquine are considered safe to use in all trimesters of pregnancy. Mefloquine is the agent of choice for chloroquine-resistant areas, and evidence suggests it is not associated with an increased risk to the fetus. Although the atovaquone-proguanil drug combination is not currently recommended for use during pregnancy, limited data suggest that it is not harmful to the fetus. Doxycycline and primaquine are not recommended during pregnancy.

  13. Relationship Between Time Consumption and Quality of Responses to Drug-related Queries

    DEFF Research Database (Denmark)

    Amundstuen Reppe, Linda; Lydersen, Stian; Schjøtt, Jan

    2016-01-01

    DICs in Scandinavia, and the time consumption required for processing them was estimated. Clinical pharmacologists (internal experts) and general practitioners (external experts) reviewed responses individually. We used mixed model linear regression analyses to study the associations between time...... in score, –0.05 per hour of work; 95% CI, –0.08 to –0.01; P = 0.005). No such associations were found for the internal experts’ assessment. Implications To our knowledge, this is the first study of the association between time consumption and quality of responses to drug-related queries in DICs...

  14. Green tea in transdermal formulation: HPLC method for quality control and in vitro drug release assays

    Directory of Open Access Journals (Sweden)

    Michele Campos Alves

    2014-01-01

    Full Text Available RP-HPLC based analytical method for use in both quality control of green tea in a semisolid formulation and for in vitro drug release assays was developed and validated. The method was precise (CV 0.99, robust, and specific for the determination of epigallocatechin 3-gallate (EGCG, caffeine (CAF, and gallic acid (GA. In a diffusion cell chamber, the release rate of EGCG was 8896.01 µg cm-2. This data showed that EGCG will be able to exert its systemic activity when delivered though the transdermal formulation, due to its good flux rates with the synthetic membrane.

  15. Monitoring quality and coverage of harm reduction services for people who use drugs

    DEFF Research Database (Denmark)

    Wiessing, Lucas; Ferri, Marica; Běláčková, Vendula

    2017-01-01

    indicators and to present a framework for extending them with additional indicators of coverage and quality of harm reduction services, for monitoring and evaluation at international, national or subnational levels. The ultimate aim is to improve these services in order to reduce health and social problems...... are proposed for opioid agonist therapy (OAT), needle and syringe programmes (NSP) and generic cross-cutting aspects of harm reduction (and potentially other drug) services. Under the specific OAT indicators, priority indicators included 'coverage', 'waiting list time', 'dosage' and 'availability in prisons...

  16. Present development concerning antimalarial activity of phospholipid metabolism inhibitors with special reference to in vivo activity

    Directory of Open Access Journals (Sweden)

    Marie L. Ancelin

    1994-01-01

    Full Text Available The systematic screening of more than 250 molecules against Plasmodium falciparum in vitro has previously shown that interfering with phospholipid metabolism is lethal to the malaria parasite. These compounds act by impairing choline transport in infected erythrocytes, resulting in phosphatidylcholine de novo biosynthesis inhibition. A thorough study was carried out with the leader compound G25, whose in vitro IC50 is 0.6 nM. It was very specific to mature parasites (trophozoïtes as determined in vitro with P. falciparum and in vivo with P. chabaudi -infected mice. This specificity corresponds to the most intense phase of phospholipid biosynthesis activity during the parasite cycle, thus corroborating the mechanism of action. The in vivo antimalarial activity (ED50 against P. chabaudi was 0.03 mg/kg, and a similar sensitivity was obtained with P. vinckei petteri, when the drug was intraperitoneally administered in a 4 day suppressive test. In contrast, P. berghei was revealed as less sensitive (3- to 20-fold, depending on the P. berghei-strain. This difference in activity could result either from the degree of synchronism of every strain, their invasion preference for mature or immature red blood cells or from an intrinsically lower sensitivity of the P. berghei strain to G25. Irrespective of the mode of administration, G25 had the same therapeutic index (lethal dose 50 (LD50/ED50 but the dose to obtain antimalarial activity after oral treatment was 100-fold higher than after intraperitoneal (or subcutaneous administration. This must be related to the low intestinal absorption of these kind of compounds. G25 succeeded to completely inhibiting parasitemia as high as 11.2% without any decrease in its therapeutic index when administered subcutaneously twice a day for at least 8 consecutive days to P. chabaudi -infected-rodent model. Transition to human preclinical investigations now requires a synthesis of molecules which would permit oral

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

    Directory of Open Access Journals (Sweden)

    Juliana B R Corrêa Soares

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

  18. Development and optimization of a novel 384-well anti-malarial imaging assay validated for high-throughput screening.

