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Sample records for antimalarial drug quality

  1. Use and quality of antimalarial drugs in the private sector in Viet Nam.

    OpenAIRE

    Cong, L D; Yen, P. T.; Nhu, T. V.; Binh, L N

    1998-01-01

    This study examines the use and quality of antimalarial drugs in the growing private sector of Viet Nam. The practices of drug vendors (called alternative treatment providers (ATPs)) as well as their stocks and the quality of drugs sold by them, and the local production and distribution of antimalarials were investigated. Antimalarials were sold by the vast majority of ATPs, almost all the common antimalarials being available for sale. The practices and indications for sale, however, varied. ...

  2. 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. PMID:25897063

  3. Antimalarial drug resistance: An overview

    OpenAIRE

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, a...

  4. Antimalarial drug resistance: An overview.

    Science.gov (United States)

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, as it is one of the key factors in the emergence and spread of drug resistance. This review summarizes the commonly used antimalarial drugs, their mechanism of action and the genetic markers validated so far for the detection of drug-resistant parasites. PMID:26998432

  5. 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.

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

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    Roger Bate

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

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

    OpenAIRE

    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 a...

  8. Counterfeit and Substandard Antimalarial Drugs

    Science.gov (United States)

    ... drug is in its original packaging. Inspect the packaging because many times poor quality printing indicates a counterfeited product. Be suspicious of tablets that have a peculiar odor, taste, or color, or that are extremely brittle. Get Email Updates ...

  9. Antimalarial drug resistance and combination chemotherapy.

    OpenAIRE

    White, N.

    1999-01-01

    Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the cha...

  10. 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

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

    Directory of Open Access Journals (Sweden)

    Rajeev K. Mehlotra

    2011-04-01

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

  12. Anticancer properties of distinct antimalarial drug classes.

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    Rob Hooft van Huijsduijnen

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

  13. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

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

  14. 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

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

    OpenAIRE

    MEHLOTRA, RAJEEV K.; Grimberg, Brian T

    2011-01-01

    The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, th...

  16. Drug resistance genomics of the antimalarial drug artemisinin

    OpenAIRE

    Elizabeth A Winzeler; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast...

  17. 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

  18. The role of anti-malarial drugs in eliminating malaria.

    OpenAIRE

    White, NJ

    2008-01-01

    Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and tran...

  19. The role of anti-malarial drugs in eliminating malaria

    OpenAIRE

    White Nicholas J

    2008-01-01

    Abstract Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia...

  20. Development of a Specific Monoclonal Antibody-Based ELISA to Measure the Artemether Content of Antimalarial Drugs

    OpenAIRE

    Suqin Guo; Yongliang Cui; Lishan He; Liang Zhang; Zhen Cao; Wei Zhang; Rui Zhang; Guiyu Tan; Baomin Wang; Liwang Cui

    2013-01-01

    Artemether is one of the artemisinin derivatives that are active ingredients in antimalarial drugs. Counterfeit and substandard antimalarial drugs have become a serious problem, which demands reliable analytical tools and implementation of strict regulation of drug quality. Structural similarity among artemisinin analogs is a challenge to develop immunoassays that are specific to artemisinin derivatives. To produce specific antibodies to artemether, we used microbial fermentation of artemethe...

  1. Drug resistance genomics of the antimalarial drug artemisinin.

    Science.gov (United States)

    Winzeler, Elizabeth A; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene. PMID:25470531

  2. Antimalarial drug resistance in Africa: key lessons for the future

    OpenAIRE

    Takala-Harrison, Shannon; Laufer, Miriam K

    2015-01-01

    Drug-resistant parasites repeatedly arise as a result of widespread use of antimalarial drugs and have contributed significantly to the failure to control and eradicate malaria throughout the world. In this review, we describe the spread of resistance to chloroquine and sulfadoxine–pyrimethamine, two old drugs that are no longer used owing to high rates of resistance, and examine the effect of the removal of drug pressure on the survival of resistant parasites. Artemisinin-resistant malaria i...

  3. From hybrid compounds to targeted drug delivery in antimalarial therapy.

    Science.gov (United States)

    Oliveira, Rudi; Miranda, Daniela; Magalhães, Joana; Capela, Rita; Perry, Maria J; O'Neill, Paul M; Moreira, Rui; Lopes, Francisca

    2015-08-15

    The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented. PMID:25913864

  4. 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...

  5. Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs

    OpenAIRE

    Mhando, Linus; Jande, Mary B.; Liwa, Anthony; Mwita, Stanley; Marwa, Karol J.

    2016-01-01

    Background. The illicit trade in counterfeit antimalarial drugs is a major setback to the fight against malaria. Information on public awareness and ability to identify counterfeit drugs is scanty. Aim. Therefore, the present study aimed at assessing public awareness and the ability to identify counterfeit antimalarial drugs based on simple observations such as appearance of the drugs, packaging, labelling, and leaflets. Methodology. A cross-sectional study was conducted using interviewer adm...

  6. Artemisinin anti-malarial drugs in China.

    Science.gov (United States)

    Guo, Zongru

    2016-03-01

    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. PMID:27006895

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

    Directory of Open Access Journals (Sweden)

    Lee Sue J

    2009-11-01

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

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

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    Nuno eVale

    2014-12-01

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

  9. Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine

    OpenAIRE

    Islahudin, Farida; Khozoie, Combiz; Bates, Steven; Ting, Kang-Nee; Pleass, Richard J.; Avery, Simon V.

    2013-01-01

    Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbi...

  10. Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs

    Directory of Open Access Journals (Sweden)

    Linus Mhando

    2016-01-01

    Full Text Available Background. The illicit trade in counterfeit antimalarial drugs is a major setback to the fight against malaria. Information on public awareness and ability to identify counterfeit drugs is scanty. Aim. Therefore, the present study aimed at assessing public awareness and the ability to identify counterfeit antimalarial drugs based on simple observations such as appearance of the drugs, packaging, labelling, and leaflets. Methodology. A cross-sectional study was conducted using interviewer administered structured questionnaire and a checklist. Respondents were required to spot the difference between genuine and counterfeit antimalarial drugs given to them. Data was analysed using SPSS version 20. Results. The majority of respondents, 163 (55.6%, were able to distinguish between genuine and counterfeit antimalarial drugs. Respondents with knowledge on health effects of counterfeit drugs were more likely to identify genuine and counterfeit drugs than their counterparts (P=0.003; OR = 2.95; 95% CI: 1.47–5.65. The majority of respondents, 190 (64.8%, perceived the presence of counterfeit drugs to be a big problem to the community. Conclusions. A substantial proportion of respondents were able to distinguish between genuine and counterfeit antimalarial drugs. Public empowerment in identifying counterfeit drugs by simple observations is a major step towards discouraging the market of counterfeit drugs.

  11. Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance.

    Science.gov (United States)

    von Seidlein, Lorenz; Dondorp, Arjen

    2015-06-01

    The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured. PMID:25831482

  12. Antimalarial drugs for rheumatoid disease during pregnancy.

    OpenAIRE

    Koren, G

    1999-01-01

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

  13. Cloroquine – miscellaneous properties of the antimalarial drug

    Directory of Open Access Journals (Sweden)

    Robert Jarzyna

    2002-06-01

    Full Text Available Chloroquine is a drug with over 60 years of safe clinical use in the treatment of malaria. The multiple mechanisms of chloroquine action have appeared to be useful in the therapy of many miscellaneous disorders well beyond its original antimalarial purposes. This paper is focused on the application of chloroquine for the treatment of malaria, porphyria cutanea tarda, rheumatoid arthritis, palindromic rheumatism and lupus. The possibility of the use of chloroquine in the therapy of other disorders such as diabetes mellitus, AIDS, hyperlipidemia, sarcoidosis, hypercalcemia, and melanoma is reviewed. Mechanisms of action of the drug as well as side effects on metabolism are discussed in view of recent discoveries.

  14. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.

    Science.gov (United States)

    Mott, Bryan T; Eastman, Richard T; Guha, Rajarshi; Sherlach, Katy S; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A; Ferrer, Marc; Renslo, Adam R; Inglese, James; Yuan, Jing; Roepe, Paul D; Su, Xin-Zhuan; Thomas, Craig J

    2015-01-01

    Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

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

    Directory of Open Access Journals (Sweden)

    Newton Paul N

    2011-12-01

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

  16. Home treatment of febrile children with antimalarial drugs in Togo.

    OpenAIRE

    Deming, M. S.; Gayibor, A.; Murphy, K; Jones, T. S.; Karsa, T.

    1989-01-01

    In Togo, the principal strategy for preventing death from malaria in children is prompt treatment of fever with antimalarial drugs. A household survey was conducted in a rural area of south-central Togo in which information was collected from mothers on the treatment received by 507 children under 5 years of age who, according to their mothers, had recently had fever. Altogether, 20% of the children (95% confidence interval (Cl): 15-25%) were seen at a health centre during their illness, whil...

  17. 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...... action on human mononuclear cells of the various antimalarial drugs and the potential adverse effects of antimalarial chemotherapy are discussed....... 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...

  18. 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. PMID:26259943

  19. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

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

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria. PMID:26983887

  20. Development of a specific monoclonal antibody-based ELISA to measure the artemether content of antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    Suqin Guo

    Full Text Available Artemether is one of the artemisinin derivatives that are active ingredients in antimalarial drugs. Counterfeit and substandard antimalarial drugs have become a serious problem, which demands reliable analytical tools and implementation of strict regulation of drug quality. Structural similarity among artemisinin analogs is a challenge to develop immunoassays that are specific to artemisinin derivatives. To produce specific antibodies to artemether, we used microbial fermentation of artemether to obtain 9-hydroxyartemether, which was subsequently used to prepare a 9-O-succinylartemether hapten for conjugation with ovalbumin as the immunogen. A monoclonal antibody (mAb, designated as 2G12E1, was produced with high specificity to artemether. 2G12E1 showed low cross reactivities to dihydroartemisinin, artemisinin, artesunate and other major antimalarial drugs. An indirect competitive enzyme linked immunosorbent assay (icELISA developed showed a concentration causing 50% of inhibition for artemether as 3.7 ng mL⁻¹ and a working range of 0.7-19 ng mL⁻¹. The icELISA was applied for determination of artemether content in different commercial drugs and the results were comparable to those determined by high-performance liquid chromatography analysis. In comparison with reported broad cross activity of anti-artemisinin mAbs, the most notable advantage of the 2G12E1-based ELISA is its high specificity to artemether only.

  1. 云南省抗疟药品质量状况分析%Quality analysis of anti-malarials drug in Yunnan Province

    Institute of Scientific and Technical Information of China (English)

    郭志鑫; 姜典财; 黄志禄; 范兵; 李哲媛; 刘继华; 王幸

    2011-01-01

    本文通过对云南省流通领域抗疟药的抽样、检验和结果分析,考察云南省市场流通的抗疟药品质V状况,探讨我国抗疟药目前存在的主要质量问题,并提出对策和建议.%By analysis of the sampling and testing result of anti - malarials in Yunnan Province, the quality of markted anti - malarials in Yunnan Province were studied, and main quality problems currently existed of anti - malarials in China were discussed, also some suggestions and strategies were presented.

  2. 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

  3. Targeting protein kinases in the malaria parasite: update of an antimalarial drug target.

    Science.gov (United States)

    Zhang, Veronica M; Chavchich, Marina; Waters, Norman C

    2012-01-01

    Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance. PMID:22242850

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

    OpenAIRE

    Newton Paul N; Green Michael D; Mildenhall Dallas C; Plançon Aline; Nettey Henry; Nyadong Leonard; Hostetler Dana M; Swamidoss Isabel; Harris Glenn A; Powell Kristen; Timmermans Ans E; Amin Abdinasir A; Opuni Stephen K; Barbereau Serge; Faurant Claude

    2011-01-01

    Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African coun...

  5. A review of age-old antimalarial drug to combat malaria:efficacy upgradation by nanotechnology based drug delivery

    Institute of Scientific and Technical Information of China (English)

    Satyajit; Tripathy; Somenath; Roy

    2014-01-01

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

  6. Evaluation of the effect of pyrimethamine, an anti-malarial drug, on HIV-1 replication

    OpenAIRE

    Oguariri, Raphael M.; Joseph W Adelsberger; Michael W Baseler; Imamichi, Tomozumi

    2010-01-01

    Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of PYR and two other clinical anti-malarial drugs (chloroquine [CQ] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIVNL4.3 strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 μM...

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

    OpenAIRE

    Asrar Alam

    2014-01-01

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

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

    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...... resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug...

  13. Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas

    OpenAIRE

    Greenwood Brian

    2010-01-01

    Abstract Anti-malarial drugs can make a significant contribution to the control of malaria in endemic areas when used for prevention as well as for treatment. Chemoprophylaxis is effective in preventing deaths and morbidity from malaria, but it is difficult to sustain for prolonged periods, may interfere with the development of naturally acquired immunity and will facilitate the emergence and spread of drug resistant strains if applied to a whole community. However, chemoprophylaxis targeted ...

  14. 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

    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......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...... 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....

  15. Metabolic Dysregulation Induced in Plasmodium falciparum by Dihydroartemisinin and Other Front-Line Antimalarial Drugs.

    Science.gov (United States)

    Cobbold, Simon A; Chua, Hwa H; Nijagal, Brunda; Creek, Darren J; Ralph, Stuart A; McConville, Malcolm J

    2016-01-15

    Detailed information on the mode of action of antimalarial drugs can be used to improve existing drugs, identify new drug targets, and understand the basis of drug resistance. In this study we describe the use of a time-resolved, mass spectrometry (MS)-based metabolite profiling approach to map the metabolic perturbations induced by a panel of clinical antimalarial drugs and inhibitors on Plasmodium falciparum asexual blood stages. Drug-induced changes in metabolite levels in P. falciparum-infected erythrocytes were monitored over time using gas chromatography-MS and liquid chromatography-MS and changes in specific metabolic fluxes confirmed by nonstationary [(13)C]-glucose labeling. Dihydroartemisinin (DHA) was found to disrupt hemoglobin catabolism within 1 hour of exposure, resulting in a transient decrease in hemoglobin-derived peptides. Unexpectedly, it also disrupted pyrimidine biosynthesis, resulting in increased [(13)C]-glucose flux toward malate production, potentially explaining the susceptibility of P. falciparum to DHA during early blood-stage development. Unique metabolic signatures were also found for atovaquone, chloroquine, proguanil, cycloguanil and methylene blue. We also show that this approach can be used to identify the mode of action of novel antimalarials, such as the compound Torin 2, which inhibits hemoglobin catabolism. PMID:26150544

  16. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

    Directory of Open Access Journals (Sweden)

    Jason P Wendler

    Full Text Available BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

  17. 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 medicines. PMID:25897069

  18. Prioritization of anti-malarial hits from nature: chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs

    OpenAIRE

    Egieyeh, Samuel Ayodele; Syce, James; Malan, Sarel F.; Christoffels, Alan

    2016-01-01

    Background A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Methods Natural products with in vitro antiplasmodial activities (NAA) we...

  19. Surveillance of antimalarial drug resistance in China in the 1980s–1990s

    OpenAIRE

    Liu, De-Quan

    2014-01-01

    Since the successful preparation of the microplates and the medium for field application, the resistance degree and its geographical distribution of chloroquine-resistant Plasmodium falciparum, the fluctuation of the resistance degree of P. falciparum to chloroquine, and the sensitivity of the parasite to commonly used antimalarial drugs were investigated between 1980 and 2003 by the in vitro microtest and the in vivo four-week test recommended by the World Health Organization (WHO). The resu...

  20. Amazonian plant natural products:perspectives for discovery of new antimalarial drug leads

    OpenAIRE

    Lucio H Freitas-Junior; Pedro Cravo; Marcus Vinícius Guimarães Lacerda; André Machado Siqueira; Carolina Borsoi Moraes; Gina Frausin; Luiz Francisco Rocha e Silva; Stefanie Costa Pinto Lopes; Renata Braga Souza Lima; Fabio Trindade Maranhão Costa; Adrian Martin Pohlit

    2013-01-01

    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 cau...

  1. Antimalarial Drugs Clear Resistant Parasites from Partially Immune Hosts

    OpenAIRE

    Cravo, Pedro; Culleton, Richard; Hunt, Paul; Walliker, David; Mackinnon, Margaret J.

    2001-01-01

    Circumstantial evidence in human malaria suggests that elimination of parasites by drug treatment meets higher success rates in individuals having some background immunity. In this study, using the rodent malaria model Plasmodium chabaudi, we show that drug-resistant parasites can be cleared by drugs when the host is partially immune.

  2. 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; Hooft van Huijsduijnen, Rob; Duparc, Stephan; Leroy, Didier; Wells, Timothy N C; Baker, Mark; Möhrle, Jörg J

    2016-06-01

    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

  3. 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

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

    OpenAIRE

    Tabernero, Patricia; Facundo M Fernández; Green, Michael; Guerin, Philippe J; Newton, Paul N.

    2014-01-01

    Background Poor quality medicines threaten the lives of millions of patients and are alarmingly common in many parts of the world. Nevertheless, the global extent of the problem remains unknown. Accurate estimates of the epidemiology of poor quality medicines are sparse and are influenced by sampling methodology and diverse chemical analysis techniques. In order to understand the existing data, the Antimalarial Quality Scientific Group at WWARN built a comprehensive, open-access, global datab...

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-04-01

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

  7. Molecular Basis of Antimalarial Drug Resistance in Indonesia

    OpenAIRE

    Syafruddin D

    2003-01-01

    Malaria continues to be a major public health problem in Indonesia. In fact over 3 million clinical cases of malaria and about 100 deaths are reported annually through hospitals and public health centres (Ministry of Health, The Republic of Indonesia, compiled data, 1998). The spread of drug-resistant parasites and the recent outbreaks and re-emergence of malaria in places previously declared malaria-free have forced the Government of Indonesia to re-assess the current national malaria contro...

  8. Plasmodium falciparum susceptibility to anti-malarial drugs in Dakar, Senegal, in 2010: an ex vivo and drug resistance molecular markers study

    OpenAIRE

    Fall, Bécaye; Pascual, Aurélie; Sarr, Fatoumata; Wurtz, Nathalie; Richard, Vincent; Baret, Eric; Diémé, Yaya; Briolant, Sébastien; Bercion, Raymond; Wade, Boubacar; Tall, Adama; Pradines, Bruno

    2013-01-01

    BACKGROUND: In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. Since the introduction of ACT, there have been very few reports on the level of resistance of P. falciparum to anti-malarial drugs. To determine whether parasite susceptibility has been affected by the new anti-malarial policies, an ex vivo susceptibility and drug resistance molecular marker study was conducted on...

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Madeeha Malik

    2013-01-01

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

  11. Virtual Screening and Docking Studies of Synthesized Chalcones: Potent Anti-Malarial Drug

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    Prashant Singh

    2016-03-01

    Full Text Available A novel series of Chalcones were synthesized targets asexual blood stages of Plasmodium falciparum has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significant structure-based quantitative structure activity relationships models were generated and validated through acceptable predictive ability to support internal and external set of compounds. Screening of most valuable drug among of pre-synthesized drug on the basis of binding efficiency to target receptor was carried out by docking view. Prior this pre-computed Mean IC50 and MIC value were also taken in consideration. The most effective compound on the basis all consideration was found. Previous studies have suggested that Ca2+-ATPase (PfATP6 of P. falciparum is the target of many anti-malarial drugs. However, the mechanism of inhibition of Ca2+- ATPase (PfATP6 is not known. Here we address this issue using bioinformatics tools. We generated a molecular model of Ca2+-ATPase (PfATP6 of P. falciparum and performed molecular docking of all chalcones. Molecular docking programme Glide iGEMDock was used to determine binding feasibility of 52 analogues of chalcones. The comparison of docking parameters showed, more than 5 analogues are better ligands of PfATP6. The binding of chalocones to PFATP6 is mediated by both hydrogen bonding, hydrophobic and polar interactions. Our results suggest that chalcones analogues are promising lead compounds for the development of anti-malarial drugs

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

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    Roman Deniskin

    2016-04-01

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

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

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    Huthmacher Carola

    2010-08-01

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

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

    Science.gov (United States)

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

    2015-01-01

    The spread of Plasmodium falciparum multidrug resistance highlights the urgency to discover new targets and chemical scaffolds. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle. Chemogenomic profiling is an established tool for classification of drugs with similar mechanisms of action by comparing drug fitness profiles in a collection of mutants. Inferences of drug mechanisms of action and targets can be obtained by associations between shifts in drug fitness and specific genetic changes in the mutants. In this screen, P. falciparum, piggyBac single insertion mutants were profiled for altered responses to antimalarial drugs and metabolic inhibitors to create chemogenomic profiles. Drugs targeting the same pathway shared similar response profiles and multiple pairwise correlations of the chemogenomic profiles revealed novel insights into drugs’ mechanisms of action. A mutant of the artemisinin resistance candidate gene - “K13-propeller” gene (PF3D7_1343700) exhibited increased susceptibility to artemisinin drugs and identified a cluster of 7 mutants based on similar enhanced responses to the drugs tested. Our approach of chemogenomic profiling reveals artemisinin functional activity, linked by the unexpected drug-gene relationships of these mutants, to signal transduction and cell cycle regulation pathways. PMID:26541648

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

    Institute of Scientific and Technical Information of China (English)

    Satyajit Tripathy; Somenath Roy

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Doerig Christian

    2010-07-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Umberto D'Alessandro

    1998-09-01

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

  20. 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.

  1. 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

  2. Availability of antimalarial drugs and evaluation of the attitude and practices for the treatment of uncomplicated malaria in bangui, central african republic.

    Science.gov (United States)

    Manirakiza, Alexandre; Njuimo, Siméon Pierre; Le Faou, Alain; Malvy, Denis; Millet, Pascal

    2010-01-01

    National malaria management policy is based upon the availability of effective and affordable antimalarial drugs. This study was undertaken to evaluate the quality of the treatment of uncomplicated malaria cases in Bangui, an area with multidrug-resistant parasites, at a time preceding implementation of a new therapeutic policy relying on the artemisinin derivative combined treatment artemether-lumefantrine. A cross-sectional study was carried out in Bangui city to assess availability of antimalarial drugs and the performances of health workers in the management of uncomplicated malaria. Availability of drugs was recorded in all drugs wholesalers (n = 3), all pharmacies in health facilities (n = 14), private drugstores (n = 15), and in 60 non-official drug shops randomly chosen in the city. Despite a limited efficacy at the time of the survey, chloroquine remained widely available in the official and nonofficial markets. Artemisinin derivatives used in monotherapy or in combination were commonly sold. In health care facilities, 93% of the uncomplicated malaria cases were treated in the absence of any laboratory confirmation and the officially recommended treatment, amodiaquine-sulfadoxine/pyrimethamine, was seldom prescribed. Thus, the national guidelines for the treatment of uncomplicated malaria are not followed by health professionals in Bangui. Its use should be implemented while a control of importation of drug has to be reinforced. PMID:20339579

  3. Global gene expression profiling of Plasmodium falciparum in response to the anti-malarial drug pyronaridine

    Directory of Open Access Journals (Sweden)

    Chavalitshewinkoon-Petmitr Porntip

    2011-08-01

    Full Text Available Abstract Background Pyronaridine (PN and chloroquine (CQ are structurally related anti-malarial drugs with primarily the same mode of action. However, PN is effective against several multidrug-resistant lines of Plasmodium falciparum, including CQ resistant lines, suggestive of important operational differences between the two drugs. Methods Synchronized trophozoite stage cultures of P. falciparum strain K1 (CQ resistant were exposed to 50% inhibitory concentrations (IC50 of PN and CQ, and parasites were harvested from culture after 4 and 24 hours exposure. Global transcriptional changes effected by drug treatment were investigated using DNA microarrays. Results After a 4 h drug exposure, PN induced a greater degree of transcriptional perturbation (61 differentially expressed features than CQ (10 features. More genes were found to respond to 24 h treatments with both drugs, and 461 features were found to be significantly responsive to one or both drugs across all treatment conditions. Filtering was employed to remove features unrelated to primary drug action, specifically features representing genes developmentally regulated, secondary stress/death related processes and sexual stage development. The only significant gene ontologies represented among the 46 remaining features after filtering relate to host exported proteins from multi-gene families. Conclusions The malaria parasite's molecular responses to PN and CQ treatment are similar in terms of the genes and pathways affected. However, PN appears to exert a more rapid response than CQ. The faster action of PN may explain why PN is more efficacious than CQ, particularly against CQ resistant isolates. In agreement with several other microarray studies of drug action on the parasite, it is not possible, however, to discern mechanism of drug action from the drug-responsive genes.

  4. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

    OpenAIRE

    Mu, Jianbing; Myers, Rachel A.; Jiang, Hongying; Liu, Shengfa; Ricklefs, Stacy; Waisberg, Michael; Chotivanich, Kesinee; Wilairata, Polrat; Krudsood, Srivicha; White, Nicholas J; Udomsangpetch, Rachanee; Cui, Liwang; Ho, May; Ou, Fengzheng; Li, Haibo

    2010-01-01

    Antimalarial drugs impose strong pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome 1,2. Search for signals of selection may lead to genes encoding drug or immune targets 3. The lack of high-throughput genotyping methods, inadequate knowledge of parasite population history, and time-consuming adaptations of parasites to in vitro culture have hampered genome-wide association studies (GWAS) of parasite traits. Here we report genotyping of DNA fr...

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

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    Joël Lelièvre

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

  6. Thermodynamic Studies of Antimalarial Drugs and Their Interaction with Myoglobin, Hemoglobin and Phospholipid Model Membranes

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    Samira A. Barghouthi

    2005-01-01

    Full Text Available In this research we present binding studies of some selected antimalarial drugs such as primaquine and quinacrine with biomolecules. Ultraviolet-visible spectrophotometry and fluorescence spectrophotometry along with equilibrium dialysis techniques were used to monitor the interaction of these drugs with myoglobin, hemoglobin albumin and with phospholipid unilamellar vesicles. Fluorescence spectrophotometry, UV-visible difference spectrophotometry and equilibrium dialysis showed no evidence of any binding of these drugs to myoglobin or hemoglobin. However, binding to albumin was evident from a blue shift in UV-Vis absorption spectra. Both primaquine and quinacrine were found to bind to phospholipid vesicles with binding constants of 2.7 ± 0.4x102 and 8.1 ± 0.8x104, respectively. As for the number of molecules per binding site, we found that eight molecules of primaquine occupies ten binding sites and in case of quinacrine two drug molecule for each ten binding sites. Physical parameters for primaquine are determined via UV-Vis absorption at a wavelength of 350 nm. In case of quinacrine fluorescence intensity was employed to measure concentrations with an excitation wavelength of 425 nm and an emission wavelength at 497 nm.

  7. 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.

  8. Combating poor-quality anti-malarial medicines: a call to action.

    Science.gov (United States)

    Bassat, Quique; Tanner, Marcel; Guerin, Philippe J; Stricker, Kirstin; Hamed, Kamal

    2016-01-01

    The circulation of poor-quality medicines continues to undermine the fight against many life-threatening diseases. Anti-malarial medicines appear to have been particularly compromised and present a major public health threat in malaria-endemic countries, negatively affecting individuals and their communities. Concerted collaborative efforts are required from global, regional and national organizations, involving the public and private sectors, to address the problem. While many initiatives are underway, a number of unmet needs deserve urgent and increased multisector attention. At the global level, there is a need for an international public health legal framework or treaty on poor-quality medicines, with statutes suitable for integration into national laws. In addition, increased international efforts are required to strengthen the governance of global supply chains and enhance cooperation between national medicine regulation authorities and law enforcement bodies. Increased investment is needed in innovative technologies that will enable healthcare teams to detect poor-quality medicines at all levels of the supply chain. At the regional level, a number of initiatives would be beneficial-key areas are standardization, simplification, and reciprocal recognition of registration processes and development of quality control capacity in regional centres of excellence that are better aligned with public health needs; improved surveillance methods and creation of a framework for compulsory and transparent reporting of poor-quality medicines; additional support for national medicine regulation authorities and other national partner authorities; and an increase in support for regional laboratories to boost their capabilities in detecting poor-quality medicines. It is vital that all stakeholders involved in efforts against poor-quality anti-malarial medicines extend and strengthen their actions in these critical areas and thus effectively support global health development

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

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    Cervantes, Serena; Prudhomme, Jacques; Carter, David; Gopi, Krishna G; Li, Qian; Chang, Young-Tae; Le Roch, Karine G

    2009-01-01

    Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS) to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency. PMID:19515257

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

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    McKenzie F Ellis

    2010-07-01

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

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

    OpenAIRE

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

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo...

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

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    Kamau Edwin

    2012-01-01

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

  13. 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.

  14. Role of PfATP6 and pfMRP1 in Plasmodium falciparum resistance to antimalarial drugs

    OpenAIRE

    Dahlström, Sabina

    2009-01-01

    Half of the world s population live at risk for malaria and nearly one million people die from the disease every year. The malaria burden is greatest in children and pregnant women in sub-Saharan Africa. As effective treatment is crucial for malaria control, the spread of antimalarial drug resistance has contributed significantly to malaria attributed morbidity and mortality. The current cornerstones in malaria treatment are artemisininbased combination therapy (ACT) for tre...

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

    International Nuclear Information System (INIS)

    We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC5) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 ± 21 μM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 μM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin

  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. 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. PMID:26130467

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

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    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.

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

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    Zaloumis Sophie

    2012-08-01

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

  20. Assay method for quality control and stability studies of a new antimalarial agent (CDRI 99/411)$

    Institute of Scientific and Technical Information of China (English)

    Kiran Khandelwal; Shakti Deep Pachauri; Sofia Zaidi; Pankaj Dwivedi; Ashok Kumar Sharma; Chandan Singh; Anil Kumar Dwivedi

    2013-01-01

    CDRI compound no. 99/411 is a potent 1,2,4-trioxane antimalarial candidate drug under development at our Institute. An HPLC method for determination of CDRI 99/411 with its starting material and intermediates has been developed and validated for in process quality control and stability studies. The analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and lower limit of quantification (LLOQ) were determined according to International Conference on Harmonization ICH Q2(R1) guidelines. HPLC separation was achieved on a RP-select B Lichrospheres column (250 mm  4 mm, 5μm, Merck) using water containing 0.1%glacial acetic acid and acetonitrile as the mobile phase in a gradient elution. The eluents were monitored by a photo diode array detector at 245 and 275 nm. Based on signal to noise ratio of 3 and 10 the LOD of CDRI 99/411 was 0.55 mg/mL, while the LLOQ was 1.05 mg/mL. The calibration curves were linear in the range of 1.05-68 mg/mL. Precision of the method was determined by inter- and intra-assay variations within the acceptable range.

  1. Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya.

    Science.gov (United States)

    Okombo, John; Kamau, Alice W; Marsh, Kevin; Sutherland, Colin J; Ochola-Oyier, Lynette Isabella

    2014-12-01

    Molecular surveillance of drug resistance markers through time provides crucial information on genomic adaptations, especially in parasite populations exposed to changing drug pressures. To assess temporal trends of established genotypes associated with tolerance to clinically important antimalarials used in Kenya over the last two decades, we sequenced a region of the pfcrt locus encompassing codons 72-76 of the Plasmodium falciparum chloroquine resistance transporter, full-length pfmdr1 - encoding multi-drug resistance protein, P-glycoprotein homolog (Pgh1) and pfdhfr encoding dihydrofolate reductase, in 485 archived Plasmodium falciparum positive blood samples collected in coastal Kenya at four different time points between 1995 and 2013. Microsatellite loci were also analyzed to compare the genetic backgrounds of parasite populations circulating before and after the withdrawal of chloroquine and sulfadoxine/pyrimethamine. Our results reveal a significant increase in the prevalence of the pfcrt K76 wild-type allele between 1995 and 2013 from 38% to 81.7% (p drug in contrast to a selective sweep around the triple mutant pfdhfr allele, leading to a mono-allelic population at this locus. These findings highlight the importance of continual surveillance and characterization of parasite genotypes as indicators of the therapeutic efficacy of antimalarials, particularly in the context of changes in malaria treatment policy. PMID:25516825

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

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    Krettli Antoniana U

    2001-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Zoraima Neto

    2013-01-01

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

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

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    Mwafongo Winfred

    2010-10-01

    the potential to alleviate restricted availability of anti-malarial drugs or other medicines in rural or under-resourced areas.

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

    International Nuclear Information System (INIS)

    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.

  6. 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

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

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    Monica Shah

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

  8. Exploring QSAR for Antimalarial Activities and Drug Distribution within Blood of a Series of 4-Aminoquinoline Drugs Using Genetic-MLR

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    Amir Najafi

    2013-01-01

    Full Text Available Malaria has been one of the most significant public health problems for centuries. QSAR modeling of the antimalarial activity and blood-to-plasma concentration ratio of Chloroquine and a new series of 4-aminoquinoline derivatives were developed using genetic algorithms with multiple linear regression (GA-MLR method. We obtained two different models against Chloroquine-sensitive (3D7 and Chloroquine-resistant (W2 strains of Plasmodium falciparum with good adjustment levels. Drug distribution in blood, defined as drug blood-to-plasma concentration ratio (Rb, is related to molecular descriptors. Leave-many-out (LMO and Y-randomization methods confirmed the models' robustness.

  9. Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.

    Science.gov (United States)

    Moon, Deuk Kyu; Singhal, Vandana; Kumar, Nirbhay; Shapiro, Theresa A; Posner, Gary H

    2009-01-01

    Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. PMID:20686674

  10. 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

  11. 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

  12. Stability profiling of anti-malarial drug piperaquine phosphate and impurities by HPLC-UV, TOF-MS, ESI-MS and NMR

    OpenAIRE

    Yan, Fang; Liu, Jie; Zeng, Xuefang; Zhang, Yuan; Hang, Taijun

    2014-01-01

    Background Piperaquine, 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is an anti-malarial compound belonging to the 4-aminoquinolines, which has received renewed interest in treatment of drug resistant falciparum malaria in artemisinin-based combination therapy with dihydroartemisinin. The impurity profile of this drug product is paid an ever-increasing attention. However, there were few published studies of the complete characterization of related products or impurities in piperaqu...

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

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    Vreeke Ed

    2007-07-01

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

  14. 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.

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

    OpenAIRE

    Travers Dominique; Amalvict Rémy; Baret Eric; Basco Leonardo K; Pascual Aurélie; Rogier Christophe; Pradines Bruno

    2011-01-01

    Abstract Background The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. Methods The susceptibility of 36 pre-identified parasite strains from a...

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

    OpenAIRE

    Ringsted Frank M; Massawe Isolide S; Lemnge Martha M; Bygbjerg Ib C

    2011-01-01

    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 u...

  17. 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.

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

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    Neelima Mishra

    2013-12-01

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

  19. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

    Science.gov (United States)

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197–3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick

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

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    Rajesh Kumar Kesharwani

    2013-04-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

  2. Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine

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    Duchateau Luc

    2011-02-01

    Full Text Available Abstract Background Lumefantrine (benflumetol is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs and finished pharmaceutical products (FPPs. Methods Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®. Results Several new impurities are identified, of which the desbenzylketo derivative (DBK is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself. Conclusions From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs. The in-silico toxicological investigation (Toxtree® and Derek® indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.

  3. Adverse drug events resulting from use of drugs with sulphonamide-containing anti-malarials and artemisinin-based ingredients: findings on incidence and household costs from three districts with routine demographic surveillance systems in rural Tanzania

    OpenAIRE

    Njau, JD; Kabanywanyi, AM; Goodman, CA; Macarthur, JR; Kapella, BK; Gimnig, JE; Kahigwa, E.; Bloland, PB; Abdulla, SM; Kachur, SP

    2013-01-01

    Background: Anti-malarial regimens containing sulphonamide or artemisinin ingredients are widely used in malaria-endemic countries. However, evidence of the incidence of adverse drug reactions (ADR) to these drugs is limited, especially in Africa, and there is a complete absence of information on the economic burden such ADR place on patients. This study aimed to document ADR incidence and associated household costs in three high malaria transmission districts in rural Tanzania covered by dem...

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

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    Virginia Wiseman

    2006-10-01

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

  5. 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.

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

    Institute of Scientific and Technical Information of China (English)

    Santoshkumar R Jeevangi; Manjunath S; Sharanabasappa M Awanti

    2010-01-01

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

  7. World Antimalarial Resistance Network (WARN) III: Molecular Markers for Drug Resistant Malaria

    OpenAIRE

    Sibley Carol H; Shafer Robert W; Price Ric N; Naidoo Inbarani; Mugittu Kefas; Meshnick Steven R; Mbacham Wilfred; Joshi Hema H; Happi Christian T; Barnwell John W; Roper Cally; Plowe Christopher V; Sutherland Colin J; Zimmerman Peter A; Rosenthal Philip J

    2007-01-01

    Abstract Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, ...

  8. World antimalarial resistance network (WARN) III: Molecular markers for drug resistant malaria

    OpenAIRE

    plowe, cv; Roper, C.; Barnwell, JW; Happi, CT; Joshi, HH; Mbacham, W.; Meshnick, SR; Mugittu, K; Naidoo, I; Price, RN; Shafer, RW; Sibley, CH; Sutherland, CJ; Zimmerman, PA; Rosenthal, PJ

    2007-01-01

    Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effe...

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

    Directory of Open Access Journals (Sweden)

    Travers Dominique

    2011-01-01

    Full Text Available Abstract Background The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. Methods The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2® system and compared to controlled incubator conditions (5% CO2 and 10% O2. Results The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2 and 10% O2 were significantly higher than those of Genbag® conditions (2738 cpm vs 2282 cpm, p 50 estimated under the incubator atmospheric conditions was significantly lower for atovaquone (1.2 vs 2.1 nM, p = 0.0011 and higher for the quinolines: chloroquine (127 vs 94 nM, p 50 between the 2 conditions for dihydroartemisinin, doxycycline and pyrimethamine. To reduce this difference in term of anti-malarial susceptibility, a specific cut-off was estimated for each drug under Genbag® conditions by regression. The cut-off was estimated at 77 nM for chloroquine (vs 100 nM in 10% O2, 611 nM for quinine (vs 800 nM, 30 nM for mefloquine (vs 30 nM, 61 nM for monodesethylamodiaquine (vs 80 nM and 1729 nM for pyrimethamine (vs 2000 nM. Conclusions The atmospheric generators for capnophilic bacteria Genbag CO2® is an appropriate technology that can be transferred to the field for epidemiological surveys of drug-resistant malaria. The present data suggest the importance of the gas mixture on in vitro

  10. 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.

  11. 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)

    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)

  12. Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study

    OpenAIRE

    Liu, Haining; Ding, Yuanqing; Walker, Larry A.; Doerksen, Robert J

    2013-01-01

    We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin’s ionization potential (IP). Our results showed that PQ and its derivatives do not significantly lower the hemoglobin IP, disproving the hypothesis.

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

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    Gonzalez-Block Miguel A

    2005-10-01

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

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

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    Rath Srikanta

    2011-05-01

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

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

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    Denis Zofou

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

  16. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

    OpenAIRE

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David; Davis, Timothy M. E.

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using establis...

  17. Collaborative Health and Enforcement Operations on the Quality of Antimalarials and Antibiotics in Southeast Asia

    OpenAIRE

    Yong, Yuk Lin; Plançon, Aline; Lau, Yen Hui; Hostetler, Dana M.; Facundo M Fernández; 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.

    2015-01-01

    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 te...

  18. Recent developments in naturally derived antimalarials: cryptolepine analogues.

    Science.gov (United States)

    Wright, Colin W

    2007-06-01

    Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues. PMID:17637183

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

    Science.gov (United States)

    Kabongo Kamitalu, Ramsès; Aloni, Michel Ntetani

    2016-01-01

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

  20. Absence of Association between Polymorphisms in the RING E3 Ubiquitin Protein Ligase Gene and Ex Vivo Susceptibility to Conventional Antimalarial Drugs in Plasmodium falciparum Isolates from Dakar, Senegal.

    Science.gov (United States)

    Gendrot, Mathieu; Fall, Bécaye; Madamet, Marylin; Fall, Mansour; Wade, Khalifa Ababacar; Amalvict, Rémy; Nakoulima, Aminata; Benoit, Nicolas; Diawara, Silman; Diémé, Yaya; Diatta, Bakary; Wade, Boubacar; Pradines, Bruno

    2016-08-01

    The RING E3 ubiquitin protein ligase is crucial for facilitating the transfer of ubiquitin. The only polymorphism identified in the E3 ubiquitin protein ligase gene was the D113N mutation (62.5%) but was not significantly associated with the 50% inhibitory concentration (IC50) of conventional antimalarial drugs. However, some mutated isolates (D113N) present a trend of reduced susceptibility to piperaquine (P = 0.0938). To evaluate the association of D113N polymorphism with susceptibility to antimalarials, more isolates are necessary. PMID:27185795

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

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2009-10-01

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

  2. 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.

  3. 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

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

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    Rita Tewari

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2010-01-01

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

  6. Plasmodium falciparum resistance to anti-malarial drugs in Papua New Guinea: evaluation of a community-based approach for the molecular monitoring of resistance

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    Reeder John C

    2010-01-01

    Full Text Available Abstract Background Molecular monitoring of parasite resistance has become an important complementary tool in establishing rational anti-malarial drug policies. Community surveys provide a representative sample of the parasite population and can be carried out more rapidly than accrual of samples from clinical cases, but it is not known whether the frequencies of genetic resistance markers in clinical cases differ from those in the overall population, or whether such community surveys can provide good predictions of treatment failure rates. Methods Between 2003 and 2005, in vivo drug efficacy of amodiaquine or chloroquine plus sulphadoxine-pyrimethamine was determined at three sites in Papua New Guinea. The genetic drug resistance profile (i.e., 33 single nucleotide polymorphisms in Plasmodium falciparum crt, mdr1, dhfr, dhps, and ATPase6 was concurrently assessed in 639 community samples collected in the catchment areas of the respective health facilities by using a DNA microarray-based method. Mutant allele and haplotype frequencies were determined and their relationship with treatment failure rates at each site in each year was investigated. Results PCR-corrected in vivo treatment failure rates were between 12% and 28% and varied by site and year with variable longitudinal trends. In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time. Mutant allele frequencies in pfdhfr were moderate and those in pfdhps were low. No mutations were detected in pfATPase6. There was much more variation between sites than temporal, within-site, variation in allele and haplotype frequencies. This variation did not correlate well with treatment failure rates. Allele and haplotype frequencies were very similar in clinical and community samples from the same site. Conclusions The relationship between parasite genetics and in vivo treatment failure rate is not straightforward. The

  7. 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

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

    DEFF Research Database (Denmark)

    Khalil, Insaf F; Alifrangis, Michael; Recke, Camilla;

    2011-01-01

    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......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...... resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma....

  9. 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)

    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.

  10. A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

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    Oyoo George O

    2011-03-01

    Full Text Available Abstract Background Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product were reported. The maximum concentration (Cmax was 160-200 nM and after 6 hours, the effective concentration (Ceff was Conclusion Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

  11. Improving Pharmacokinetic-Pharmacodynamic Modeling to Investigate Anti-Infective Chemotherapy with Application to the Current Generation of Antimalarial Drugs

    OpenAIRE

    Katherine Kay; Hastings, Ian M.

    2013-01-01

    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 ha...

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

    Directory of Open Access Journals (Sweden)

    Klein Eili Y

    2012-04-01

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

  13. 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

    2016-01-01

    This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (<8 %) were found in just two of the countries, whilst substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting. PMID:26873700

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

    Science.gov (United States)

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

    2015-11-01

    In order to reaction the quality present situation, problems on the current quality of animal sources of drugs are summed up by using test data analysis, literature search and marketing research. This paper can also help the improvement of the quality management, the revision of the relevant department policy system and the improvement of standards. PMID:27071276

  15. Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

    Science.gov (United States)

    Pathak, Vrushali; Colah, Roshan; Ghosh, Kanjaksha

    2015-08-01

    Development of the antimalarial drug resistant strains has currently become a major public health challenge. There is an urgent need to develop new antimalarial drugs. Tyrosine kinase inhibitors (TKIs) are receiving increasing attention as anticancer therapy. It has revolutionarised the management of CML to say the least. TKIs are also increasingly being implicated in complicated but vital life cycle of malaria parasite. Hence we tested two commonly used but different classes of TKIs (imatinib and sorafenib) in-vitro for their antimalarial activity and possible synergistic activity with existing antimalarial drug. Antimalarial activity was tested with the help of modified WHO microtest technique in-vitro for five different Plasmodium falciparum laboratory strains (3D7, Dd2, 7G8, MRC2, PKL9). Imatinib and sorafenib showed a promising antimalarial activity with all the strains. These compounds caused dose dependent inhibition of parasite maturation. The isobologram analysis of the interactions of these TKIs with standard antimalarial drug, artesunate revealed distinct patterns of synergism, additivity and antagonism at different ratios. Imatinib showed worthwhile synergism with artesunate indicating imatinib and other tyrosine kinase inhibitors may have significant antimalarial activity and can be used in combination therapy. PMID:26142327

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

    OpenAIRE

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

    2015-01-01

    Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artem...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    Katherine Kay

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

  19. 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

  20. Towards optimal design of anti-malarial pharmacokinetic studies.

    OpenAIRE

    White Nicholas J; Price Ric N; Jamsen Kris M; Simpson Julie A; Lindegardh Niklas; Tarning Joel; Duffull Stephen B

    2009-01-01

    Abstract Background Characterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance. Population pharmacokinetic studies determine the drug concentration time profiles in the target patient populations, including children who have limited sampling options. Currently, population pharmacokinetic studies of anti-malarial drugs are designed based on logistical, financial and ethi...