    Science.gov (United States)

    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.

  19. Antimalarial activity of phenazines from lapachol, beta-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

    Science.gov (United States)

    de Andrade-Neto, Valter F; Goulart, Marília O F; da Silva Filho, Jorge F; da Silva, Matuzalém J; Pinto, Maria do Carmo F R; Pinto, Antônio V; Zalis, Mariano G; Carvalho, Luzia H; Krettli, Antoniana U

    2004-03-08

    The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.

  20. The potential of anti-malarial compounds derived from African medicinal plants, part I: a pharmacological evaluation of alkaloids and terpenoids.

    Science.gov (United States)

    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.

  1. The effectiveness of group selection theory on the quality of drug addicted life

    Directory of Open Access Journals (Sweden)

    M Sodani

    2017-01-01

    Full Text Available Backgrounds and aim: Increase in addiction in the community and the plight of its people demand for improving the problems of addicts, indicate a need for individuals to interventions and training expertise. The aim of this study was to investigate the effectiveness of group selection theory on the quality of drug addicted life.  .  Methods: This study is an quasi-experimental design with pretest-posttest and follow up with the control group. The study population included: all addicted people who referred to ahvaz addiction treatment center in 2015. 50 addicts were selected by using of  available sampling and randomly divided into  two experimental group (number=25 and control group (number=25. The participants were completed the quality of life inventory in three stages (pre-test, post-test and follow-up after 60 days. The experimental group was received group training of the concepts of selection theory of 10 sessions of 90 minutes per week.Statistical data were analyzed  using of covariance(ANCOVA analysis. Results: Group training theory led to a significant difference among pretest, posttest, and follow-up of quality of addicted people life (p <0.001. In this case, the post-test and follow-up, after controlling of pre-test score, the experimental group compared to the control group higher quality of life was reported. Conclusion: Group training of selected theory about the role of choosing a behavior, five senses  the importance of self control, the role of effective behavior, the way of need fulfilment, responsibility, self worth, Quality world, seven destructive behavior, seven caring behavior, faiure identification and success identification can result in increasing the quality of life for addicted people.

  2. in vitro surveillance of drug resistant falciparum malaria in north ...

    African Journals Online (AJOL)

    Dr Oboro VO

    ABSTRACT. Background: drug resistant malaria is spreading inexorably to areas with drug sensitive malaria parasites. This study compared the in vitro sensitivities of Plasmodium falciparum fresh parasite isolates, to some standard antimalarial drugs, in Makurdi and Masaka located over 300 km apart, in north central.

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

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

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

  4. Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data.

    Science.gov (United States)

    Williams, John; Bialer, Meir; Johannessen, Svein I; Krämer, Günther; Levy, René; Mattson, Richard H; Perucca, Emilio; Patsalos, Philip N; Wilson, John F

    2003-01-01

    To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.

  5. Eliciting the Intension of Drug Value Sets – Principles and Quality Assurance Applications

    Science.gov (United States)

    Bahr, Nathan J.; Nelson, Scott D.; Winnenburg, Rainer; Bodenreider, Olivier

    2018-01-01

    Value sets (VSs) used in electronic clinical quality measures are lists of codes from standard terminologies (“extensional” VSs), whose purpose (“intension”) is not always explicitly stated. We elicited the intension for the 09/01/2014 release of extensional medication value sets by comparison to drug classes from the October 2014 release of RxClass. Value sets matched drug classes if they shared common ingredients, as evidenced by Jaccard similarity score. We elicited the intension of 80 extensional value sets. The average Jaccard similarity was 0.65 for single classes and 0.80 for combination classes, with 34% (27/80) of the value sets having high similarity scores. Manual review by a pharmacist indicated 51% (41/80) of the drug classes selected as the best mapping for a value set matched the intension reflected in that value set name. This approach has the potential for facilitating the development and maintenance of medication value sets. PMID:29295218

  6. Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

    Science.gov (United States)

    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. Exploring Drug Targets in Isoprenoid Biosynthetic Pathway for Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Tabish Qidwai

    2014-01-01

    Full Text Available Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

  8. Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold.

    Science.gov (United States)

    Ciana, Claire-Lise; Siegrist, Romain; Aissaoui, Hamed; Marx, Léo; Racine, Sophie; Meyer, Solange; Binkert, Christoph; de Kanter, Ruben; Fischli, Christoph; Wittlin, Sergio; Boss, Christoph

    2013-02-01

    A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Batch-to-batch quality consistency evaluation of botanical drug products using multivariate statistical analysis of the chromatographic fingerprint.

    Science.gov (United States)

    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.