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

    Directory of Open Access Journals (Sweden)

    Offianan AT

    2011-11-01

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

  2. On peroxide antimalarials

    Directory of Open Access Journals (Sweden)

    IGOR OPSENICA

    2007-12-01

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

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    M. El-Duah & K. Ofori-Kwakye

    2012-09-01

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

  5. A microarray-based system for the simultaneous analysis of single nucleotide polymorphisms in human genes involved in the metabolism of anti-malarial drugs

    Directory of Open Access Journals (Sweden)

    Qi Weihong

    2009-12-01

    Full Text Available Abstract Background In order to provide a cost-effective tool to analyse pharmacogenetic markers in malaria treatment, DNA microarray technology was compared with sequencing of polymerase chain reaction (PCR fragments to detect single nucleotide polymorphisms (SNPs in a larger number of samples. Methods The microarray was developed to affordably generate SNP data of genes encoding the human cytochrome P450 enzyme family (CYP and N-acetyltransferase-2 (NAT2 involved in anti-malarial drug metabolisms and with known polymorphisms, i.e. CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NAT2. Results For some SNPs, i.e. CYP2A6*2, CYP2B6*5, CYP2C8*3, CYP2C9*3/*5, CYP2C19*3, CYP2D6*4 and NAT2*6/*7/*14, agreement between both techniques ranged from substantial to almost perfect (kappa index between 0.61 and 1.00, whilst for other SNPs a large variability from slight to substantial agreement (kappa index between 0.39 and 1.00 was found, e.g. CYP2D6*17 (2850C>T, CYP3A4*1B and CYP3A5*3. Conclusion The major limit of the microarray technology for this purpose was lack of robustness and with a large number of missing data or with incorrect specificity.

  6. In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs

    OpenAIRE

    Pradines, B; Rogier, C.; Fusai, T; Tall, A; Trape, Jean-François; Doury, J C

    1998-01-01

    The in vitro activity of artemether against 56 African isolates of #Plasmodium falciparum$ from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM vers...

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

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar;

    2013-01-01

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

  8. Antimalarial natural products: a review

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    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.

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

    International Nuclear Information System (INIS)

    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

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

    Directory of Open Access Journals (Sweden)

    Natalie Jane Spillman

    2015-12-01

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

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

    Science.gov (United States)

    Spillman, Natalie Jane; Kirk, Kiaran

    2015-12-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na(+) concentration and the plasma membrane P-type cation translocating ATPase 'PfATP4' has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's 'Malaria Box'. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na(+). Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field. PMID:26401486

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

    Science.gov (United States)

    Spillman, Natalie Jane; Kirk, Kiaran

    2015-01-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's ‘Malaria Box’. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na+. Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field. PMID:26401486

  13. 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.

  14. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    OpenAIRE

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

    2014-01-01

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

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

    OpenAIRE

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F.

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in...

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

    OpenAIRE

    Natalie Jane Spillman; Kiaran Kirk

    2015-01-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antim...

  17. 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.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    The parasite Plasmodium falciparum is the main agent responsible for malaria. In this study, we exploited a recently published chemical library from GlaxoSmithKline (GSK) that had previously been confirmed to inhibit parasite growth of the wild type (3D7) and the multi-drug resistance (D2d) strai...

  19. Socioeconomic differences in drug use among older people : Trends, polypharmacy, quality and new drugs

    OpenAIRE

    Haider, Syed Imran

    2008-01-01

    Polypharmacy and potentially inappropriate drug use (IDU) is a major patient safety and public health concern in the elderly, resulting in an increased likelihood of adverse drug reactions, drug-drug interactions (DDI), hospitalization, poor quality of life and mortality. This doctoral thesis investigated the complex relationship between drug use and socioeconomic position (SEP) and characterized the drug use, quality of prescribing, development of drug use over time, and u...

  20. 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.

  1. Potential antimalarial activity of indole alkaloids

    OpenAIRE

    Frederich, Michel; Tits, Monique; Angenot, Luc

    2008-01-01

    New antimalarial treatments are now urgently required, following the emergence of resistance to the most used drugs. Natural products contribute greatly to the therapeutic arsenal in this area, including artemisinin and quinine (and atovaquone, semi-synthetic). Among the natural products, indole alkaloids represent an interesting class of compounds. Screening carried out to date has revealed several substances active in vitro under the micromolar range and with a good selectivity index. This ...

  2. Synthesis and evaluation of antimalarial activity of curcumin derivatives

    International Nuclear Information System (INIS)

    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 (IC50 values ranging from 1.7 to 15.2 μg mL-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)

  3. [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. PMID:11640680

  4. Antimalarial activity of extracts of Malaysian medicinal plants.

    Science.gov (United States)

    Najib Nik A Rahman, N; Furuta, T; Kojima, S; Takane, K; Ali Mohd, M

    1999-03-01

    In vitro and in vivo studies revealed that Malaysian medicinal plants, Piper sarmentosum, Andrographis paniculata and Tinospora crispa produced considerable antimalarial effects. Chloroform extract in vitro did show better effect than the methanol extract. The chloroform extract showed complete parasite growth inhibition as low as 0.05 mg/ml drug dose within 24 h incubation period (Andrographis paniculata) as compared to methanol extract of drug dose of 2.5 mg/ml but under incubation time of 48 h of the same plant spesies. In vivo activity of Andrographis paniculata also demonstrated higher antimalarial effect than other two plant species. PMID:10363840

  5. Chitosan-based nanocarriers for antimalarials

    Science.gov (United States)

    Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Bende, A.; Borodi, Gh.; Bratu, I.

    2012-02-01

    The objective of this research was to synthesize and characterize chitosan-based liquid and solid materials with unique absorptive and mechanical properties as carriers for quinine - one of the most used antimalarial drug. The use of chitosan (CTS) as base in polyelectrolyte complex systems, to prepare solid release systems as sponges is presented. The preparation by double emulsification of CTS hydrogels carrying quinine as anti-malarial drug is reported. The concentration of quinine in the CTS hydrogel was 0.08 mmol. Chitosan - drug loaded hydrogel was used to generate solid sponges by freeze-drying at -610°C and 0.09 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-VIS), spectrofluorimetry, differential scanning calorimetry (DSC) and X-ray diffractometry. The results indicated that the drug molecule is forming temporary chelates in CTS hydrogels and sponges. Electron paramagnetic resonance (EPR) demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan - drug supramolecular cross-linked assemblies.

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

    Directory of Open Access Journals (Sweden)

    Rodney Alexandre Ferreira Rodrigues

    2006-04-01

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

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

    Science.gov (United States)

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

    2016-02-01

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

  8. The interaction of x-rays and antimalarials

    International Nuclear Information System (INIS)

    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 3H-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 (ID50) 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 ID50 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 (2001

  9. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

    OpenAIRE

    Sara E. McCarty; Amanda Schellenberger; Douglas C. Goodwin; Ngolui Rene Fuanta; Tekwani, Babu L.; Calderón, Angela I.

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences...

  10. Detecting Counterfeit Antimalarial Tablets by Near-Infrared Spectroscopy

    Science.gov (United States)

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

  11. Antimalarial Activity of Azadipeptide Nitriles

    OpenAIRE

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

    2009-01-01

    Azadipeptide nitriles – novel cysteine protease inhibitors – display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite’s haemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of...

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

    Directory of Open Access Journals (Sweden)

    E. O. Ajaiyeoba

    2013-01-01

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

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

    OpenAIRE

    Jerapan Krungkrai; Sudaratana Rochanakij Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Art...

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Harparkash Kaur

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

  16. In vitro antimalarial activity of novel semisynthetic nocathiacin I antibiotics.

    Science.gov (United States)

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F

    2015-01-01

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

  17. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure

    Directory of Open Access Journals (Sweden)

    Neelima Mishra

    2016-01-01

    Interpretation & conclusion: 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.

  18. New Analytical Monographs on TCM Herbal Drugs for Quality Proof.

    Science.gov (United States)

    Wagner, Hildebert; Bauer, Rudolf; Melchart, Dieter

    2016-01-01

    Regardless of specific national drug regulations there is an international consensus that all TCM drugs must meet stipulated high quality standards focusing on authentication, identification and chemical composition. In addition, safety of all TCM drugs prescribed by physicians has to be guaranteed. During the 25 years history of the TCM hospital Bad Kötzting, 171 TCM drugs underwent an analytical quality proof including thin layer as well as high pressure liquid chromatography. As from now mass spectroscopy will also be available as analytical tool. The findings are compiled and already published in three volumes of analytical monographs. One more volume will be published shortly, and a fifth volume is in preparation. The main issues of the analytical procedure in TCM drugs like authenticity, botanical nomenclature, variability of plant species and parts as well as processing are pointed out and possible ways to overcome them are sketched. PMID:27271998

  19. 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

  20. Evaluation of antimalarial activity of leaves of Acokanthera schimperi and Croton macrostachyus against Plasmodium berghei in Swiss albino mice

    OpenAIRE

    Mohammed, Tigist; Erko, Berhanu; Giday, Mirutse

    2014-01-01

    Background Malaria is one of the most important tropical diseases and the greatest cause of hospitalization and death. Recurring problems of drug resistance are reinforcing the need for finding new antimalarial drugs. In this respect, natural plant products are the main sources of biologically active compounds and have potential for the development of novel antimalarial drugs. A study was conducted to evaluate extracts of the leaves of Croton macrostachyus and Acokanthera schimperi for their ...

  1. PfMDR2 and PfMDR5 are dispensable for Plasmodium falciparum asexual parasite multiplication but change in vitro susceptibility to anti-malarial drugs

    NARCIS (Netherlands)

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

    2015-01-01

    BACKGROUND: Membrane-associated ATP binding cassette (ABC) transport proteins hydrolyze ATP in order to translocate a broad spectrum of substrates, from single ions to macromolecules across membranes. In humans, members from this transport family have been linked to drug resistance phenotypes, e.g.,

  2. The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance

    NARCIS (Netherlands)

    J.P. van Geertruyden (Jean Pierre); J. Menten (Joris); R. Colebunders (Robert); E.L. Korenromp (Eline); U. D'Alessandro (Umberto)

    2008-01-01

    textabstractBackground. HIV-related immune-suppression increases the risk of malaria (infection, disease and treatment failure) and probably the circulating parasite biomass, favoring the emergence of drug resistance parasites. Methods. The additional malaria parasite biomass related to HIV-1 co-inf

  3. [Generic drugs: we must cut pharmaceutical spending but undertaking drug quality].

    Science.gov (United States)

    Carrillo Norte, Juan Antonio; Postigo Mota, Salvador

    2012-02-01

    The World Health Organization and all drug regulatory agencies (DRA) support the commercialization of generic medicines because they control costs and are irreplaceable therapeutic options in countries lacking the innovator product. Generic drugs are widely considered to be cost-efficient substitutes for brand-name medications. They make up about 20% of the total number of prescriptions in Spain, a figure that is still far from the use of generic drugs in USA and other European countries. Despite economical interest in this issue, in this article we review the interest of generic drugs from a pharmacological and clinical perspective that must undertake drug quality to ensure drug efficacy and safety of the patients. A generic drug (generic drugs, short: generics) is defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use". Both the reference drug and the generic drug have to demonstrate previously they are therapeutically equivalent. With the exception of parenteral drugs, two products have demonstrated to be therapeutically equivalent if after administration in the same molar dose, their effects with respect to both efficacy and safety are essentially the same, as determined from bioequivalence studies in terms of comparison of appropriate pharmacokinetic parameters and bioavailability. Parenteral formulations, however, are not required to demonstrate therapeutic equivalence because it may be considered self-evident. Such assumptions have never been challenged, but there are reasons to do so for parenteral antimicrobials. It is interesting to highlight that although brand-name drugs and generic drugs are both approved by DRA and may be interchangeable with respect to their clinical effects, they can differ substantially in their appearance. Consumers of brand-name medications receive identical-appearing batches of pills with

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

    OpenAIRE

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

    2015-01-01

    Introduction: The risk of drug resistance and the use of medicinal plants in malaria prevention and treatment have led to the search for new antimalarial compounds with natural origin. Methods: In the current study, six extracts with different polarity from aerial parts and rhizomes of Eremostachys macrophylla Montbr. & Auch., were screened for their antimalarial properties by cell-free beta-hematin formation assay. Results: Dichloromethane (DCM) extracts of both parts of plant showed s...

  5. Evaluation of plants used for antimalarial treatment by the Maasai of Kenya.

    Science.gov (United States)

    Koch, A; Tamez, P; Pezzuto, J; Soejarto, D

    2005-10-01

    Semi-structured interviews with three Maasai herbalists led to the identification and collection of 21 species of plants used to treat malaria. Extracts were evaluated using in vitro antimalarial and cytotoxicity assays. Of the species tested, over half were antiplasmodial (IC5020 microg/ml) against cultured KB cells. The results of this preliminary investigation support the traditional knowledge of Maasai herbalists and justify ethnomedical inquiry as a promising method, specifically, in antimalarial therapy, to yield leads for drug discovery. PMID:15878245

  6. Systematic pharmacognostical study on Panax drugs and Curcuma drugs : Phylogenetic analysis, molecular authentication and quality evaluation

    OpenAIRE

    Komatsu, Katsuko; Zhu, Shu; Sasaki, Yohei

    2004-01-01

    We proposed pharmacognostical studies in the prime of molecular biology, citing the systematic studies of Panax drugs and Curcuma drugs. Each study was composed of three approaches, phylogenetic analysis of plants based on nuclear 18S rRNA and chloroplast trnK gene sequences, molecular authentication of herbal drugs, and quality evaluation on bioactive chemical constituents or pharmacological effect. Parsimony analysis of the combined trnK-18S rRNA gene sequence data yielded a well-resolved p...

  7. Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

    Directory of Open Access Journals (Sweden)

    Mariana Conceição Souza

    2015-06-01

    Full Text Available A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3 inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

  8. Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake

    Directory of Open Access Journals (Sweden)

    Carmen E Contreras

    2004-03-01

    Full Text Available The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

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

    Science.gov (United States)

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

    2015-01-01

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

  10. Hallazgos complementarios sobre la actividad antimalarica del azul de metileno = Complementary findings on the antimalarial activity and toxicity of methylene blue

    OpenAIRE

    G. Garavito; Bertani, S; Deharo, Eric

    2008-01-01

    Methylene blue was reported as the first synthetic antimalarial by Ehrlich in 1881. It is currently no longer used for that purpose but it should be reconsidered since new economic alternatives are urgently needed in the arsenal of antimalarial drugs. The antimalarial activity of methylene blue is investigated here in vivo against rodent malaria parasites. 15 mg/kg daily dose of methylene blue inhibits 50% of the erythrocytic parasite growth of Plasmodium berghei and R yoelii nigeriensis, whi...

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

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    Cravo Pedro VL

    2009-04-01

    Full Text Available Abstract 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.

  12. 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...

  13. Systematic review on quality control for drug management programs: Is quality reported in the literature?

    OpenAIRE

    Eng Benjamin; Schaaf David; McAdam-Marx Carrie; Holtorf Anke-Peggy; Oderda Gary

    2009-01-01

    Abstract Background Maintaining quality of care while managing limited healthcare resources is an ongoing challenge in healthcare. The objective of this study was to evaluate how the impact of drug management programs is reported in the literature and to identify potentially existing quality standards. Methods This analysis relates to the published research on the impact of drug management on economic, clinical, or humanistic outcomes in managed care, indemnity insurance, VA, or Medicaid in t...

  14. Systematic review on quality control for drug management programs: Is quality reported in the literature?

    OpenAIRE

    Holtorf, Anke-Peggy; McAdam-Marx, Carrie; Schaaf, David; Eng, Benjamin; Oderda, Gary

    2009-01-01

    Background Maintaining quality of care while managing limited healthcare resources is an ongoing challenge in healthcare. The objective of this study was to evaluate how the impact of drug management programs is reported in the literature and to identify potentially existing quality standards. Methods This analysis relates to the published research on the impact of drug management on economic, clinical, or humanistic outcomes in managed care, indemnity insurance, VA, or Medicaid in the USA pu...

  15. Antimalarials and the fight against malaria in Brazil

    Directory of Open Access Journals (Sweden)

    Luiz MA Carmargo

    2009-04-01

    Full Text Available Luiz MA Carmargo1, Saulo de Oliveira2, Sergio Basano3, Célia RS Garcia21ICBV-USP, Monte Negro, Rondônia, Brasil; 2Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, SP, Brazil; 3CEMETRON, Porto Velho, Guaporé, BrazilAbstract: Malaria, known as the “fevers,” has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named “Jesuits’ powder.” Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira–Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients.Keywords: Plasmodium falciparum, malaria, antimalarials, calcium

  16. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

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    Dea Shahinas

    2013-02-01

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

  17. In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine

    OpenAIRE

    Sahu, Rajnish; Walker, Larry A.; Tekwani, Babu L.

    2014-01-01

    Background Several antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics. Methods Tigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falcip...

  18. Antimalarial potential of homeopathic medicines against schizont maturation of Plasmodium berghei in short-term in vitro culture

    OpenAIRE

    Upma Bagai; Aswathy Rajan

    2012-01-01

    In vitro assessment of antimalarial drug susceptibility of Plasmodium has been a major research success, which has paved the way for the understanding of parasite and rapid screening of antimalarial drugs for their effectiveness. In the present study a preliminary screening to check the antiplasmodial activity of mother tincture (ϕ) and various potencies (6C, 30C, 200C) of homeopathic medicines Cinchona officinalis/china (Chin.), Chelidonium majus (Chel.) and Arsenicum album (Ars.) were done ...

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

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    N. Shafiq

    2014-01-01

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

  20. Potential antimalarials from African natural products: a review

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    Bashir Lawal

    2015-12-01

    Full Text Available Ethnopharmacological relevance: Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in-vivo or invi-tro against malaria parasite. Methods: Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, Science domain that report on antiplasmodial activity of natural products from differernts Africa region. Results: A Total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%, Fababceae (8.128%, Euphorbiaceae (5.52%, Rubiaceas (5.52% and Apocyanaceae (5.214%, have received more scientific validation than others. Conclusion: African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products is of paramount importance. [J Intercult Ethnopharmacol 2015; 4(4.000: 318-343

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

    OpenAIRE

    Rijpma, S.R.; Heuvel, J. J.; van de Velden, M.; 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 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 pharmaceutica...

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

    Science.gov (United States)

    Copeland, C

    1999-04-01

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

  3. Liposomal Drug Products: A Quality by Design Approach

    Science.gov (United States)

    Xu, Xiaoming

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

  4. 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.

  5. The de novo selection of drug-resistant malaria parasites.

    OpenAIRE

    White, N.J.; Pongtavornpinyo, W.

    2003-01-01

    Antimalarial drug resistance emerges de novo predominantly in areas of low malaria transmission. Because of the logarithmic distribution of parasite numbers in human malaria infections, inadequately treated high biomass infections are a major source of de novo antimalarial resistance, whereas use of antimalarial prophylaxis provides a low resistance selection risk. Slowly eliminated antimalarials encourage resistance largely by providing a selective filter for resistant parasites acquired fro...

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

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    Jerapan Krungkrai

    2016-05-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Leslie Toby

    2008-12-01

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

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

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    Littrell Megan

    2011-10-01

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

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

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    Mpimbaza Arthur

    2008-06-01

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

  11. Injection Drug Use Quality of Life scale (IDUQOL): A validation study

    OpenAIRE

    Palepu Anita; Russell Lara B; Hubley Anita M

    2005-01-01

    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 injec...

  12. 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)

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

    Directory of Open Access Journals (Sweden)

    Shen S

    2015-06-01

    Full Text Available Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data

  14. Antimalarials and the fight against malaria in Brazil.

    Science.gov (United States)

    Carmargo, Luiz Ma; de Oliveira, Saulo; Basano, Sergio; Garcia, Célia Rs

    2009-08-01

    Malaria, known as the "fevers," has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea) from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named "Jesuits' powder." Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira-Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients. PMID:19753125

  15. Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Garavito G.

    2007-06-01

    Full Text Available Methylene blue (MB is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.

  16. 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.

  17. Development, validation and comparison of NIR and Raman methods for the identification and assay of poor-quality oral quinine drops.

    OpenAIRE

    Mbinze Kidenge, Jérémie(*); Sacre, Pierre-Yves; Yemoa, Achille; Mavar Tayey Mbay, Jean; Habyalimana, Védaste; Kalenda, Nick; HUBERT, Philippe; Marini Djang'Eing'A, Roland; Ziemons, Eric

    2015-01-01

    Poor quality antimalarial drugs are one of the public’s major health problems in Africa. The depth of this problem may be explained in part by the lack of effective enforcement and the lack of efficient local drug analysis laboratories. To tackle part of this issue, two spectroscopic methods with the ability to detect and to quantify quinine dihydrochloride in children’s oral drops formulations were developed and validated. Raman and Near Infrared (NIR) spectroscopy were selected for the drug...

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

    Science.gov (United States)

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

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance. PMID:25267670

  19. Pilot study of essential drug quality in two major cities in India.

    Directory of Open Access Journals (Sweden)

    Roger Bate

    Full Text Available BACKGROUND: India is an increasingly influential player in the global pharmaceutical market. Key parts of the drug regulatory system are controlled by the states, each of which applies its own standards for enforcement, not always consistent with others. A pilot study was conducted in two major cities in India, Delhi and Chennai, to explore the question/hypothesis/extent of substandard and counterfeit drugs available in the market and to discuss how the Indian state and federal governments could improve drug regulation and more importantly regulatory enforcement to combat these drugs. METHODOLOGY/PRINCIPAL FINDINGS: Random samples of antimalarial, antibiotic, and antimycobacterial drugs were collected from pharmacies in urban and peri-urban areas of Delhi and Chennai, India. Semi-quantitative thin-layer chromatography and disintegration testing were used to measure the concentration of active ingredients against internationally acceptable standards. 12% of all samples tested from Delhi failed either one or both tests, and were substandard. 5% of all samples tested from Chennai failed either one or both tests, and were substandard. Spatial heterogeneity between pharmacies was observed, with some having more or less substandard drugs (30% and 0% respectively, as was product heterogeneity, with some drugs being more or less frequently substandard (12% and 7% respectively. CONCLUSIONS/SIGNIFICANCE: In a study using basic field-deployable techniques of lesser sensitivity rather than the most advanced laboratory-based techniques, the prevalence of substandard drugs in Delhi and Chennai is confirmed to be roughly in accordance with the Indian government's current estimates. However, important spatial and product heterogeneity exists, which suggests that India's substandard drug problem is not ubiquitous, but driven by a subset of manufacturers and pharmacies which thrive in an inadequately regulated environment. It is likely that the drug regulatory

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

    Directory of Open Access Journals (Sweden)

    Antia R

    2003-02-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-06-01

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

  3. Are Patent Medicine Vendors Effective Agents in Malaria Control? Using Lot Quality Assurance Sampling to Assess Quality of Practice in Jigawa, Nigeria

    OpenAIRE

    Sima Berendes; Olusegun Adeyemi; Edward Adekola Oladele; Olusola Bukola Oresanya; Festus Okoh; Joseph J Valadez

    2012-01-01

    BACKGROUND: Patent medicine vendors (PMV) provide antimalarial treatment and care throughout Sub-Saharan Africa, and can play an important role in the fight against malaria. Their close-to-client infrastructure could enable lifesaving artemisinin-based combination therapy (ACT) to reach patients in time. However, systematic assessments of drug sellers' performance quality are crucial if their role is to be managed within the health system. Lot quality assurance sampling (LQAS) could be an eff...

  4. Injection Drug User Quality of Life Scale (IDUQOL): Findings from a content validation study

    OpenAIRE

    Palepu Anita; Hubley Anita M

    2007-01-01

    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...

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

    Directory of Open Access Journals (Sweden)

    David J Sullivan

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

  6. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    Directory of Open Access Journals (Sweden)

    Norazsida Ramli

    2014-01-01

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

  7. Investigation of Traditional Palestinian Medicinal Plant Inula viscosa as Potential Anti-malarial Agent

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    M. Akkawi

    2014-10-01

    Full Text Available Malaria is a life threatening parasitic disease which is prevalent mainly in developing countries; it is the main cause of global mortality and morbidity. Development and search of novel and effective anti-malarial agents to overcome chloroquine resistance have become a very important issue. Most anti-malarial drugs target the erythrocytic stage of malaria infection, where hemozoin synthesis takes place and is considered a crucial process for the parasite survival. Throughout last decades, natural products have been a significant source of chemotherapeutics especially against malaria. Inula viscosa, Inula viscosa , is a shrub that grows around the Mediterranean basin and considered as an important Palestinian traditional medicinal herb. In this research it was found that the Palestinian flora Inula viscosa alcoholic extract has a significant and promising anti-malarial effect in both in vitro and in vivo systems. The crude alcoholic extract of Inula viscosa has the capability to impede the formation of &beta-hematin in vitro; with an efficiency of about 93% when compared to the standard chloroquine which gave 94% at comparable concentrations. in vivo studies showed that this crude extract inhibited the growth of Plasmodium parasites in the red blood cells at a rate of about 96.6%, with an EC50 value of 0.55 ng/mL. Several secondary plant metabolites may be responsible for this anti-malarial activity; the effect also may be most probably due to the presence of high concentrations of nerolidol which has often been found at high concentrationsin this plant. Nerolidol shows a stronger inhibition of hypoxanthine incorporation than quinine. Its anti-malarial effect is potentiated by other essential oils. Nerolidol is also found in several Artemisia species and in Cymbopogon citratus (lemongrass and Virola surinamensis, all plants known for their anti-malarial properties.

  8. Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals.

    Science.gov (United States)

    Fügi, Matthias A; Wittlin, Sergio; Dong, Yuxiang; Vennerstrom, Jonathan L

    2010-03-01

    Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ277. The antagonism observed for combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that the formation of carbon-centered radicals is critical for the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend toward greater antagonism with artemisinin than they did with OZ277, an observation that can be explained by the greater tendency of artemisinin-derived carbon-centered radicals to undergo internal self-quenching reactions, resulting in a lower proportion of radicals available for subsequent chemical reactions such as the alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their nonperoxidic analogs. The latter had no effect on the antimalarial activities of the former. These data indicate that the antimalarial properties of peroxides do not derive from reversible interactions with parasite targets. PMID:20028825

  9. Evaluation of antiretroviral drug measurements by an interlaboratory quality control program.

    NARCIS (Netherlands)

    Droste, J.A.H.; Aarnoutse, R.E.; Koopmans, P.P.; Hekster, Y.A.; Burger, D.M.

    2003-01-01

    Since 1999 an ongoing international interlaboratory quality control program has analyzed antiretroviral drugs in plasma. Results of the third round of this program are presented. Quality control samples were prepared by spiking drug-free plasma with varying concentrations of the currently available

  10. A Chemical Proteomics Approach for the Search of Pharmacological Targets of the Antimalarial Clinical Candidate Albitiazolium in Plasmodium falciparum Using Photocrosslinking and Click Chemistry

    OpenAIRE

    Diana Marcela Penarete-Vargas; Anaïs Boisson; Serge Urbach; Hervé Chantelauze; Suzanne Peyrottes; Laurent Fraisse; Vial, Henri J

    2014-01-01

    Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an origi...

  11. The Multi-State Information System Drug Exception System: A Quality Assurance Tool

    OpenAIRE

    Siegel, Carole; Laska, Eugene; Fischer, Susan

    1981-01-01

    This paper reports on the development of computerized systems designed to be used as tools by mental health environments to assist them in carrying out their mandates of quality of care review. It begins with a description of the operational Multi-State Information System's Drug Exception Reporting (DER) component, an automated drug review system. The system is designed to be used in conjunction with a facility's drug utilization review process, to ensure that patients are receiving drugs in ...

  12. Extensive Drug Resistance in Malaria and Tuberculosis

    OpenAIRE

    Wongsrichanalai, Chansuda; Varma, Jay K.; Juliano, Jonathan J; Kimerling, Michael E.; MacArthur, John R

    2010-01-01

    Drug resistance in malaria and in tuberculosis (TB) are major global health problems. Although the terms multidrug-resistant TB and extensively drug-resistant TB are precisely defined, the term multidrug resistance is often loosely used when discussing malaria. Recent declines in the clinical effectiveness of antimalarial drugs, including artemisinin-based combination therapy, have prompted the need to revise the definitions of and/or to recategorize antimalarial drug resistance to include ex...

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

    OpenAIRE

    Bertocchi Paola; Antoniella Eleonora; Cocchieri Emilia; Di Maggio Anna; Gaudiano Maria; Alimonti Stefano; Valvo Luisa

    2007-01-01

    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 ...

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

    OpenAIRE

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

    2003-01-01

    Antimalarial drug resistance has now become a serious global challenge and is the principal reasonfor the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficaciousdrugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rollingback malaria. Artemisinin-based combinations offer a new and potentially highly effective way tocounter drug resistance. Clinical trials conducted in African children have attested to the good toler...

  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...

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

    Science.gov (United States)

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

    2015-09-18

    A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs. PMID:26295174

  17. Report of the WHO Collaborating Centre for Quality Assurance of Essential Drugs

    OpenAIRE

    Drs. R. Pandjaitan

    2012-01-01

    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 H...

  18. Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology

    OpenAIRE

    Ruscoe, J. E.; Tingle, M. D.; O’Neill, P. M.; S.A. Ward; Park, B K

    1998-01-01

    The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5′ position of amodiaquine reduced or elimi...

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

    Science.gov (United States)

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

    2016-06-23

    Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compounds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chemistry efforts yielding molecules that have reached the clinic. PMID:26791529

  20. Synthesis and in vitro antimalarial activity of novel chalcone derivatives / Frans Johannes Smit

    OpenAIRE

    Smit, Frans Johannes

    2014-01-01

    Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as c...

  1. Barrier qualities of the mouse eye to topically applied drugs.

    Science.gov (United States)

    Wang, Zhao; Do, Chi Wai; Avila, Marcel Y; Stone, Richard A; Jacobson, Kenneth A; Civan, Mortimer M

    2007-07-01

    The mouse eye displays unusually rapid intraocular pressure (IOP) responses to topically applied drugs as measured by the invasive servo-null micropipette system (SNMS). To learn if the time course reflected rapid drug transfer across the thin mouse cornea and sclera, we monitored a different parameter, pupillary size, following topical application of droplets containing 40 microM (0.073 microg) carbachol. No miosis developed from this low carbachol concentration unless the cornea was impaled with an exploring micropipette as used in the SNMS. We also compared the mouse IOP response to several purinergic drugs, measured by the invasive SNMS and non-invasive pneumotonometry. Responses to the previously studied non-selective adenosine-receptor (AR) agonist adenosine, the A(3)-selective agonist Cl-IB-MECA and the A(3)-selective antagonist MRS 1191 were all enhanced to varying degrees, in time and magnitude, by corneal impalement. We conclude that the thin ocular coats of the mouse eye actually present a substantial barrier to drug penetration. Corneal impalement with even fine-tipped micropipettes can significantly enhance entry of topically-applied drugs into the mouse aqueous humor, reflecting either direct diffusion around the tip or a more complex impalement-triggered change in ocular barrier properties. Comparison of invasive and non-invasive measurement methods can document drug efficacy at intraocular target sites even if topical drug penetration is too slow to manifest convincing physiologic effects in intact eyes. PMID:17490649

  2. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Biswas S

    2001-10-01

    Full Text Available BAKGROUND: The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml. RESULTS: At highest concentration (40 micro/ml, parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

  3. Barrier Qualities of the Mouse Eye to Topically Applied Drugs

    OpenAIRE

    Wang, Zhao; Do, Chi Wai; Avila, Marcel Y.; Stone, Richard A.; Jacobson, Kenneth A.; Civan, Mortimer M.

    2007-01-01

    The mouse eye displays unusually rapid intraocular pressure (IOP) responses to topically applied drugs as measured by the invasive servo-null micropipette system (SNMS). To learn if the time course reflected rapid drug transfer across the thin mouse cornea and sclera, we monitored a different parameter, pupillary size, following topical application of droplets containing 40 μM (0.073μg) carbachol. No miosis developed from this low carbachol concentration unless the cornea was impaled with an ...

  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. "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; Vestergaard, Lasse S; Chandler, Clare I R

    2014-01-01

    . 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...

  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. Evaluation on antimalarial activity of 3 artemisinin drugs using SYBR green Ⅰ and flow cytometry in vitro%用SYBR green Ⅰ法和流式细胞术体外评价3种青蒿素类药物的抗疟活性

    Institute of Scientific and Technical Information of China (English)

    薛丹; 程慧芳; 毋海兰; 赵青; 王锐利; 张淑秋

    2014-01-01

    目的 用SYBR green Ⅰ法和流式细胞术评价3种青蒿素类药物对体外培养恶性疟原虫的抗疟活性. 方法 采用SYBR green Ⅰ法观察不同浓度的青蒿素(arteminisinin,ART)、蒿甲醚(artemether,AM)及双氢青蒿素(dihydroartemisinin,DHA)对体外培养的恶性疟原虫增殖的抑制作用.ART、AM、DHA的抑制浓度依次为6、6×10-1、6×10-2、6×10-3、6×10-4 μmol/L,4、4×10-1、4×10-2、4×10-3、4× 10-4 μmol/L及3×10-1、3×10-2、3×10-3、3×10-4、3×10-5 μmol/L,设空白组与对照组.体外药物作用72 h后,SYBR green Ⅰ法测得其抑制率,用50%抑制浓度(50% inhibitory concentraton,IC50)及95%抑制浓度(95% inhibitory concentraton,IC95)反映其抑制作用,并与流式细胞术所测得的疟原虫DNA含量的变化进行比较. 结果 SYBR green Ⅰ法结果显示其抑制率随药物浓度的增加而增大,ART、AM与DHA的IC50值分别为11.29、3.32、0.66 nmol/L,IC95值分别为42.55、17.89、4.02 nmol/L;流式细胞术结果中其DNA含量随药物浓度的降低而增加,与SYBR green Ⅰ法结果一致且更具直观性. 结论 SYBR green Ⅰ法的灵敏性与流式细胞术的直观性可以满足体外测定抗疟药对疟原虫抑制作用的需要,均可适于抗疟药物体外活性评价;ART、AM与DHA的体外抗疟活性由高到低的次序为DHA>AM>ART.%Objective To evaluate the antimalarial activity against Plasmodiumfalciparum in vitro by SYBR green Ⅰ and flow cytometry.Methods SYBR green Ⅰ was used to evaluate the inhibition to proliferation of Plasmodium falciparum in vitro treated by artimisinin(ART),artemether(AM) and dihydroartemisinine(DHA) at different concentrations.The intervention concentrations of ART,AM and DHA were 6,6×10-1,6×10-2,6×103,6×10-4μmol/L,4,4×10-1,4×10-2,4×10-3,4×10-4 μmol/L,and 3×10-1,3×10-2,3×10-3,3×10-4,3×10-5 μmol/L respectively,a blank control group was set up.After 72 h of drug intervention in vitro,the inhibition

  8. Evaluation of the ex vivo antimalarial activity of organotin (IV) ethylphenyldithiocarbamate on erythrocytes infected with Plasmodium berghei NK 65.

    Science.gov (United States)

    Awang, Normah; Jumat, Hafizah; Ishak, Shafariatul Akmar; Kamaludin, Nurul Farahana

    2014-06-01

    Malaria is the most destructive and dangerous parasitic disease. The commonness of this disease is getting worse mainly due to the increasing resistance of Plasmodium falciparum against antimalarial drugs. Therefore, the search for new antimalarial drug is urgently needed. This study was carried out to evaluate the effects of dibutyltin (IV) ethylphenyldithiocarbamate (DBEP), diphenyltin (IV) ethylphenyldithiocarbamate (DPEP) and triphenyltin (IV) ethylphenyldithiocarbamate (TPEP) compounds as antimalarial agents. These compounds were evaluated against erythrocytes infected with Plasmodium berghei NK65 via ex vivo. Organotin (IV) ethylphenyldithiocarbamate, [R(n)Sn(C9H10NS2)(4-n)] with R = C4H9 and C6H5 for n = 2; R = C6H5 for n = 3 is chemically synthesised for its potential activities. pLDH assay was employed for determination of the concentration that inhibited 50% of the Plasmodium's activity (IC50) after 24 h treatment at concentration range of 10-0.0000001 mg mL(-1). Plasmodium berghei NK65 was cultured in vitro to determine the different morphology of trophozoite and schizont. Only DPEP and TPEP compounds have antimalarial activity towards P. berghei NK65 at IC50 0.094±0.011 and 0.892±0.088 mg mL(-1), respectively. The IC50 of DPEP and TPEP were lowest at 30% parasitemia with IC50 0.001±0.00009 and 0.0009±0.0001 mg mL(-1), respectively. In vitro culture showed that TPEP was effective towards P. berghei NK65 in trophozoite and schizont morphology with IC50 0.0001±0.00005 and 0.00009±0.00003 μg mL(-1), respectively. In conclusion, DPEP and TPEP have antimalarial effect on erythrocytes infected with P. berghei NK65 and have potential as antimalarial and schizonticidal agents. PMID:26035957

  9. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

    Directory of Open Access Journals (Sweden)

    Swain Bijay K

    2009-02-01

    Full Text Available Abstract Background Herbal extracts of Andrographis paniculata (AP and Hedyotis corymbosa (HC are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20 and resistant (MRC-pf-303 strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50 of AP (7.2 μg/ml was found better than HC (10.8 μg/ml. Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC and their individual synergism with curcumin (AP+CUR, HC+CUR were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs.

  10. Antimalarial activity of some Colombian medicinal plants

    OpenAIRE

    Garavito, G. (G.); Rincon, J.; Arteaga, L.; Hata, Y; Bourdy, Geneviève; Gimenez, A.; Pinzon, R.; Deharo, Eric

    2006-01-01

    Antimalarial activity of 10 vegetal extracts (9 ethanolic extracts and 1 crude alkaloid extract), obtained from eight species traditionally used in Colombia to treat malaria symptoms, was evaluated in culture using Plasmodium falciparum chloroquine resistant (FcB2) strain and in vivo on rodent malaria Plasmodium berghei. The activity on ferriprotoporphyrin biomineralization inhibition test (FBIT) was also assessed. Against Plasmodium falciparum, eight extracts displayed good activity Abuta gr...

  11. 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.

  12. 76 FR 50741 - 2011 Parenteral Drug Association/Food and Drug Administration Joint Public Conference; Quality...

    Science.gov (United States)

    2011-08-16

    ... Administration Joint Public Conference; Quality and Compliance in Today's Regulatory Enforcement Environment... entitled ``Quality and Compliance in Today's Regulatory Enforcement Environment.'' The conference will span... register at their earliest convenience. The PDA registration fees cover the cost of facilities,...

  13. 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

    -prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. RESULTS: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16...

  14. The effect of hypotensive drugs on the quality of life

    OpenAIRE

    Jachuck, S J; Brierley, H; Jachuck, S; Willcox, P. M.

    1982-01-01

    Quality of life after antihypertensive therapy was assessed in 75 patients with controlled hypertension using questionnaires given to patients, close companions and doctors. The overall assessments of the three groups differed significantly.

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

    Science.gov (United States)

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

    2007-09-01

    The Injection Drug User Quality of life Scale (IDUQOL) measures the unique and individual circumstances that determine the quality of life of injection drug users. This paper reports the psychometric properties of the Spanish version, for drug dependent persons with or without injectable consumption using a revised instrument: Drug user Quality of Life Scale-Spanish (DUQOL-Spanish). We studied 169 outpatients in 9 Spanish drug treatment centers. Factor analysis, internal consistency, test-retest reliability and criterion-related validity were assessed. The results show the essential unidimensionality of the scale, which supports the use of a total score. Both internal consistency (Cronbach's alpha: 0.86), and test-retest reliability (r=0.79) of the total score were high. Criterion-related validity supports the interpretation of the DUQOL-Spanish total score as measuring a construct consistent with quality of life. This study suggests that the DUQOL-Spanish is a valid instrument to measure subjective quality of life in Spanish drug users, and allows the identification of life areas that are considered by the patient important to change in order to improve their quality of life. PMID:17240076

  16. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

    Science.gov (United States)

    Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  17. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

    Science.gov (United States)

    Vaidya, Akhil B; Morrisey, Joanne M; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M; Otto, Thomas D; Spillman, Natalie J; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F; Price, Ric N; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  18. EVALUATION OF NEPETA LEAVIGATA, NEPETA KURRAMENSIS AND RHYNCHOSIA RENIFORMIS ON ANTIMALARIAL AND ANTILEISHMANIAL ACTIVITIES

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    Memoona A, Amir MK, Sultan A, Razia P, Sumera P, Lal M, Nisar Ahmed*

    2012-10-01

    Full Text Available The pharmacological investigation of methanolic extracts and different fractions of the Nepeta leavigata, Nepeta kurramensis and Rhynchosia reniformis were designed to assess the antimalarial and antileishmanial screening of medicinal plants for development of drugs. Materials and Methods: The shade-dried whole plant material of Nepeta leavigata was soaked in methanol for 10 days. The powdered drug was extracted with 80 % methanol three times and filtered at room temperature. The filtrate was evaporated in rotary to get a dark-greenish residue (extract, which was further suspended in water and partitioned successively with n-hexane, chloroform, ethyl acetate and n-butanol to obtain n-hexane-soluble, chloroform-soluble, ethyl acetate-soluble, n-butanol-soluble and aqueous fractions, respectively (Khan, et al., 2010a. Same extraction and fractionation procedure was adopted for Nepeta kurramensis and Rhynchosia reniformis. The antimalarial / antileishmanial activity of crude extracts/fractions was determined through standard protocol (Kerharo & Adam, 1974/. Results: The crude extract, chloroform fraction of Nepeta leavigata and fractions chloroform and ethyl acetate of Nepeta kurramensis showed promising antileishmanial and antimalarial activity against parasites of leishmania and malaria (promistogetes and schizonts by observing 1 or 0 number of parasites on slide field where ≤ 1 level is significant, while all fractions of Rhynchosia reniformis did not showed any action against promistigotes and schizonts. Conclusions: The bioassays guided isolation and phytochemical screening of active fractions against these activities will further enhance research in the field of pharmacology.

  19. Are patent medicine vendors effective agents in malaria control? Using lot quality assurance sampling to assess quality of practice in Jigawa, Nigeria.

    Directory of Open Access Journals (Sweden)

    Sima Berendes

    Full Text Available BACKGROUND: Patent medicine vendors (PMV provide antimalarial treatment and care throughout Sub-Saharan Africa, and can play an important role in the fight against malaria. Their close-to-client infrastructure could enable lifesaving artemisinin-based combination therapy (ACT to reach patients in time. However, systematic assessments of drug sellers' performance quality are crucial if their role is to be managed within the health system. Lot quality assurance sampling (LQAS could be an efficient method to monitor and evaluate PMV practice, but has so far never been used for this purpose. METHODS: In support of the Nigeria Malaria Booster Program we assessed PMV practices in three Senatorial Districts (SDs of Jigawa, Nigeria. A two-stage LQAS assessed whether at least 80% of PMV stores in SDs used national treatment guidelines. Acceptable sampling errors were set in consultation with government officials (alpha and beta <0.10. The hypergeometric formula determined sample sizes and cut-off values for SDs. A structured assessment tool identified high and low performing SDs for quality of care indicators. FINDINGS: Drug vendors performed poorly in all SDs of Jigawa for all indicators. For example, all SDs failed for stocking and selling first-line antimalarials. PMV sold no longer recommended antimalarials, such as Chloroquine, Sulfadoxine-Pyrimethamine and oral Artesunate monotherapy. Most PMV were ignorant of and lacked training about new treatment guidelines that had endorsed ACTs as first-line treatment for uncomplicated malaria. CONCLUSION: There is urgent need to regularly monitor and improve the availability and quality of malaria treatment provided by medicine sellers in Nigeria; the irrational use of antimalarials in the ACT era revealed in this study bears a high risk of economic loss, death and development of drug resistance. LQAS has been shown to be a suitable method for monitoring malaria-related indicators among PMV, and should be

  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. 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. PMID:12463231

  2. Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) with Nonperoxidic Isosteres and Nitroxyl Radicals ▿

    OpenAIRE

    Fügi, Matthias A.; Wittlin, Sergio; Dong, Yuxiang; Vennerstrom, Jonathan L.

    2009-01-01

    Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ27...

  3. 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

  4. 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 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

  5. Bilayer Effects of Antimalarial Compounds.

    Directory of Open Access Journals (Sweden)

    Nicole B Ramsey

    Full Text Available Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity in a gramicidin-based stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05; MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all.

  6. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery.

    Science.gov (United States)

    McCarty, Sara E; Schellenberger, Amanda; Goodwin, Douglas C; Fuanta, Ngolui Rene; Tekwani, Babu L; Calderón, Angela I

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial. PMID:26111176

  7. Plasmodium falciparum Thioredoxin Reductase (PfTrxR and Its Role as a Target for New Antimalarial Discovery

    Directory of Open Access Journals (Sweden)

    Sara E. McCarty

    2015-06-01

    Full Text Available The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR, an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial.