  10. The role of private drug vendors as malaria treatment providers in selected malaria endemic areas of Sri Lanka

    DEFF Research Database (Denmark)

    Rajakaruna, R S; Weerasinghe, M; Alifrangis, M

    2006-01-01

    and improve adherence to the government's malaria drug policy. Results of a study on the knowledge and practices of the private drug vendors conducted in seven districts in Sri Lanka, mostly in malarious areas are presented. METHODS: Data on awareness of government's malaria drug policy, practice of issuing......BACKGROUND AND OBJECTIVES: The involvement of private drug vendors in malaria treatment is particularly high in developing countries and understanding their practices and knowledge about antimalarials and malaria treatment will aid in devising strategies to increase the correct use of antimalarials...... was applied taking all response variables as binary outcome. RESULTS: Vendors' knowledge on antimalarials was poor with 58% of the vendors being unaware of the government malaria drug policy in the country. Also, the advice provided to customers buying antimalarials was limited. However, the majority...

  11. Analysis of the importance of drug packaging quality for end users and pharmaceutical industry as a part of the quality management system

    Directory of Open Access Journals (Sweden)

    Lončar Irma M.

    2013-01-01

    Full Text Available In this study, we collected and analyzed information on the importance of drug packaging quality to end users and pharmaceutical industry, as an indicator of the process of traceability and originality of drugs. Two surveys were conducted: one among the end users of drugs (252 patients and the other among professionals working in seven pharmaceutical companies in Serbia. For most end users (82.5% quality on the packaging of drugs was important, but only 41.8% of them thought that the appearance of the packaging could be an indicator of genuinity of drugs. The existence of the control marks (KM on drug packaging was not of great importance, since most of them (86.9% know, its function, but majority (60.2% would nevertheless decide to buy the drug without KM. Regarding the experts from the pharmaceutical industry, more then two-thirds of them (68.4% believed that the existence of KM did not contribute to efficient operations. Although a great number of pharmaceutical industry professionals (84.2% answered that the introduction of GS1 DataMatrix system would allow for complete traceability of the drug from the manufacturer to the end user, only 22.2% of them introduced this system to their products. This study also showed that domestic producers did not have a great interest for additional protection (special inks, holograms, special graphics, smart multicolor design, watermark, chemically labeled paper and cardboard etc.. on their products, given that only 15.8 % of them had some kind of additional protection against counterfeiting. Monitoring drug traceability from a manufacturer to end user is achieved by many complex activities regulated by law. A high percentage of responders said they were satisfied with the functionality of traceability systems used in their companies. As a way to increase the quality of drug packaging and business performance most responders saw in the continuous improvement of the system of traceability within the company

  12. Mono- and bis-thiazolium salts have potent antimalarial activity.

    Science.gov (United States)

    Hamzé, Abdallah; Rubi, Eric; Arnal, Pascal; Boisbrun, Michel; Carcel, Carole; Salom-Roig, Xavier; Maynadier, Marjorie; Wein, Sharon; Vial, Henri; Calas, Michèle

    2005-05-19

    Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50)

  13. Quality of Life in Arthritis Patients Using Nonsteroidal Anti-Inflammatory Drugs

    Directory of Open Access Journals (Sweden)

    Ingela Wiklund

    1999-01-01

    Full Text Available Arthritis is a painful and disabling condition. To suppress the pain and the inflammatory process, patients are often chronic nonsteroidal anti-inflammatory drug (NSAID users. Chronic use of NSAIDs may induce peptic ulcer, dyspeptic problems and heartburn. Therefore, these patients are often provided with treatment to relieve and/or protect against gastrointestinal problems. Rheumatic disorders also affect a range of health-related quality of life domains. In one study, patients with NSAID-associated gastroduodenal lesions complained about lack of energy, sleep disturbances, emotional distress and social isolation in addition to pain and mobility limitations. The degree of distress and dysfunction differed markedly from scores in an unselected population. Clinical trial data suggest that acid-suppressing therapy with omeprazole is superior to therapy with misoprostol and ranitidine in healing gastroduodenal lesions and preventing abdominal pain, heartburn and indigestion symptoms during continued NSAID treatment. Because arthritic patients are severely incapacitated by their condition regarding most aspects of health-related quality of life, it is important to offer a treatment that is effective in healing and preventing NSAID-induced ulcers and gastrointestinal symptoms during continued NSAID treatment without further compromising the patients’ quality of life. Treatment with omeprazole once daily has been shown to be superior to that with ranitidine and misoprostol in this respect.

  14. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries.

    Science.gov (United States)

    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

  15. Exploring the scope of new arylamino alcohol derivatives: Synthesis, antimalarial evaluation, toxicological studies, and targe