  8. Patients’ perception and satisfaction on quality of laboratory malaria diagnostic service in Amhara Regional State, North West Ethiopia

    OpenAIRE

    Bogale, Agajie Likie; Kassa, Habtamu Belay; Ali, Jemal Haidar

    2015-01-01

    Background The most effective strategies in the fight against malaria are to correctly diagnose and timely treat the illness. A diagnosis based on clinical symptoms alone is subjected to misuse of anti-malarial drugs, increased costs to the health services, patient dissatisfaction and also contributes to an increase in non-malaria morbidity and mortality. Among others, inappropriate perception and inadequate satisfaction of patients are significant challenges reported to affect the quality of...

  9. In vitro and in vivo characterization of the antimalarial lead compound SSJ-183 in Plasmodium models

    Directory of Open Access Journals (Sweden)

    Schleiferböck S

    2013-11-01

    Full Text Available Sarah Schleiferböck,1,2 Christian Scheurer,1,2 Masataka Ihara,3,4 Isamu Itoh,3,4 Ian Bathurst,5,† Jeremy N Burrows,5 Pascal Fantauzzi,5 Julie Lotharius,5 Susan A Charman,6 Julia Morizzi,6 David M Shackleford,6 Karen L White,6 Reto Brun,1,2 Sergio Wittlin1,21Swiss Tropical and Public Health Institute, Basel, 2University of Basel, Basel, Switzerland; 3Drug Discovery Science Research Center, Hoshi University, Shinagawa, Tokyo, Japan; 4Synstar Japan Co, Ltd, Odawara, Japan; 5Medicines for Malaria Venture, Geneva, Switzerland; 6Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia †Ian Bathurst passed away on 26 June 2011Abstract: The objective of this work was to characterize the in vitro (Plasmodium falciparum and in vivo (Plasmodium berghei activity profile of the recently discovered lead compound SSJ-183. The molecule showed in vitro a fast and strong inhibitory effect on growth of all P. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. Furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite strains. In vivo, SSJ-183 showed a rapid onset of action, comparable to that seen for the antimalarial drug artesunate. SSJ-183 exhibited a half-life of about 10 hours and no significant differences in absorption or exposure between noninfected and infected mice. SSJ-183 appears to be a promising new lead compound with an attractive antimalarial profile.Keywords: antimalarial studies, cross-resistance, stage-specificity, Plasmodium falciparum

  10. 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.

  11. Antimalarial activity of Ageratum conyzoides in combination with chloroquine and artesunate

    Institute of Scientific and Technical Information of China (English)

    Ukwe Chinwe V; Ekwunife Obinna I; Epueke Ebele A; Ubaka Chukwuemeka M

    2010-01-01

    Objective: To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides (A. conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice. Methods: Using malaria (Plasmodium berghei) infected albino mice of both sexes, aqueous extracts of A. conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity, respectively. Four-day suppressive test and Rane's curative test were carried out. Results: Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations. Suppressive activities of both extract-drug combinations were greater than the individual drugs alone. Extract-chloroquine (100:5) produced the highest suppressive effect (98% suppression). Curative tests showed absolute survival in two extract-drug combinations. Two extract-drug combinations produced higher curative effects than the individual drugs alone. The highest dose combinations of extract-chloroquine (100:5) and extract-artesunate (100:5) produced absolute parasitemia clearance (cure) in the infected mice. Conclusions: The study indicated that aqueous extract of A. conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice. It contributes a lot in the malaria endemic and poverty stricken tropics.

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

    OpenAIRE

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

    1994-01-01

    A simple, low-cost, accurate thin-layer chromatography (TLC) method has been used to establish the first drug quality screening laboratory in Swaziland. For this purpose, office space at the central medical stores was first converted into a simple laboratory. Basic equipment, supplies, and materials were purchased, existing manpower was trained to perform accurately the TLC procedure, and a system was established for the qualitative/quantitative screening of selected drugs purchased by the Mi...

  13. Natural and Semi synthetic Antimalarial Compounds: Emphasis on the Terpene Class.

    Science.gov (United States)

    Silva, G N S; Rezende, L C D; Emery, F S; Gosmann, G; Gnoatto, S C B

    2015-01-01

    Malaria is one of the most important tropical diseases since more than 40% of the world population is at risk. This disease is endemic to more than 100 nations and remains one of the main leading causes of death in children less than five years of age worldwide. Natural product-derived compounds have played a major role in drug discovery, often as prototypes to obtain more active semi synthetic derivatives. Antimalarial pharmacotherapy is a significant example of plant-derived medicines, such as quinine and artemisinin. This review highlights studies on terpenes and their semi synthetic derivatives from natural sources with antimalarial activity reported in the literature during eleven years (2002-2013). A total of 114 compounds are found among terpenes and their semi synthetic derivatives. Cytotoxicity of the compounds is also found in this review. Furthermore, the physicochemical properties of the terpenes addressed are discussed based on seven well established descriptors, which provide a useful source for the elaboration of a terpene library of antimalarial compounds. PMID:25553426

  14. Statins as Potential Antimalarial Drugs: Low Relative Potency and Lack of Synergy with Conventional Antimalarial Drugs▿

    OpenAIRE

    Wong, Rina P. M.; Davis, Timothy M. E.

    2009-01-01

    The in vitro sensitivity of Plasmodium falciparum to atorvastatin and rosuvastatin was assessed using chloroquine-sensitive and chloroquine-resistant strains. Although atorvastatin was more potent, it had weak activity (mean 50% inhibitory concentration of ≥17 μM) and an indifferent interaction with chloroquine and dihydroartemisinin. Bioassay of plasma from an atorvastatin-treated subject showed similar results.

  15. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection

    DEFF Research Database (Denmark)

    Chen, M; Theander, T G; Christensen, S B;

    1994-01-01

    Licochalcone A, isolated from Chinese licorice roots, inhibited the in vitro growth of both chloroquine-susceptible (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains in a [3H]hypoxanthine uptake assay. The growth inhibition of the chloroquine-resistant strain by licochalcone A was...... licochalcone A exhibits potent antimalarial activity and might be developed into a new antimalarial drug....

  16. Rapid evaluation of artesunate quality with a specific monoclonal antibody-based lateral flow dipstick.

    Science.gov (United States)

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

    2016-09-01

    Artesunate is a frontline antimalarial drug for treating Plasmodium falciparum malaria. To produce specific antibodies to artesunate, the carboxyl group of artesunate was directly conjugated to carrier protein as the immunogen. A specific monoclonal antibody (mAb) 3D82G6 against artesunate was obtained by high-throughput screening of positive hybridoma clones. This monoclonal antibody had 4.0, 0.5, and 0.9 % cross reactivities with artemisinin, dihydroartemisinin, and artemether, respectively. A dipstick immunoassay was developed, and the indicator range for artesunate was 1000-2000 ng mL(-1). No interference was observed with artemisinin, dihydroartemisinin, artemether, and other commonly used antimalarial drugs for up to 20,000 ng mL(-1). The dipsticks were used for determination of artesunate contents in commercial drugs, and the results were agreeable with those determined by high-performance liquid chromatography. This dipstick, with its specificity and sensitivity for artesunate and simplicity to use, makes it a potential point-of-care device for rapid quality evaluation of artesunate-containing antimalarial drugs. Graphical Abstract Specific monoclonal antibody-based lateral flow dipstick for artesunate. PMID:26873200

  17. Antimalarial and cytotoxic properties of Chukrasia tabularis A. Juss and Turraea vogelii Hook F. Ex. Benth.

    Science.gov (United States)

    Ogbole, Omonike O; Saka, Yusuf A; Fasinu, Pius S; Fadare, Adenike A; Ajaiyeoba, Edith O

    2016-04-01

    Malaria, caused by plasmodium parasite, is at the moment the highest cause of morbidity and mortality in the tropics. Recently, there is increasing efforts to develop more potent antimalarials from plant sources that will have little or no adverse effects. This study is aimed at investigating the in vivo mice antimalarial and in vitro antiplasmodial effects of two Meliaceae plants commonly used in Nigerian ethnomedicine as part of recipe for treating malaria infection: Chukrasia tabularis and Turraea vogelii. Hot water decoction and methanol extract of both plants were evaluated for their antimalarial activity in vivo using the mice model assay and in vitro using the parasite lactate dehydrogenase (pLDH) assay. The extracts were also assessed for toxicity with brine shrimp lethality assay and in mammalian cell lines using the neural red assay. The in vivo mice model antimalarial study showed that the methanol extract of the stem bark of C. tabularis exhibited the highest % chemosuppression (83.65 ± 0.66) at the highest dosage administered (800 mg/kg) when compared with chloroquine diphosphate, the standard reference drug which had a % suppression of 90.36 ± 0.04 (p < 0.05). The in vitro antiplasmodial study indicated that the aqueous extract of the stem bark of C. tabularis displayed good activity against Plasmodium falciparum chloroquine-sensitive (D6) strain (IC50 of 10.739 μg/mL) and chloroquine-resistant (W2) strain. Chloroquine and artemisinin had <0.163 and <0.0264, respectively. PMID:26911147

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  19. 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.

  20. The Art of Managing Conversions between Antiepileptic Drugs: Maximizing Patient Tolerability and Quality of Life

    OpenAIRE

    St. Louis, Erik K.

    2010-01-01

    Conversion between anti-epilectic drugs (AEDs) is frequently necessary in epilepsy care, exposing patients to a risk of incurring adverse effects and reduced quality of life. Little practical guidance is available to practitioners to guide conversions between AED monotherapies, or in adding a new adjunctive AED into a polytherapy regimen. This article reviews the impact of adverse effects of AEDs on quality of life in epilepsy patients, then reviews several important patient-related factors s...

  1. Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy.

    Science.gov (United States)

    Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M; Li, Yuexin; Mather, Michael W; Meermeier, Erin; Pershing, April M; Forquer, Isaac P; Miley, Galen P; Pou, Sovitj; Winter, Rolf W; Hinrichs, David J; Kelly, Jane X; Kim, Kami; Vaidya, Akhil B; Riscoe, Michael K; Nilsen, Aaron

    2015-06-01

    Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development. PMID:25918204

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

    Science.gov (United States)

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

    2015-07-27

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

  3. 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

  4. 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

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

    Science.gov (United States)

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

    2016-10-01

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

  6. Prescription for antibiotics at drug shops and strategies to improve quality of care and patient safety

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Buregyeya, Esther; Rutebemberwa, Elizeus; Clarke, Siân E; Lal, Sham; Hansen, Kristian S; Magnussen, Pascal; LaRussa, Philip

    2016-01-01

    private health sector in Uganda. METHODS: A survey was conducted within 57 parishes from August to October 2014 in Mukono District, Uganda. Data was captured on the following variables: drug shop characteristics, training of staff in management of pneumonia, availability of guidelines and basic equipment......OBJECTIVES: The main objective of this study was to assess practices of antibiotic prescription at registered drug shops with a focus on upper respiratory tract infections among children in order to provide data for policy discussions aimed at improving quality of care and patient safety in the......, available antibiotics, knowledge on treatment of pneumonia in children aged <5 years. The main study outcome was the proportion of private health facilities prescribing an antibiotic. RESULTS: A total of 170 registered drug shops were surveyed between August and October 2014. The majority of drug shops, 93...

  7. Quality indicators of preventable adverse drug events in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Thomsen, Linda Aagaard

    need quality improvement. One study concerned the four indicators on inadequate preventive treatment after acute myocardial infarction (AMI) (Article 4), and another study concerned the four indicators on inadequate monitoring of HbA1c resulting in admission with hyper- or iii hypoglycemia (Article 5...... preventable adverse drug events in the primary care setting (Article 1). Construction of the preventable adverse drug events assessment model required four steps. The first step consisted of the development, validation, and feasibility of preventable adverse drug event indicators for type 2 diabetes (Articles...... 10% of the Danish 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...

  8. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    International Nuclear Information System (INIS)

    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)

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

    OpenAIRE

    Shen S; Liu SZ; Zhang YS; Du MB; Liang AH; Song LH; Ye ZG

    2015-01-01

    Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel ...

  10. Anti-malarial activity and toxicity assessment of Himatanthus articulatus, a plant used to treat malaria in the Brazilian Amazon

    OpenAIRE

    Vale, Valdicley V; Thyago C. Vilhena; Trindade, Rafaela C Santos; Ferreira, Márlia Regina C; Percário, Sandro; Soares, Luciana F; Pereira, Washington Luiz A; Geraldo C. Brandão; Oliveira, Alaíde B; Dolabela, Maria F; De Vasconcelos, Flávio

    2015-01-01

    Background Plasmodium falciparum has become resistant to some of the available drugs. Several plant species are used for the treatment of malaria, such as Himatanthus articulatus in parts of Brazil. The present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of H. articulatus. Methods Ethanol and dichloromethane extracts were obtained from the powder of stem barks of H. articulatus and later fractionated and analysed. The anti-plasmod...

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

    OpenAIRE

    Sumsakul, Wiriyaporn; Plengsuriyakarn, Tullayakorn; Chaijaroenkul, Wanna; Viyanant, Vithoon; Karbwang, Juntra; Na-Bangchang, Kesara

    2014-01-01

    Background Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. Methods In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I base...

  12. Antimalarial Synergy of Cysteine and Aspartic Protease Inhibitors

    OpenAIRE

    Semenov, Andrey; Olson, Jed E.; Rosenthal, Philip J.

    1998-01-01

    It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease ...

  13. The use of genotyping in antimalarial clinical trials: a systematic review of published studies from 1995–2005

    Directory of Open Access Journals (Sweden)

    Rosenthal Philip J

    2006-12-01

    Full Text Available Abstract Background The use of genotyping to distinguish recrudescent from new infections is currently recommended for all clinical antimalarial efficacy trials by the World Health Organization. However, genotyping-adjusted drug efficacy estimates may vary between trials due to the use of different genotyping methods and to the different settings in which these methods are applied. Methods A systematic review of all clinical antimalarial efficacy trials published from 1995–2005 was performed to characterize the use of genotyping, including the methods used and the effect of these methods on estimates of drug efficacy. Results In a multivariate analysis, the method of interpretation of genotyping results, the studied therapy, the location of the trial, and the duration of study follow-up all had statistically significant effects on the percent of genotyped outcomes classified as new infections. Conclusion Criteria for defining appropriate, standardized genotyping methods for use in different settings are needed to enable more accurate estimates of antimalarial drug efficacy and better comparison between trials. The advantages and disadvantages of different genotyping methods and their potential impact in various settings are discussed.

  14. Drug-resistant malaria

    OpenAIRE

    Hyde, John E

    2005-01-01

    In the past 21 years, a modest increase in the range of antimalarial drugs approved for clinical use has been complemented by a more impressive expansion in the analysis and understanding of the molecular mechanisms underlying resistance to these agents. Such resistance is a major factor in the increasing difficulty in controlling malaria, and important developments during this period are recounted here.

  15. New Congressional Bill Attempts to Aid Pharmacy Response to Drug Shortages: Compounding and Tracing Provisions Seek to Improve Quality of Drug Supply

    OpenAIRE

    Barlas, Stephen

    2014-01-01

    The Drug Quality and Security Act is intended to prevent the sale of contaminated compounded agents, but the way in which facilities will be regulated is still unclear. Many safeguards will need to be implemented.

  16. A review of quality of life in Alzheimer's disease. Part 2: Issues in assessing drug effects.

    Science.gov (United States)

    Salek, S S; Walker, M D; Bayer, A J

    1998-12-01

    There are numerous methods available for assessing patients with Alzheimer's disease (AD) or other forms of dementia. Quality-of-life (QOL) assessment is unique among these methods. The subjective nature of quality of life provides healthcare professionals with the opportunity of incorporating the value systems of patients and their carers into their assessments. A systematic review was carried out to assess the published data (and some unpublished data) on QOL assessment tools and instruments that claim to measure quality of life in dementia. A number of measures or methods used in the literature for assessing the quality of life of patients with dementing illnesses were identified. It was decided to present the resultant review in 2 parts that correspond to the 2 main groups into which the instruments were categorised. The first (part 1), looked at measures used to assess the impact of disease as well as instruments at a developmental or testing stage. The second (part 2), includes instruments that claim to measure quality of life in studies documenting the impact of a drug in this therapeutic area. This second group consists mainly of instruments identified as being used to assess quality of life during clinical trials in dementia/AD. As in part 1, this part of the review was unable to identify any validated methods of assessing the quality of life of both patients with dementia and their carers at the same time. The ideal instrument must show that it can reliably, reproducibly and comprehensively assess quality of life for both patients with dementia and their carers. It should also demonstrate that it can measure quality of life effectively using a practical administration technique that does not place any unnecessary burden on either informal carers, other healthcare workers involved or the patient themselves. In addition, any measure intended for use in assessing the impact of drug treatment on quality of life must demonstrate sensitivity to change, also

  17. 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)

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3H-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 (IC50s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC50 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

  18. Implications of the Food, Drug, and Cosmetic Act on the quality assurance of radiopharmaceuticals used in the United States

    International Nuclear Information System (INIS)

    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

  19. Effectiveness of Mindfulness-Based Stress Reduction Intervention for Health-Related Quality of Life in Drug-Dependent Males

    OpenAIRE

    Hosseinzadeh Asl, Navid Reza; Hosseinalipour, Fattaneh

    2014-01-01

    Background: Nowadays drug dependence has become one of the main concerns worldwide. Indeed, drug dependence and abuse have become personal, social and, health problems that intensively threat human resources. Objectives: This study aimed to examine the effect of mindfulness-based stress reduction (MBSR) on health-related quality of life (HRQOL) in drug-dependent males. Patients and Methods: An experimental research with pretest/posttest design and a control group was conducted on 49 drug-depe...

  20. 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.

  1. EFFECT OF ANTIHYPERTENSIVE DRUGS ON QUALITY OF LIFE IN PATIENTS WITH ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    G. F. Andreeva

    2016-01-01

    Full Text Available Aim. To study effect of antihypertensive drugs on quality of life (QoL of patients with stable arterial hypertension (HT.Material and methods. Results of some studies with similar design involving totally 170 patients with HT, aged 57,2±8,8 y.o., were analyzed. HT duration was 11,2±8,3 years. Patients received antihypertensive monotherapy with diltiazem, amlodipine, enalapril, lisinopril, metoprolol and telmisartan during 1-3 months. 24-hour blood pressure (BP monitoring, QoL was performed before and after treatment.Results. All antihypertensive drugs significantly reduced systolic and diastolic BP and did not affect QoL. ACE inhibitors similarly improved QoL.Conclusion. Antihypertensive drugs (diltiazem, amlodipine, enalapril, lisinnopril, metoprolol, telmisartan do not worsen QoL of patients with HT.

  2. Malaria, anaemia and antimalarial drug resistance in African children

    NARCIS (Netherlands)

    Obonyo, C.O.

    2006-01-01

    Malaria-associated anaemia is a potentially preventable cause of severe morbidity and mortality in children < 5years of age, in areas of high malaria transmission in sub-Saharan Africa. In a cross-sectional study of 3586 children, 80% were anaemic (haemoglobin [Hb]<11g/dL) and 3% had severe anaemia

  3. Identification and Characterization of Novel Drug Resistance Loci in Plasmodium falciparum

    OpenAIRE

    Van Tyne, Daria Natalie

    2012-01-01

    Malaria has plagued mankind for millennia. Antimalarial drug use over the last century has generated highly drug-resistant parasites, which amplify the burden of this disease and pose a serious obstacle to control efforts. This dissertation is motivated by the simple fact that malaria parasites have become resistant to nearly every antimalarial drug that has ever been used, yet the precise genetic mechanisms of parasite drug resistance remain largely unknown. Our work pairs genomics-age techn...

  4. Proposal for a new therapy for drug-resistant malaria using Plasmodium synthetic lethality inference ☆

    OpenAIRE

    Lee, Sang Joon; Seo, Eunseok; Cho, Yonghyun

    2013-01-01

    Many antimalarial drugs kill malaria parasites, but antimalarial drug resistance (ADR) and toxicity to normal cells limit their usefulness. To solve this problem, we suggest a new therapy for drug-resistant malaria. The approach consists of data integration and inference through homology analysis of yeast–human–Plasmodium. If one gene of a Plasmodium synthetic lethal (SL) gene pair has a mutation that causes ADR, a drug targeting the other gene of the SL pair might be used as an effective tre...

  5. 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.

  6. Substandard/Counterfeit Antimicrobial Drugs

    OpenAIRE

    Kelesidis, Theodoros; Falagas, Matthew E

    2015-01-01

    Substandard/counterfeit antimicrobial drugs are a growing global problem. The most common substandard/counterfeit antimicrobials include beta-lactams (among antibiotics) and chloroquine and artemisin derivatives (among antimalarials). The most common type of substandard/counterfeit antimicrobial drugs have a reduced amount of the active drug, and the majority of them are manufactured in Southeast Asia and Africa. Counterfeit antimicrobial drugs may cause increased mortality and morbidity and ...

  7. 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.

  8. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya

    Science.gov (United States)

    Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L.; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E. Jane

    2016-01-01

    Objective To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB) in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS) methodology. Design The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance. Results This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains. Conclusion Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints. PMID:27167381

  9. 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

  10. Assessment of Malaria In Vitro Drug Combination Screening and Mixed-Strain Infections Using the Malaria Sybr Green I-Based Fluorescence Assay▿

    OpenAIRE

    Co, Edgie-Mark A.; Dennull, Richard A.; Reinbold, Drew D.; Waters, Norman C; Johnson, Jacob D.

    2009-01-01

    Several drug development strategies, including optimization of new antimalarial drug combinations, have been used to counter malaria drug resistance. We evaluated the malaria Sybr green I-based fluorescence (MSF) assay for its use in in vitro drug combination sensitivity assays. Drug combinations of previously published synergistic (atovaquone and proguanil), indifferent (chloroquine and azithromycin), and antagonistic (chloroquine and atovaquone) antimalarial drug interactions were tested ag...

  11. Antimalarial activity of some Colombian medicinal plants.

    Science.gov (United States)

    Garavito, G; Rincón, J; Arteaga, L; Hata, Y; Bourdy, G; Gimenez, A; Pinzón, R; Deharo, E

    2006-10-11

    Antimalarial activity of 10 vegetal extracts (9 ethanolic extracts and 1 crude alkaloid extract), obtained from eight species traditionally used in Colombia to treat malaria symptoms, was evaluated in culture using Plasmodium falciparum chloroquine resistant (FcB2) strain and in vivo on rodent malaria Plasmodium berghei. The activity on ferriprotoporphyrin biomineralization inhibition test (FBIT) was also assessed. Against Plasmodium falciparum, eight extracts displayed good activity Abuta grandifolia (Mart.) Sandwith (Menispermaceae) leaves, Acacia farnesiana (L.) Willd. (Mimosaceae) leaves, Acnistus arborescens (L.) Schltdl. (Solanaceae) aerial part, Croton leptostachyus Kunth (Euphorbiaceae) aerial part, Piper cumanense Kunth (Piperaceae) fruits and leaves, Piper holtonii C. DC. (Piperaceae) aerial part and Xylopia aromatica (Lam.) Mart. (Annonaceae) bark with IC(50) values ranging from <1 to 2.1 microg/ml, while in the in vivo model only Abuta grandifolia alkaloid crude extract exhibits activity, inhibiting 66% of the parasite growth at 250 mg/kg/day. In the FBIT model, five extracts were active (Abuta grandifolia, Croton leptostachyus, Piper cumanense fruit and leaves and Xylopia aromatica). PMID:16713157

  12. 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.

  13. Quality of Reporting of Serious Adverse Drug Events to an Institutional Review Board

    Science.gov (United States)

    Dorr, David A.; Burdon, Rachel; West, Dennis P.; Lagman, Jennifer; Georgopoulos, Christina; Belknap, Steven M.; McKoy, June M.; Djulbegovic, Benjamin; Edwards, Beatrice J.; Weitzman, Sigmund A.; Boyle, Simone; Tallman, Martin S.; Talpaz, Moshe; Sartor, Oliver; Bennett, Charles L.

    2009-01-01

    Purpose Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB. Experimental Design sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed. Results Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources. Conclusions The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients. PMID:19458059

  14. New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

    Science.gov (United States)

    Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

    2015-06-01

    Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. PMID:25920564

  15. Drug-Resistant Malaria Parasites Introduced into Madagascar from Comoros Islands

    OpenAIRE

    Ménard, Didier; 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.

  16. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes.

    Science.gov (United States)

    Goodman, Christopher D; Siregar, Josephine E; Mollard, Vanessa; Vega-Rodríguez, Joel; Syafruddin, Din; Matsuoka, Hiroyuki; Matsuzaki, Motomichi; Toyama, Tomoko; Sturm, Angelika; Cozijnsen, Anton; Jacobs-Lorena, Marcelo; Kita, Kiyoshi; Marzuki, Sangkot; McFadden, Geoffrey I

    2016-04-15

    Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control. PMID:27081071

  17. 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....

  18. Towards more effective public health programming for injection drug users: development and evaluation of the injection drug user quality of life scale.

    Science.gov (United States)

    Brogly, Susan; Mercier, Céline; Bruneau, Julie; Palepu, Anita; Franco, Eduardo

    2003-06-01

    The psychometric properties of the Injection Drug User Quality of Life Scale (IDUQOL) were assessed in 61 Montreal IDUs in 2001, 85% of whom were reinterviewed within four weeks. The reliability of the IDUQOL was acceptable (ICC = 0.71) and concordance between the IDUQOL and the Flanagan Quality of Life Scale was moderate (Pearson coefficient = 0.57). Quality of life was negatively associated with injection cocaine and emergency department use with both instruments; these results were more striking for the IDUQOL. The IDUQOL is a culturally relevant quality of life instrument with good psychometric properties. The IDUQOL may be useful in the development and evaluation of interventions for IDUs. PMID:12801151

  19. Case series in drug safety: a review to determine characteristics and quality.

    Science.gov (United States)

    Abou Chakra, Claire Nour; Pariente, Antoine; Pinet, Marion; Nkeng, Lenhangmbong; Moore, Nicholas; Moride, Yola

    2010-12-01

    Case series and case reports are a cornerstone of drug safety research; however, the characteristics of case series published in the literature remain poorly examined. A narrative review of case series addressing drug safety, published in the literature between 1 January 2003 and 15 July 2009, and identified through a PubMed search, was conducted in order to determine their characteristics and quality according to the criteria found in the US FDA Pharmacovigilance Guidance 2005. Of 130 publications that met the search criteria, 11.5% included an analytical component and 88.5% were descriptive. The median number of cases included in a given case series was 7 (range 2-2195) and the median time period for recruitment of the cases was 23 months (range 0.5-96). Overall, 43.1% of case series consisted of individual case reports, while 24.6% originated from cohorts and 21% from pharmacovigilance databases. Of the case series, 65.1% concerned adults (age ≥18 years), 11.6% elderly (age ≥65 years) and 8.5% youth (<18 years). Adverse effects involved mainly the skin (18.5%) and the circulatory system (13.8%). The main suspected drug classes (Anatomical Therapeutic Chemical classification) were nervous system drugs (23.1%) and antineoplastic and immunomodulating agents (20.0%). On average, six out of the possible nine US FDA Pharmacovigilance Guidance Criteria were fulfilled, with 27% of publications fulfilling at least seven criteria. Only 10% reported data on co-morbidity. In conclusion, this review highlights the reporting gaps and heterogeneity in published case series with respect to size, recruitment period and quality. PMID:21077699

  20. 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.

  1. Anti-malarial market and policy surveys in sub-Saharan Africa

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    Sevcsik Ann-Marie

    2010-04-01

    Full Text Available Abstract At a recent meeting (Sept 18, 2009 in which reasons for the limited access to artemisinin-based combination therapy (ACT in sub-Saharan Africa were discussed, policy and market surveys on anti-malarial drug availability and accessibility in Burundi and Sierra Leone were presented in a highly interactive brainstorming session among key stakeholders across private, public, and not-for-profit sectors. The surveys, the conduct of which directly involved the national malaria control programme managers of the two countries, provides the groundwork for evidence-based policy implementation. The results of the surveys could be extrapolated to other countries with similar socio-demographic and malaria profiles. The meeting resulted in recommendations on key actions to be taken at the global, national, and community level for better ACT accessibility. At the global level, both public and private sectors have actions to take to strengthen policies that lead to the replacement of loose blister packs with fixed-dose ACT products, develop strategies to ban inappropriate anti-malarials and regulate those bans, and facilitate technology and knowledge transfer to scale up production of fixed-dose ACT products, which should be readily available and affordable to those patients who are in the greatest need of these medicines. At the national level, policies that regulate the anti-malarial medicines market should be enacted and enforced. The public sector, including funding donors, should participate in ensuring that the private sector is engaged in the ACT implementation process. Research similar to the surveys discussed is important for other countries to develop and evaluate the right incentives at a local level. At the community level, community outreach and education about appropriate preventive and treatment measures must continue and be strengthened, with service delivery systems developed within both public and private sectors, among other measures

  2. Quality of the cardiovascular drugs prescribing in Zagreb during the period 2001- 2004

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    Dražen Stojanović

    2009-02-01

    Full Text Available Aim To investigate the outpatient utilisation of cardiovasculardrugs in Zagreb, during the 2001-2004 period, and to identify thepossible association between the increase in the utilisation of particulardrug groups and decrease in the number of hospital admissions.Methods The number of DDD per thousand inhabitants per day(DDDs/TID was calculated from data on the number and size ofdispensed drug packages, obtained from the Zagreb Pharmacies.Drug Utilisation 90% (DU90% method was used on assessmentof drug prescribing quality.Results Total utilisation of the cardiovascular drugs was high inZagreb during the 2001-2004 period (between 402.9 DDDs/TIDand 406.9 DDDs/TID. Agents acting on the renin-angiotensinsystem (C09 (121.3 DDDs/TID and calcium channel blockers(C08 (87.5 DDDs/TID accounted for more than 50% of drugsused for the treatment of hypertension in 2004. The greatest utilisationincrease was observed for statins (78.3%. Comparison ofDU90% segment between 2001 and 2004 revealed pentoxifyllineand amiodarone to be absent, whereas cilazapril and ramipril intheir combination with HCTZ, bisoprolol, valsartan and losartanalone or in their combination with HCTZ were added in 2004,DU90% segment still contain doxazosin and propafenone, whichhad no grounds in therapeutic guidelines.Conclusion The outpatient utilisation of cardiovascular drugs washigh during the 2001-2004 period. The utilization pattern was improved.The result was a decrease in the number of hospital admissionsfor main cardiovascular events.

  3. Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents

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    Jiayi Wang

    2014-05-01

    Full Text Available Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3 to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively and Plasmodium falciparum (K1 dual drug resistant strain (IC50 41 and 15 μM, respectively, but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively. To expand the structure–activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic “capping acids”, and polyamines including spermine (PA3-4-3 and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10–92 nM but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM. There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia.

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

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    Gayan S. Bamunuarachchi

    2013-12-01

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

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

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    Steven Maranz

    2012-01-01

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

  6. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

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    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.

  7. In vitro Potentiation of Antimalarial Activities by Daphnetin Derivatives Against Plasmodium falciparum

    Institute of Scientific and Technical Information of China (English)

    FANG HUANG; LIN-HUA TANG; LIN-QIAN YU; YI-CHANG NI; QIN-MEI WANG; FA-JUN NAN

    2006-01-01

    Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum (FCC1) was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodium falciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.

  8. 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 <10 %). Cell-based assays are often considered superior related to the biological significance, however, typically they cannot still be considered as really quantitative, in particular when results are compared over longer periods of time or between laboratories. A very careful choice of assays is therefore recommended. Strategies to further optimize assays are outlined, considering the evaluation and the decrease of the relevant error sources. Analytical performance and data quality are still advancing and will further advance the progress in drug development. PMID:26070362

  9. "This body does not want free medicines": South African consumer perceptions of drug quality.

    Science.gov (United States)

    Patel, Aarti; Gauld, Robin; Norris, Pauline; Rades, Thomas

    2010-01-01

    OBJECTIVES Like many other developing countries, South Africa provides free medicines through its public health care facilities. Recent policies encourage generic substitution in the private sector. This study explored South African consumer perceptions of drug quality and whether these perceptions influenced how people procured and used their medicines. METHODS The study was undertaken in Durban, Cape Town and Johannesburg in South Africa between December 2005 and January 2006. A combination of purposive and snowball sampling was used to recruit participants from low and middle socio-economic groups as well as the elderly and teenagers. Data were collected through 12 focus group discussions involving a total of 73 participants. Interviews were tape-recorded. Thematic analysis was performed on the transcripts. RESULTS Irrespective of socio-economic status, respondents described medicine quality in terms of the effect the medicine produced on felt symptoms. Generic medicines, as well as medicines supplied without charge by the state, were considered to be poor quality and treated with suspicion. Respondents obtained medicines from three sources: public sector hospitals and/or clinics, dispensing doctors and community pharmacies. Cost, avoidance of feeling 'second-class', receiving individualized care and choice in drug selection were the main determinants influencing their procurement behaviour. Selection of over-the-counter medicines was influenced by prior knowledge of products, through advertising and previous use. Participants perceived that they had limited influence on selection of prescription medicines. Generic substitution would be supported if the doctor, rather than the pharmacist, recommended it. CONCLUSIONS Our findings emphasize the importance of meaningful consumer involvement in the development of national medicines policies, and strategic campaigns targeting consumers and prescribers regarding the quality of generic and essential medicines. Where

  10. Ligand-based virtual screening and in silico design of new antimalarial compounds using nonstochastic and stochastic total and atom-type quadratic maps.

    Science.gov (United States)

    Marrero-Ponce, Yovani; Iyarreta-Veitía, Maité; Montero-Torres, Alina; Romero-Zaldivar, Carlos; Brandt, Carlos A; Avila, Priscilla E; Kirchgatter, Karin; Machado, Yanetsy

    2005-01-01

    Malaria has been one of the most significant public health problems for centuries. It affects many tropical and subtropical regions of the world. The increasing resistance of Plasmodium spp. to existing therapies has heightened alarms about malaria in the international health community. Nowadays, there is a pressing need for identifying and developing new drug-based antimalarial therapies. In an effort to overcome this problem, the main purpose of this study is to develop simple linear discriminant-based quantitative structure-activity relationship (QSAR) models for the classification and prediction of antimalarial activity using some of the TOMOCOMD-CARDD (TOpological MOlecular COMputer Design-Computer Aided "Rational" Drug Design) fingerprints, so as to enable computational screening from virtual combinatorial datasets. In this sense, a database of 1562 organic chemicals having great structural variability, 597 of them antimalarial agents and 965 compounds having other clinical uses, was analyzed and presented as a helpful tool, not only for theoretical chemists but also for other researchers in this area. This series of compounds was processed by a k-means cluster analysis in order to design training and predicting sets. Afterward, two linear classification functions were derived in order to discriminate between antimalarial and nonantimalarial compounds. The models (including nonstochastic and stochastic indices) correctly classify more than 93% of the compound set, in both training and external prediction datasets. They showed high Matthews' correlation coefficients, 0.889 and 0.866 for the training set and 0.855 and 0.857 for the test one. The models' predictivity was also assessed and validated by the random removal of 10% of the compounds to form a new test set, for which predictions were made using the models. The overall means of the correct classification for this process (leave group 10% full-out cross validation) using the equations with nonstochastic

  11. Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

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    Mullié Catherine

    2012-03-01

    Full Text Available Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ (+- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R -enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S and (R-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.

  12. Quality control of the paracetamol drug by chemometrics and imaging spectroscopy in the near infrared region

    Science.gov (United States)

    Baptistao, Mariana; Rocha, Werickson Fortunato de Carvalho; Poppi, Ronei Jesus

    2011-09-01

    In this work, it was used imaging spectroscopy and chemometric tools for the development and analysis of paracetamol and excipients in pharmaceutical formulations. It was also built concentration maps to study the distribution of the drug in the tablets surface. Multivariate models based on PLS regression were developed for paracetamol and excipients concentrations prediction. For the construction of the models it was used 31 samples in the tablet form containing the active principle in a concentration range of 30.0-90.0% (w/w) and errors below to 5% were obtained for validation samples. Finally, the study of the distribution in the drug was performed through the distribution maps of concentration of active principle and excipients. The analysis of maps showed the complementarity between the active principle and excipients in the tablets. The region with a high concentration of a constituent must have, necessarily, absence or low concentration of the other one. Thus, an alternative method for the paracetamol drug quality monitoring is presented.

  13. Analysis of the importance of drug packaging quality for end users and pharmaceutical industry as a part of the quality management system

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    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

  14. Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children

    Science.gov (United States)

    Parikh, Sunil; Kajubi, Richard; Huang, Liusheng; Ssebuliba, Joshua; Kiconco, Sylvia; Gao, Qin; Li, Fangyong; Were, Moses; Kakuru, Abel; Achan, Jane; Mwebaza, Norah; Aweeka, Francesca T.

    2016-01-01

    Background. The optimal treatment of malaria in human immunodeficiency virus (HIV)–infected children requires consideration of critical drug–drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes. Methods. We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated. Results. One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART. Conclusions. The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted. PMID:27143666

  15. 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. PMID:27483471

  16. Malaria healthcare policy change in Kenya: Implications on sales and marketing of antimalarials

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    Peter K. Ngure , Lorraine Nyaoke & David Minja

    2012-03-01

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

  17. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

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    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.

  18. Drug: D02547 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02547 Drug Pamaquine; Plasmoquine [veterinary] (TN) C19H29N3O 315.2311 315.4531 D0...2547.gif Antimalarial [veterinary] veterinary medicine map07025 Quinolines CAS: 491-92-9 PubChem: 17396718 L

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

    OpenAIRE

    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; Facundo M Fernández; Green, Michael D.

    2015-01-01

    In 2003, a stratified random sample survey was conducted in the Lao People's Democratic Republic (Laos) to study the availability and quality of antimalarials in the private sector. In 2012, this survey was repeated to allow a statistically valid analysis of change through time. The counterfeit detection device 3 (CD-3) was used to assess packaging quality in the field and HPLC and mass spectroscopy analysis chemical analysis performed. The availability of oral artesunate monotherapies had si...

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

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    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

  1. In-silico studies on DegP protein of Plasmodium falciparum in search of anti-malarials.

    Science.gov (United States)

    Sharma, Drista; Soni, Rani; Patel, Sachin; Joshi, Deepti; Bhatt, Tarun Kumar

    2016-09-01

    Despite encouraging progress over the past decade, malaria caused by the Plasmodium parasite continues to pose an enormous disease burden and is one of the major global health problems. The extreme challenge in malaria management is the resistance of parasites to traditional monochemotherapies like chloroquine and sulfadoxine-pyrimethamine. No vaccine is yet in sight, and the foregoing effective drugs are also losing ground against the disease due to the resistivity of parasites. New antimalarials with novel mechanisms of action are needed to circumvent existing or emerging drug resistance. DegP protein, secretory in nature has been shown to be involved in regulation of thermo-oxidative stress generated during asexual life cycle of Plasmodium, probably required for survival of parasite in host. Considering the significance of protein, in this study, we have generated a three-dimensional structure of PfDegP followed by validation of the modeled structure using several tools like RAMPAGE, ERRAT, and others. We also performed an in-silico screening of small molecule database against PfDegP using Glide. Furthermore, molecular dynamics simulation of protein and protein-ligand complex was carried out using GROMACS. This study substantiated potential drug-like molecules and provides the scope for development of novel antimalarial drugs. PMID:27491850

  2. Antimalarial potential of homeopathic medicines against schizont maturation of Plasmodium berghei in short-term in vitro culture

    Directory of Open Access Journals (Sweden)

    Upma Bagai

    2012-12-01

    Full Text Available In vitro assessment of antimalarial drug susceptibility of Plasmodium has been a major research success, which has paved the way for the understanding of parasite and rapid screening of antimalarial drugs for their effectiveness. In the present study a preliminary screening to check the antiplasmodial activity of mother tincture (ϕ and various potencies (6C, 30C, 200C of homeopathic medicines Cinchona officinalis/china (Chin., Chelidonium majus (Chel. and Arsenicum album (Ars. were done by assessing the in vitro schizont maturation inhibition assay. A significant reduction in the growth of intraerythrocytic stages of P. berghei was observed with decreasing dilution of ϕ and various potencies of Chin., Chel. and Ars. exhibiting a dose dependent effect. Maximum schizont maturation inhibition was observed by Chin. ϕ (1:1, Chin. 30 (1:1, 1:2 and Chel. 30 (1:1 i.e. 80%. The standard drug CQ at 10 µM concentration exhibited 95.4±1.6% inhibition of schizont maturation. Ars. 30 (1:1 also have been found to possess strong antiplasmodial efficacy with 75.5±2.6% schizont inhibition. The presence of free merozoites in Ars. 200 with weak schizonticidal inhibition activity (40-45% also pointed towards the ability of parasite to survive in the given drug pressure.

  3. Gas chromatographic method for the determination of lumefantrine in antimalarial finished pharmaceutical products

    Directory of Open Access Journals (Sweden)

    Sultan Suleman

    2015-09-01

    Full Text Available A simple method has been developed and validated for quantitative determination of lumefantrine in antimalarial finished pharmaceutical products using gas chromatography coupled to flame ionization detector. Lumefantrine was silylated with N,O–bis(trimethyl-silyltrifluoro-acetamide at 70°C for 30 minutes, and chromatographic separation was conducted on a fused silica capillary (HP-5, 30 m length × 0.32 mm i.d., 0.25 μm film thickness column. Evaluation of the method within analytical quality-by-design principles, including a central composite face-centered design for the sample derivatization process and Plackett–Burman robustness verification of the chromatographic conditions, indicated that the method has acceptable specificity toward excipients and degradants, accuracy [mean recovery = 99.5%, relative standard deviation (RSD = 1.0%], linearity (=0.9986, precision (intraday = 96.1% of the label claim, RSD = 0.9%; interday = 96.3% label claim, RSD = 0.9%, and high sensitivity with detection limits of 0.01 μg/mL. The developed method was successfully applied to analyze the lumefantrine content of marketed fixed-dose combination antimalarial finished pharmaceutical products.

  4. 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...

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

    Directory of Open Access Journals (Sweden)

    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

  6. Adherence of community caretakers of children to pre-packaged antimalarial medicines (HOMAPAK) among internally displaced people in Gulu district, Uganda.

    OpenAIRE

    Opwonya John; Ojok Naptalis; Kolaczinski Jan H; Meek Sylvia; Collins Andrew

    2006-01-01

    Abstract Background In 2002, home-based management of fever (HBMF) was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs) who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK®) free of charge to caretakers of febrile children. Adherence of caretakers to this regimen has not been studied. Methods A questionnaire-based survey combined ...

  7. Self-medication with anti-malarials is a common practice in rural communities of Kilosa district in Tanzania despite the reported decline of malaria

    OpenAIRE

    Chipwaza, Beatrice; Joseph P Mugasa; Mayumana, Iddy; Amuri, Mbaraka; Makungu, Christina; Gwakisa, Paul S.

    2014-01-01

    Background Self-medication has been widely practiced worldwide particularly in developing countries including Tanzania. In sub-Saharan Africa high incidences of malaria have contributed to self-medication with anti-malarial drugs. In recent years, there has been a gain in malaria control, which has led to decreased malaria transmission, morbidity and mortality. Therefore, understanding the patterns of self-medication during this period when most instances of fever are presumed to be due to no...

  8. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

    OpenAIRE

    Swain Bijay K; Dash Aditya P; Mishra Kirti; Dey Nrisingha

    2009-01-01

    Abstract Background Herbal extracts of Andrographis paniculata (AP) and Hedyotis corymbosa (HC) are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20) and resistant (MRC-pf-303) strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using diff...

  9. 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

    2016-09-01

    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. PMID:27343901

  10. Identity, strength, purity, quality, and safety: Common goals for new drugs

    International Nuclear Information System (INIS)

    Before a radiopharmaceutical can be sold or distributed to the medical community in the US, a New Drug Application (NDA) must be approved by the FDA, a process which can be long and arduous. The most common impediments to NDA approval are the chemistry questions. The myriad issues involved - process and product control, analytical methods development and validation, stability testing - narrow down to five basic questions: identity, strength, purity, quality, and safety, the litany of good manufacturing practices (GMP). If it is assumed that the competent manufacturer will be carrying out the intent of the GMP's, then the goal of the chemistry section of the NDA is to document those procedures in such a way as to convince an impartial observer that the product delivered to the consumer will have the properties it is supposed to have

  11. 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. PMID:27092277

  12. Influence of anaesthetic drugs on the epididymal sperm quality in domestic cats.

    Science.gov (United States)

    Jiménez, E; Pérez-Marín, C C; Millán, Y; Agüera, E

    2011-02-01

    The present study investigated the effect of different anaesthetic agents commonly used in cats on the fresh and frozen-thawed epididymal sperm. Seventeen male domestic cats were castrated using pentobarbital, ketamine HCl or isoflurane. Sperm samples were recovered from epididymides and evaluated before and after freezing, determining the vigor, motility, morphology, acrosome status, sperm viability and functional membrane integrity. Fresh epididymal sperm was influenced by the drugs used, noting that motility features, i.e. vigor (p≤0.05) and progressive motility (p≤0.05), were higher for the inhalation anaesthetic while the others did not showed statistical differences. In frozen-thawed sperm samples, cats treated with barbiturics showed lower values for acrosome status (p≤0.05) and integrity and functionality of membrane (p≤0.05 and p≤0.01, respectively) than in the others groups. Results suggested that drugs used for castration in cats could affect the sperm quality and this should be considered when implementing sperm cryopreservation in the feline. PMID:21288668

  13. An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients

    OpenAIRE

    Naumann Terryn; Wilbur Kerry; Bandali Shakeel; Marra Carlo; Frighetto Luciana; Jewesson Peter

    2004-01-01

    Abstract Background Hospitalization can significantly disrupt sleeping patterns. In consideration of the previous reports of insomnia and apparent widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted a study to assess quality of sleep and hypnotic drug use in our acute care adult patient population. The primary objectives of this study were to assess sleep disturbance and its determinants including the use of drugs with sedating properties. Methods This...

  14. Analysis of the physico-chemical quality Enalapril and Simvastatin drugs manipulated in magistral pharmacies from Belo Horizonte, MG, Brazil

    International Nuclear Information System (INIS)

    The increasing expansion of compounding pharmacy associated with several reports on variances in the quality of compounded drugs demonstrates the need for verification of quality, safety and efficacy of these products. In this work, physical and chemical analyzes were performed to evaluate the quality of some capsules manipulated enalapril and simvastatin, acquired in five pharmacies in Belo Horizonte /Brazil. Among the analyzes are pharmacopoeial tests for appearance, identification, determination of weight, content, related compounds and uniformity of dosage units, and was also performed neutron activation analysis for the determination of inorganic impurities in drugs sampled. The results showed that 60% of the samples were unsatisfactory for pharmacopoeial tests. The contents of the capsules sampled for individual testing unit dose uniformity between 0% and 136.2%. This test is important in evaluating the quality, which influences the safety and efficacy of drug treatment, since it allows you to check if the product contains the proper dosage and necessary for successful pharmacotherapy. On the other hand, underdosing can lead to reduced or absent desired therapeutic response, and overdoses can provide an undesirable effects and even toxic. The concentration of inorganic impurities was considered to be relatively small. However, no specific limits for some chemical elements in medicine hamper a better thread. In addition, further studies must be performed to assess chronic exposure to low concentrations of inorganic impurities, since drugs can be continuously used, and other sources of exposure must also be considered in order to evaluate the risk. The problems related to the quality and safety of compounded drugs are still reality in the country and reveal a serious public health problem, especially regarding the lack of uniformity between the unit doses of medications. It is suggested that the competent authorities to sanitary products, propose changes in

  15. Assessment of Quality of Sleep and Use of Drugs with Sedating Properties in Adult Patients Hospitalized in Hamadan Ekbatan Hospital

    Directory of Open Access Journals (Sweden)

    F. Zeraati

    2010-01-01

    Full Text Available Introduction & Objective: Hospitalization can significantly disrupt sleeping patterns. considering the prevalence of insomnia and widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted this study to assess the quality of sleep and hypnotic drug use in hospitalized adult patients in 2007.Materials & Methods: This descriptive analytical cross-sectional study involved an assessment of sleep quality for patients whose consent had been obtained when admitted to the internal ward of Hamadan Ekbatan hospital. The Pittsburg sleep quality index (PSQI was used to measure the quality of sleep in patients and completed at the time of admission and discharge. Also the relation of factors such as age, sex. Marital status, education and sedating drug use prior to and during hospitalization with sleep quality were assessed. 300 patients entered this study and completed PSQI sleep questionnaires two twice, at the time of admission & discharge. Results: At the time of admission only 36% of patients had good sleep quality (PSQI score <5 while this percent decreased to 18.3% at the time of discharge. Mean global PSQI score was 7.6 at the time of admission versus 9.4 at the time of discharge indicating the patients’ worse sleep quality at the time of discharge (Pv<0.05. 23% of patients received hypnotic drugs while in the hospital with no evidence of preadmission hypnotic use. Benzodiazepines were prescribed for all of them.Conclusion: Quality of sleep at the time of discharge was significantly worse than it at the time of admission and it seems that despite widespread use of sedative drug in the hospital , there are still patients with poor sleep quality in the hospital.

  16. 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

  17. Number of drugs in the medication list as an indicator of prescribing quality: a validation study of polypharmacy indicators in older hip fracture patients

    OpenAIRE

    Belfrage, Björn; Koldestam, Anders; Sjöberg, Christina; Wallerstedt, Susanna M.

    2015-01-01

    Purpose Indicators based on the number of drugs in the medication list are sometimes used to reflect quality of drug treatment. This study aimed to evaluate the concurrent validity of such polypharmacy indicators, i.e., their ability to differentiate between appropriate and suboptimal drug treatment. Methods In 200 hip fracture patients (≥65 years of age), consecutively recruited to a randomized controlled study in Sahlgrenska University Hospital in 2009, quality of drug treatment at study en...

  18. Identifying and assessing highly hazardous drugs within quality risk management programs.

    Science.gov (United States)

    Sussman, Robert G; Schatz, Anthony R; Kimmel, Tracy A; Ader, Allan; Naumann, Bruce D; Weideman, Patricia A

    2016-08-01

    Historically, pharmaceutical industry regulatory guidelines have assigned certain active pharmaceutical ingredients (APIs) to various categories of concern, such as "cytotoxic", "hormones", and "steroids". These categories have been used to identify APIs requiring segregation or dedication in order to prevent cross-contamination and protect the quality and safety of drug products. Since these terms were never defined by regulatory authorities, and many novel pharmacological mechanisms challenge these categories, there is a recognized need to modify the historical use of these terms. The application of a risk-based approach using a health-based limit, such as an acceptable daily exposure (ADE), is more appropriate for the development of a Quality Risk Management Program (QRMP) than the use of categories of concern. The toxicological and pharmacological characteristics of these categories are discussed to help identify and prioritize compounds requiring special attention. Controlling airborne concentrations and the contamination of product contact surfaces in accordance with values derived from quantitative risk assessments can prevent adverse effects in workers and patients, regardless of specific categorical designations to which these APIs have been assigned. The authors acknowledge the movement away from placing compounds into categories and, while not yet universal, the importance of basing QRMPs on compound-specific ADEs and risk assessments. Based on the results of a risk assessment, segregation and dedication may also be required for some compounds to prevent cross contamination during manufacture of APIs. PMID:27267171

  19. When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis.

    Directory of Open Access Journals (Sweden)

    Jack W Scannell

    Full Text Available A striking contrast runs through the last 60 years of biopharmaceutical discovery, research, and development. Huge scientific and technological gains should have increased the quality of academic science and raised industrial R&D efficiency. However, academia faces a "reproducibility crisis"; inflation-adjusted industrial R&D costs per novel drug increased nearly 100 fold between 1950 and 2010; and drugs are more likely to fail in clinical development today than in the 1970s. The contrast is explicable only if powerful headwinds reversed the gains and/or if many "gains" have proved illusory. However, discussions of reproducibility and R&D productivity rarely address this point explicitly. The main objectives of the primary research in this paper are: (a to provide quantitatively and historically plausible explanations of the contrast; and (b identify factors to which R&D efficiency is sensitive. We present a quantitative decision-theoretic model of the R&D process. The model represents therapeutic candidates (e.g., putative drug targets, molecules in a screening library, etc. within a "measurement space", with candidates' positions determined by their performance on a variety of assays (e.g., binding affinity, toxicity, in vivo efficacy, etc. whose results correlate to a greater or lesser degree. We apply decision rules to segment the space, and assess the probability of correct R&D decisions. We find that when searching for rare positives (e.g., candidates that will successfully complete clinical development, changes in the predictive validity of screening and disease models that many people working in drug discovery would regard as small and/or unknowable (i.e., an 0.1 absolute change in correlation coefficient between model output and clinical outcomes in man can offset large (e.g., 10 fold, even 100 fold changes in models' brute-force efficiency. We also show how validity and reproducibility correlate across a population of simulated

  20. When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis

    Science.gov (United States)

    Scannell, Jack W.; Bosley, Jim

    2016-01-01

    A striking contrast runs through the last 60 years of biopharmaceutical discovery, research, and development. Huge scientific and technological gains should have increased the quality of academic science and raised industrial R&D efficiency. However, academia faces a "reproducibility crisis"; inflation-adjusted industrial R&D costs per novel drug increased nearly 100 fold between 1950 and 2010; and drugs are more likely to fail in clinical development today than in the 1970s. The contrast is explicable only if powerful headwinds reversed the gains and/or if many "gains" have proved illusory. However, discussions of reproducibility and R&D productivity rarely address this point explicitly. The main objectives of the primary research in this paper are: (a) to provide quantitatively and historically plausible explanations of the contrast; and (b) identify factors to which R&D efficiency is sensitive. We present a quantitative decision-theoretic model of the R&D process. The model represents therapeutic candidates (e.g., putative drug targets, molecules in a screening library, etc.) within a “measurement space", with candidates' positions determined by their performance on a variety of assays (e.g., binding affinity, toxicity, in vivo efficacy, etc.) whose results correlate to a greater or lesser degree. We apply decision rules to segment the space, and assess the probability of correct R&D decisions. We find that when searching for rare positives (e.g., candidates that will successfully complete clinical development), changes in the predictive validity of screening and disease models that many people working in drug discovery would regard as small and/or unknowable (i.e., an 0.1 absolute change in correlation coefficient between model output and clinical outcomes in man) can offset large (e.g., 10 fold, even 100 fold) changes in models’ brute-force efficiency. We also show how validity and reproducibility correlate across a population of simulated screening and

  1. 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

  2. Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity

    Directory of Open Access Journals (Sweden)

    Rebecca D. Sandlin

    2014-12-01

    Full Text Available The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though in vivo formation of hemozoin occurs within the presence of neutral lipids, the lipophilic detergent NP-40 was previously shown to serve as a surrogate in the β-hematin (synthetic hemozoin formation process. Consequently, an NP-40 mediated β-hematin formation assay was developed for use in high-throughput screening. Here, the assay was utilized to screen 144,330 compounds for the identification of inhibitors of crystallization, resulting in 530 hits. To establish the effectiveness of these target-based β-hematin inhibitors against Plasmodium falciparum, each hit was further tested in cultures of parasitized red blood cells. This effort revealed that 171 of the β-hematin inhibitors are also active against the parasite. Dose–response data identified 73 of these β-hematin inhibitors have IC50 values ⩽5 μM, including 25 compounds with nanomolar activity against P. falciparum. A scaffold-based analysis of this data identified 14 primary scaffolds that represent 46% of the 530 total hits. Representative compounds from each of the classes were further assessed for hemozoin inhibitory activity in P. falciparum infected human erythrocytes. Each of the hit compounds tested were found to be positive inhibitors, while a negative control did not perturb this biological pathway in culture.

  3. Assessment of Quality of Sleep and Use of Drugs with Sedating Properties in Adult Patients Hospitalized in Hamadan Ekbatan Hospital

    OpenAIRE

    F. Zeraati; M.A. Seif Rabie; M. Araghchian; T. Sabouri

    2010-01-01

    Introduction & Objective: Hospitalization can significantly disrupt sleeping patterns. considering the prevalence of insomnia and widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted this study to assess the quality of sleep and hypnotic drug use in hospitalized adult patients in 2007.Materials & Methods: This descriptive analytical cross-sectional study involved an assessment of sleep quality for patients whose consent had been obtained when admitte...

  4. Discovery and optimisation studies of antimalarial phenotypic hits

    Science.gov (United States)

    Mital, Alka; Murugesan, Dinakaran; Kaiser, Marcel; Yeates, Clive; Gilbert, Ian H.

    2015-01-01

    There is an urgent need for the development of new antimalarial compounds. As a result of a phenotypic screen, several compounds with potent activity against the parasite Plasmodium falciparum were identified. Characterization of these compounds is discussed, along with approaches to optimise the physicochemical properties. The in vitro antimalarial activity of these compounds against P. falciparum K1 had EC50 values in the range of 0.09–29 μM, and generally good selectivity (typically >100-fold) compared to a mammalian cell line (L6). One example showed no significant activity against a rodent model of malaria, and more work is needed to optimise these compounds. PMID:26408453

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

    OpenAIRE

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

    2012-01-01

    Article summary Article focus The need for high-quality uterotonic drugs for the prevention and treatment of maternal mortality and morbidity in poor countries is indisputable. Best practice for long-term storage for all injectable uterotonics is refrigeration, which is a key logistical constraint for scale up of postpartum haemorrhage reduction strategies and is a general challenge for maternity services without consistent electricity. The objectives of the study were to assess the populatio...

  6. Intermittent Preventive Antimalarial Treatment for Children with Anaemia.

    OpenAIRE

    Athuman, Mwaka; Kabanywanyi, Abdunoor M; Rohwer, Anke C

    2015-01-01

    Background Anaemia is a global public health problem. Children under five years of age living in developing countries (mostly Africa and South-East Asia) are highly affected. Although the causes for anaemia are multifactorial, malaria has been linked to anaemia in children living in malaria-endemic areas. Administering intermittent preventive antimalarial treatment (IPT) to children might reduce anaemia, since it could protect children from new Plasmodium parasite infection (the parasites tha...

  7. Antimalarial effect of agmatine on Plasmodium berghei K173 strain

    Institute of Scientific and Technical Information of China (English)

    SURui-Bin; WEIXiao-Li; LIUYin; LIJin

    2003-01-01

    AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.

  8. Review of pyronaridine anti-malarial properties and product characteristics

    Directory of Open Access Journals (Sweden)

    Croft Simon L

    2012-08-01

    Full Text Available Abstract Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

  9. Anti-Malarial Plants of Jonai, India: an Ethnobotanical Approach

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    Tonlong WANGPAN

    2016-03-01

    Full Text Available North-East India represents a unique ecosystem with treasured medicinal plant wealth closely related with Folk medicines. A large number of plants having medicinal properties and their folk uses have remained confined to the natives of this region. The tribal community of Jonai, Assam was explored to expose the indigenous herbal remedy for malaria. Sixteen antimalarial plants belonging to 13 families were reported. The analysis revealed highest fidelity level (FL value for Ajuga integrifolia (100% followed by Ricinus communis (94%, Alstonia scholaris (88%, Oroxylum indicum (86% and Achyranthes aspera (82%. The percentage of respondent’s knowledge (PRK about anti-malarial plants showed Alstonia scholaris as the most commonly known antimalarial species (53% within this region. Preference ranking (PR unveiled eight species to be very effective against malarial parasite, which includes Allium sativum, Artemisia indica, Azadirachta indica, Carica papaya, Clerodendrum glandulosum, Ocimum tenuiflorum, Oroxylum indicum, Piper longum and Piper nigrum. All medicine preparations are made using water as the medium and are orally administered in the form of crude extract, powder, juice and decoction. Overall analysis suggested Ajuga integrifolia, Achyranthes aspera, Alstonia scholaris, Artemisia indica, Oroxylum indicum and Ricinus communis to be used for the development of novel, economical, effective and ecofriendly herbal formulations for healthcare management.

  10. An Exploration of Quality of Life and Its Predictors in Patients with Addictive Disorders: Gambling, Alcohol and Drugs

    Science.gov (United States)

    Manning, Victoria; Gomez, Brenda; Guo, Song; Low, Yee Deng; Koh, Puay Kee; Wong, Kim Eng

    2012-01-01

    The study set out to examine Quality of Life (QoL), specifically subjective well being in three different addiction populations (260 alcohol-dependent, 282 drug-dependent, and 132 pathological gambling outpatients) at their first visit to treatment, using the Personal Well being Index (PWI). The mean PWI score for all patients was significantly…

  11. Indicators of prescribing quality in drug utilisation research : report of a European meeting (DURQUIM, 13-15 May 2004)

    NARCIS (Netherlands)

    Hoven, JL; Haaijer-Ruskamp, FM; Vander Stichele, RH

    2005-01-01

    An invitational expert meeting on indicators of prescribing quality was held on 13-15 May 2004, bringing together-from 19 European countries, the US, Canada, and Australia-40 researchers specialized in the development and application of indicators. The meeting was organized by the European Drug Util

  12. Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure

    OpenAIRE

    Amin, N’Cho Christophe; Fabre, Huguette; Blanchin, Marie-Dominique; Montels, Jérôme; Aké, Michèle

    2013-01-01

    Background Artemether-lumefantrine (AL) combination therapy is now the most used anti-malarial treatment in the world. Quality control of AL formulations is still a major challenge in developing countries. Until now, only liquid chromatographic methods have been reported in the literature for their analysis. Capillary electrophoretic methods, which present various advantages (low price of capillary, low volumes of electrolyte consumption), may be an alternative to liquid chromatography method...

  13. Antimalarial activity and toxicity of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Ratchanu; Bunyong; Wanna; Chaijaroenkul; Tullayakorn; Plengsuriyakarn; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vim.Methods:The antimalarial activity of Gareinja mangostana(G.mangostana)Linn.extract against 3D7 and Kl Plasmodium falciparum(P.falciparum)clone were assessed using SYBR green I-based assay.A 4-day suppressive test of Plasmodium berghei{P.berghei)infected mouse was performed to investigate in vivo antimalarial activity.Results:The in vitro antimalarial activity was seleclive(SI>5?and classified as weak and good lo moderate activity against both 3D7 and K1 P.falciparum,clones with median IC50(range)values of 11.12(10.94-11.29)and 7.54(6.80-7.68)μg/mL,respectively.The extract was considered nontoxic to mice.The maximum tolerated doses for acute and subacute toxicity in mice were 5 000and 2 000 mg/kg,respectively.Median(range)parasite density on day 4 of the negative control group(25%Tween-80),mice treated with 250,500,1000,and 2 000 mg/kg body weight of the extract,and 10 mg/kg body weight of chloroquine for 14 d were 12.8(12.2-13.7),11.4(9.49-13.8),11.6(9.9-12.5),11.7(10.6-12.8),10.9(9.4-11.6)and 0(0-0)%respectively.Parasite density on day 4in the control group treated with Tween-80 was higher than the groups treated with chloroquine and all dose levels of the extract.Conclusions:G.mangostana linn,showed weak antimalarial activity of the extract both in vitro and in vivo could be due to limitation of absorption of the active compounds.

  14. Current therapies and future possibilities for drug development against liver-stage malaria.

    Science.gov (United States)

    Raphemot, Rene; Posfai, Dora; Derbyshire, Emily R

    2016-06-01

    Malaria remains a global public health threat, with half of the world's population at risk. Despite numerous efforts in the past decade to develop new antimalarial drugs to surmount increasing resistance to common therapies, challenges remain in the expansion of the current antimalarial arsenal for the elimination of this disease. The requirement of prophylactic and radical cure activities for the next generation of antimalarial drugs demands that new research models be developed to support the investigation of the elusive liver stage of the malaria parasite. In this Review, we revisit current antimalarial therapies and discuss recent advances for in vitro and in vivo malaria research models of the liver stage and their importance in probing parasite biology and the discovery of novel drug candidates. PMID:27249674

  15. Phytochemical screening and in vivo antimalarial activity of extracts from three medicinal plants used in malaria treatment in Nigeria.

    Science.gov (United States)

    Bankole, A E; Adekunle, A A; Sowemimo, A A; Umebese, C E; Abiodun, O; Gbotosho, G O

    2016-01-01

    The use of plant to meet health-care needs has greatly increased worldwide in the recent times. The search for new plant-derived bioactive agents that can be explored for the treatment of drug-resistant malaria infection is urgently needed. Thus, we evaluated the antimalarial activity of three medicinal plants used in Nigerian folklore for the treatment of malaria infection. A modified Peter's 4-day suppressive test was used to evaluate the antimalarial activity of the plant extracts in a mouse model of chloroquine-resistant Plasmodium berghei ANKA strain. Animals were treated with 250, 500, or 800 mg/kg of aqueous extract. It was observed that of all the three plants studied, Markhamia tomentosa showed the highest chemosuppression of parasites of 73 % followed by Polyalthia longifolia (53 %) at day 4. All the doses tested were well tolerated. Percentage suppression of parasite growth on day 4 post-infection ranged from 1 to 73 % in mice infected with P. berghei and treated with extracts when compared with chloroquine diphosphate, the standard reference drug which had a chemosuppression of 90 %. The percentage survival of mice that received extract ranged from 0 to 60 % (increased as the dose increases to 800 mg/kg). Phytochemical analysis revealed the presence of tannins, saponins, and phenolic compounds in all the three plants tested. PMID:26391173

  16. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal

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    Faye Oumar

    2007-06-01

    Full Text Available Abstract Background In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam®, artesunate plus mefloquine (Artequin®, artemether plus lumefantrine (Coartem®; four doses and six doses, and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. Methods This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. Results All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%. Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%. The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. Conclusion The four combinations are effective and well-tolerated.

  17. Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains

    Science.gov (United States)

    Yang, Tuo; Xie, Stanley C.; Cao, Pengxing; Giannangelo, Carlo; McCaw, James; Creek, Darren J.; Charman, Susan A.; Klonis, Nectarios

    2016-01-01

    Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective. PMID:27161632

  18. In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains

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    Abiodun Oyindamola O

    2013-01-01

    Full Text Available Abstract Background Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+−ATPase of Plasmodium falciparum (PfATP6. In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy. Methods Drug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay. Results The sum 50% and 90% fractional inhibitory concentration (∑FIC50, 90 of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4. Conclusion The interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets.

  19. Discovery of carbohybrid-based 2-aminopyrimidine analogues as a new class of rapid-acting antimalarial agents using image-based cytological profiling assay.

    Science.gov (United States)

    Lee, Sukjun; Lim, Donghyun; Lee, Eunyoung; Lee, Nakyung; Lee, Hong-Gun; Cechetto, Jonathan; Liuzzi, Michel; Freitas-Junior, Lucio H; Song, Jin Sook; Bae, Myung Ae; Oh, Sangmi; Ayong, Lawrence; Park, Seung Bum

    2014-09-11

    New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 μM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites. PMID:25137549

  20. Diversity and utilization of antimalarial ethnophytotherapeutic remedies among the Kikuyus (Central Kenya

    Directory of Open Access Journals (Sweden)

    Bussmann Rainer W

    2006-02-01

    Full Text Available Abstract Plants in Kenya are becoming increasingly important as sources of traditional medicines. The World Health Organization (WHO has estimated that malaria kills about 2.7 million people every year, 90% of who are from Africa. Malaria continues to be a national concern in Kenya as it plays a major role in the high mortality rates being experienced currently. The use and miss-use of chloroquine to prevent and treat falciparium malaria has led to widespread appearance of chloroquine resistant parasites in Kenya and other tropical countries. These factors and the rising costs of non-chloroquine drugs have made the local people to turn to traditional remedies for management of this menace. This paper examines the current utilization of traditional plant medicines in managing malaria menace in Central Kenya. The results show both indigenous and introduced species are in use indicating traditional medicinal practices in this region are dynamic. In total 58 species in 54 genera and 33 families were identified. The family Rubiaceae was found to have the highest number of reported species. Use of the various taxa is compared between five districts within Central Province of Kenya. The commonest species in this pharmacopoeia are: Caesalpinia volkensii Harms, Strychnos henningsii Gilg, Ajuga remota Benth., Warbugia ugandensis Sprague and Olea europaea L. The first three species are used in all the five districts while the others are restricted in some of the districts. In 74% of the anti-malarial plant species reported in this study, the remedies are obtained in destructive manner and may need conservation measures to ensure sustainable utilization. The results of this study become a basis for selecting plants for further pharmacological and phytochemical studies in developing new and locally relevant anti-malarial agents.

  1. In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

    Science.gov (United States)

    Crumb, William; Pace, Silvia; Ubben, David; Wible, Barb; Yan, Gan-Xin; Funck-Brentano, Christian

    2012-01-01

    The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (Cmax), were expressed as the fold of that particular effect with respect to their Cmax. The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (INa and IKs, respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemether-lumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and INa and IKs analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC50) of halofantrine, which was lower than its Cmax, was confirmed. All the other compounds blocked hERG, with IC50s ranging from 3- to 30-fold their Cmaxs. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its Cmax were confirmed and DHA blocked it at a concentration about 300-fold its Cmax. In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the INa ion current and did so at about 30-fold its Cmax. No effect on IKs was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents. PMID:22391528

  2. A study of the drugs used in chronic obstructive pulmonary disease and their impact on quality-of-life

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    Vishal R Mishra

    2014-10-01

    Full Text Available Objectives: The objective was to assess drugs used in treatment of chronic obstructive pulmonary disease (COPD and their impact on quality-of-life. Materials and Methods: All newly diagnosed patients visiting the pulmonary medicine OPD were enrolled for the study based on inclusion and exclusion criteria. All patients were followed up for 6 months. Symptom and drug therapy assessment was done every month, while spirometry and quality-of-life assessment was done every 2 months. St. George Respiratory questionnaire was used for quality-of-life assessment. Results: A total of 100 patients was enrolled in the study, 78 were males and 22 females with mean age being 58.91 ± 6.58 years. All 84 patients, who were smokers, smoked bidis. Statistically significant improvement was seen in dyspnea, while all other symptoms did not show such improvement. 26 patients suffered from mild COPD, 48 had a moderate severity while remaining 26 belonged to the severe form of the disease. Improvement was seen in all parameters of spirometry. Statistically significant improvement was seen in forced expiratory volume at 1 s (FEV 1 at 4 and 6 months, in forced vital capacity at 6 months, in FEV 1 % at 4 and 6 months as compared to baseline. Peak expiratory flow and forced expiratory flow 25-75 also showed statistically significant improvement at every follow-up as compared to baseline. Methylxanthines, anticholinergics, β2 agonists, and corticosteroids were the commonly prescribed drugs. Improvement was seen in quality-of-life but overall improvement was not clinically significant. A decrease in total score in quality-of-life was seen from 44.63 at baseline to 41.76 at the end of 6 months. Correlation between quality-of-life and FEV 1 was found to be extremely significant. Conclusion: Improvement in quality-of-life was not clinically significant. However, correlation between FEV 1 and quality-of-life was extremely significant.

  3. New emerging drug-resistant malaria

    OpenAIRE

    Viroj Wiwanitkit

    2010-01-01

    Viroj WiwanitkitWiwanitkit House, Bangkhae, Bangkok ThailandDate of preparation: 20th August 2008Conflict of interest: None declaredClinical question: What is the best treatment for artemisinin-resistant malaria?Results: There is still no better treatment than the presently used artemisinin-based combination therapies. A new antimalarial drug for this problem needs to be found.Implementation: Pitfalls to avoid when treating drug-resistant malaria:Keywords: malaria, drug resistance

  4. In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria.

    Science.gov (United States)

    Nondo, Ramadhani S O; Erasto, Paul; Moshi, Mainen J; Zacharia, Abdallah; Masimba, Pax J; Kidukuli, Abdul W

    2016-01-01

    Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 10(7) erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria. PMID:27144154

  5. Quality evaluation of ayurvedic crude drug daruharidra, its allied species, and commercial samples from herbal drug markets of India.

    Science.gov (United States)

    Srivastava, Sharad; Rawat, A K S

    2013-01-01

    Berberis aristata known as "Daruharidra" in Ayurveda is a versatile medicinal plant used singly or in combination with other medicinal plants for treating a variety of ailments like jaundice, enlargement of spleen, leprosy, rheumatism, fever, morning/evening sickness, snakebite, and so forth. A major bioactive marker of this genus is an alkaloid berberine, which is known for its activity against cholera, acute diarrhea, amoebiasis, and latent malaria and for the treatment of oriental sore caused by Leishmania tropica. Although the roots of B. aristata are considered as the official drug (Ayurvedic Pharmacopoeia of India), the study revealed that different species of Berberis, namely. B. asiatica, B. chitria, and B. lycium are also used under the name of Daruharidra in different parts of the country. Detailed physicochemical and phytochemical studies of subjects like total ash, acid insoluble ash, tannins, and total alkaloids were calculated from the shade dried powdered material according to the recommended procedures. Further, heavy metal studies and quantitative estimation of berberine through HPTLC have also been performed as per ICH guidelines. A detailed study of four Berberis species, namely B. aristata, B. asiatica, B. chitria, and B. lycium, which are implicated as Daruharidra and collected from wild and ten commercial samples procured from various important drug markets in India has been carried out, which may be useful to pharmaceutical industries for the authentication of the commercial samples and exploring the possibilities of using other species as a substitute of B. aristata. PMID:23431340

  6. Quality Evaluation of Ayurvedic Crude Drug Daruharidra, Its Allied Species, and Commercial Samples from Herbal Drug Markets of India

    Directory of Open Access Journals (Sweden)

    Sharad Srivastava

    2013-01-01

    Full Text Available Berberis aristata known as “Daruharidra” in Ayurveda is a versatile medicinal plant used singly or in combination with other medicinal plants for treating a variety of ailments like jaundice, enlargement of spleen, leprosy, rheumatism, fever, morning/evening sickness, snakebite, and so forth. A major bioactive marker of this genus is an alkaloid berberine, which is known for its activity against cholera, acute diarrhea, amoebiasis, and latent malaria and for the treatment of oriental sore caused by Leishmania tropica. Although the roots of B. aristata are considered as the official drug (Ayurvedic Pharmacopoeia of India, the study revealed that different species of Berberis, namely. B. asiatica, B. chitria, and B. lycium are also used under the name of Daruharidra in different parts of the country. Detailed physicochemical and phytochemical studies of subjects like total ash, acid insoluble ash, tannins, and total alkaloids were calculated from the shade dried powdered material according to the recommended procedures. Further, heavy metal studies and quantitative estimation of berberine through HPTLC have also been performed as per ICH guidelines. A detailed study of four Berberis species, namely B. aristata, B. asiatica, B. chitria, and B. lycium, which are implicated as Daruharidra and collected from wild and ten commercial samples procured from various important drug markets in India has been carried out, which may be useful to pharmaceutical industries for the authentication of the commercial samples and exploring the possibilities of using other species as a substitute of B. aristata.

  7. A retrospective analysis of the change in anti-malarial treatment policy: Peru

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    Vincent-Mark Arlene

    2009-04-01

    Full Text Available Abstract Background National malaria control programmes must deal with the complex process of changing national malaria treatment guidelines, often without guidance on the process of change. Selecting a replacement drug is only one issue in this process. There is a paucity of literature describing successful malaria treatment policy changes to help guide control programs through this process. Objectives To understand the wider context in which national malaria treatment guidelines were formulated in a specific country (Peru. Methods Using qualitative methods (individual and focus group interviews, stakeholder analysis and a review of documents, a retrospective analysis of the process of change in Peru's anti-malarial treatment policy from the early 1990's to 2003 was completed. Results The decision to change Peru's policies resulted from increasing levels of anti-malarial drug resistance, as well as complaints from providers that the drugs were no longer working. The context of the change occurred in a time in which Peru was changing national governments, which created extreme challenges in moving the change process forward. Peru utilized a number of key strategies successfully to ensure that policy change would occur. This included a having the process directed by a group who shared a common interest in malaria and who had long-established social and professional networks among themselves, b engaging in collaborative teamwork among nationals and between nationals and international collaborators, c respect for and inclusion of district-level staff in all phases of the process, d reliance on high levels of technical and scientific knowledge, e use of standardized protocols to collect data, and f transparency. Conclusion Although not perfectly or fully implemented by 2003, the change in malaria treatment policy in Peru occurred very quickly, as compared to other countries. They identified a problem, collected the data necessary to justify the

  8. Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

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    Kaludov Nikola

    2011-09-01

    Full Text Available Abstract Background Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds. Methods A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design. Results Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM, with six being very effective (IC50 ≤ 1 μM, and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a

  9. Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional foods.

    Science.gov (United States)

    Graziose, Rocky; Lila, Mary Ann; Raskin, Ilya

    2010-03-01

    Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements. PMID:20156139

  10. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    OpenAIRE

    Wanna Chaijaroenkul; Artitiya Thiengsusuk; Kanchana Rungsihirunrat; Stephen Andrew Ward; Kesara Na-Bangchang

    2014-01-01

    Objective: To investigate possible protein targets for antimalarial activity of Garcinia mangostana Linn. (G. mangostana) (pericarp) in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry (LC/MS/MS). Methods: 3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G. mangostana Linn. (pericarp) at the concentrations of 12μg/mL (IC50 level: concentration that inhibits parasite growth by 50%) and 30 μg/mL (IC90 level...

  11. 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)

  12. 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

  13. The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin

    Directory of Open Access Journals (Sweden)

    Barik Sailen

    2003-09-01

    Full Text Available Abstract Background The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA, is a specific inhibitor of heat shock protein 90 (Hsp90 and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. Results We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively and on all erythrocytic stages of the parasite. Conclusions Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.

  14. Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

    Science.gov (United States)

    Beteck, Richard M; Coertzen, Dina; Smit, Frans J; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

    2016-07-01

    As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones. PMID:27210430

  15. Influence Service Quality and Customer Satisfaction towards Drug Purchase Intention in Anggrek Outpatient Pharmacy Depo at Hasan Sadikin Hospital

    OpenAIRE

    Pratiwi; Ahmad Muhtadi; Emma Surahman

    2016-01-01

    The quality of service is an evaluation which focused on customer’s awareness about a structural construction of a service or product that involves 5 main aspects which are tangibility, empathy, responsiveness, reliability and assurance. Based on monthly reports of pharmacy installation only about 30% of patients buy drugs in the Anggrek out patient depo out off patients visiting Anggrek out patient specialist clinic in Dr. Hasan Sadikin Hospital. The aim of this study is to determine the eff...

  16. Indicators of prescribing quality in drug utilisation research: report of a European meeting (DURQUIM, 13-15 May 2004)

    OpenAIRE

    Hoven, JL; Haaijer-Ruskamp, FM; Vander Stichele, RH

    2005-01-01

    An invitational expert meeting on indicators of prescribing quality was held on 13-15 May 2004, bringing together-from 19 European countries, the US, Canada, and Australia-40 researchers specialized in the development and application of indicators. The meeting was organized by the European Drug Utilization Research Group (EuroDURG), the Belgian National Health Insurance Institute (RIZIV-INAMI), and the World Health Organisation Regional Office for Europe (WHO-Euro). The field of prescribing q...

  17. Quality check of spontaneous adverse drug reaction reporting forms of different countries.

    Science.gov (United States)

    Bandekar, M S; Anwikar, S R; Kshirsagar, N A

    2010-11-01

    Adverse drug reactions (ADRs) are considered as one of the leading causes of death among hospitalized patients. Thus reporting of adverse drug reactions become an important phenomenon. Spontaneous adverse drug reaction reporting form is an essential component and a major tool of the pharmacovigilance system of any country. This form is a tool to collect information of ADRs which helps in establishing the causal relationship between the suspected drug and the reaction. As different countries have different forms, our aim was to study, analyze the suspected adverse drug reaction reporting form of different countries, and assess if these forms can capture all the data regarding the adverse drug reaction. For this analysis we identified 18 points which are essential to make a good adverse drug reaction report, enabling proper causality assessment of adverse reaction to generate a safety signal. Adverse drug reaction reporting forms of 10 different countries were collected from the internet and compared for 18 points like patient information, information about dechallenge-rechallenge, adequacy of space and columns to capture necessary information required for its causality assessment, etc. Of the ADR forms that we analyzed, Malaysia was the highest scorer with 16 out of 18 points. This study reveals that there is a need to harmonize the ADR reporting forms of all the countries because there is a lot of discrepancy in data captured by the existing ADR reporting forms as the design of these forms is different for different countries. These incomplete data obtained result in inappropriate causality assessment. PMID:20845409

  18. Influence Service Quality and Customer Satisfaction towards Drug Purchase Intention in Anggrek Outpatient Pharmacy Depo at Hasan Sadikin Hospital

    Directory of Open Access Journals (Sweden)

    Pratiwi

    2016-04-01

    Full Text Available The quality of service is an evaluation which focused on customer’s awareness about a structural construction of a service or product that involves 5 main aspects which are tangibility, empathy, responsiveness, reliability and assurance. Based on monthly reports of pharmacy installation only about 30% of patients buy drugs in the Anggrek out patient depo out off patients visiting Anggrek out patient specialist clinic in Dr. Hasan Sadikin Hospital. The aim of this study is to determine the effect of service quality and customer satisfaction to purchase intention in the Anggrek out patient depo Hasan Sadikin hospital at Bandung. The method used in this study is analytical survey with cross sectional design. The samples used were 200 patients, consist of 104 customers who have visited more than one times and 96 first visit costumer to this clinic. Data was collected using a questionnaire and analyzed using Smart PLS V 2.0 software. The results of this study showed that the service quality with tangible dimensions, reliability, responsiveness, assurance, and empathy are affecting the customer satisfaction with a score of 12.755 t-count (greater than t-table 1.983 and a positive value of the original sample of 0.800. Customer satisfaction affecting the customer purchase intentions with t-count is greater than t-table values of 5.012 and 0.726 of the original positive sample. While the service quality does not directly influence customer purchase intention with the t-test is smaller than t-table is 1.455 and the negative of the original sample -0.287. Some of service quality influence customers that causes not purchasing drugs from the out patient depo there are effect of unavailability of counseling, long waiting time of service, the need for special counseling room, a spacious waiting room, and the completeness of drug availability.

  19. Purely in silico BCS classification: science based quality standards for the world's drugs.

    Science.gov (United States)

    Dahan, Arik; Wolk, Omri; Kim, Young Hoon; Ramachandran, Chandrasekharan; Crippen, Gordon M; Takagi, Toshihide; Bermejo, Marival; Amidon, Gordon L

    2013-11-01

    BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list

  20. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Wanna Chaijaroenkul; Artitiya Thiengsusuk; Kanchana Rungsihirunrat; Stephen Andrew Ward; Kesara Na-Bangchang

    2014-01-01

    Objective: To investigate possible protein targets for antimalarial activity of Garcinia mangostana Linn. (G. mangostana) (pericarp) in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry (LC/MS/MS). Methods: 3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn. (pericarp) at the concentrations of 12µg/mL (IC50 level: concentration that inhibits parasite growth by 50%) and 30 µg/mL (IC90 level: concentration that inhibits parasite growth by 90%) for 12 h. Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50 concentration, about 82% of the expressed parasite proteins were matched with the control (non-exposed), while at the IC90 concentration, only 15% matched proteins were found. The selected protein spots from parasite exposed to the plant extract at the concentration of 12 µg/mL were identified as enzymes that play role in glycolysis pathway, i.e., phosphoglycerate mutase putative, L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase, and fructose-bisphosphate aldolase/phosphoglycerate kinase. The proteosome was found in parasite exposed to 30 µg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G. mangostana Linn. (pericarp).

  1. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Wanna; Chaijaroenkul; Artitiya; Thiengsusuk; Kanchana; Rungsihirunrat; Stephen; Andrew; Ward; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate possible protein targets for antimalarial activity of Garcina mangostana Linn.(G.mangostana)(pericarp)in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry(LC/MS/MS).Methods:3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn.(pericarp)at the concentrations of 12μg/mL(1C50level:concentration that inhibits parasite growth by 50%)and 30μg/mL(1C90level:concentration that inhibits parasite growth by 90%)for 12 h.Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50concentration,about 82%of the expressed parasite proteins were matched with the control(non-exposed),while at the IC90concentration,only 15%matched proteins were found.The selected protein spots from parasite exposed to the plant extract at the concentration of 12μg/mL were identified as eneymes that play role in glycolysis pathway,i.e.,phosphoglyeerate mutase putative,L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase,and fruetose-bisphosphate aldolase/phosphoglyeerate kinase.The proteosome was found in parasite exposed to 30μg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G.mangostana Linn.(pericarp).

  2. Drug-free holidays: pre-travel versus during travel malaria chemoprophylaxis

    OpenAIRE

    Shanks, G D; Magill, A J; Freedman, D O; Keystone, J. S.; Bradley, D J; Steffen, R.

    2007-01-01

    Although efficacious forms of malaria chemoprophylaxis currently exist, many travelers to malaria-endemic areas fail to use them effectively. We suggest that taking antimalarial medications prior to travel may prevent more malaria by improving compliance. Treatment regimens of antimalarial drugs taken prior to travel could protect persons for up to one month of exposure. We urge additional testing of pre-travel malaria chemoprophylaxis regimens.

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

    OpenAIRE

    Wurtz Nathalie; Fall Bécaye; Pascual Aurélie; Diawara Silmane; Sow Kowry; Baret Eric; Diatta Bakary; Fall Khadidiatou B; Mbaye Pape S; Fall Fatou; Diémé Yaya; Rogier Christophe; Bercion Raymond; Briolant Sébastien; Wade Boubacar

    2012-01-01

    Abstract Background As a result of the widespread resistance to chloroquine and sulphadoxine-pyrimethamine, artemisinin-based combination therapy (ACT) (including artemether-lumefantrine and artesunate-amodiaquine) has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Intermittent preventive treatments with anti-malarial drugs based on sulphadoxine-pyrimethamine are also given to children or pregnant women once per month during the transmission season. Since 2006, ...

  4. Effect of drug utilization reviews on the quality of in-hospital prescribing: a quasi-experimental study

    Directory of Open Access Journals (Sweden)

    Chabot Isabelle

    2006-03-01

    Full Text Available Abstract Background Drug utilization review (DUR programs are being conducted in Canadian hospitals with the aim of improving the appropriateness of prescriptions. However, there is little evidence of their effectiveness. The objective of this study was to assess the impact of both a retrospective and a concurrent DUR programs on the quality of in-hospital prescribing. Methods We conducted an interrupted time series quasi-experimental study. Using explicit criteria for quality of prescribing, the natural history of cisapride prescription was established retrospectively in three university-affiliated hospitals. A retrospective DUR was implemented in one of the hospitals, a concurrent DUR in another, whereas the third hospital served as a control. An archivist abstracted records of all patients who were prescribed cisapride during the observation period. The effect of DURs relative to the control hospital was determined by comparing estimated regression coefficients from the time series models and by testing the statistical significance using a 2-tailed Student's t test. Results The concurrent DUR program significantly improved the appropriateness of prescriptions for the indication for use whereas the retrospective DUR brought about no significant effect on the quality of prescribing. Conclusion Results suggest a retrospective DUR approach may not be sufficient to improve the quality of prescribing. However, a concurrent DUR strategy, with direct feedback to prescribers seems effective and should be tested in other settings with other drugs.

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

    Directory of Open Access Journals (Sweden)

    Simiyu Chrispinus

    2011-10-01

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

  6. 药品质量管理中风险评估的应用%Drug Quality Management in the Application of Risk Assessment

    Institute of Scientific and Technical Information of China (English)

    何莎

    2015-01-01

    在药品生产与管理工作中,药品质量管理是非常重要的一项管理内容,在开展药品质量管理过程中,进行药品质量管理的风险评估十分重要。目前,药品研发与生产过程中,还存在较多的药品质量管理风险,本文就药品质量管理风险评估的主要内容予以简要分析,对药品质量管理中的风险评估流程予以简单介绍。%In pharmaceutical production and management work,the drug quality management is a management content is very important,in the development of drug quality management process,a very important job is to conduct a risk assessment of drug quality management.The current drug development and production process,there are stil many drug quality risk management,the main content of this paper is the drug quality management risk assessment to the simple analysis,a brief description of the risk assessment process of drug quality management.

  7. [Drug-induced dyschromatopsias].

    Science.gov (United States)

    Perdriel, G; Manent, P J

    1982-01-01

    Drug-induced dyschromatopsias are defined as functional or objective alterations of color sense following drug treatment. Drug induced chromatopsias are characterized by a perception of white surfaces as colored and occur following modifications of normally transparent structures or alterations of the chorioretina or higher centers. Digitalic intoxication is responsible for incorrect perception of yellow or blue; the retinal origin of the disorder is confirmed by electroretinograms and histologic modifications in the photoreceptor synapses. Santonin in doses exceeding 1 cg is associated with various color misperceptions due to injury to a peripheral neuron or problems of rhodopsin formation. Some sulfas and antibiotics may cause misperception of yellow, and the anticonvulsant drug Tridione may cause an almost complete disappearance of some colors. Chromotopsias of central origin due to direct action on cerebral neurons are rare but may follow use of phenacetine or atropine. Drug induced dyschromatopsias are more common and may be the initial symptoms of various kinds of drug intoxication. Various simple and reliable tests enable the practicing clinician to detect such disorders at an early stage. Synthetic antimalarial drugs derived from chloroquine and used in longterm treatment of rheumatism or during antimalarial prophylaxis, indomethacine, and the phenotiazins may cause dyschromatopsias due to retinal intoxication. Oral contraceptives diminish the chromatic perception in 20% of cases according to 1 author, and often cause deficits of blue-yellow perception. Disulfiram, certain antibiotics such as chloramphenicol, nystatin, isoniazide, and other drugs may cause dyschromatopsias due to alterations in the optical fibers. Ethambutol is the most harmful to color perception; its effects are usually but not always reversible on discontinuation of the drug. Systematic tests of color perception should be administered prior to and during treatment with any drug known to

  8. Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds

    Science.gov (United States)

    Johnson, Alex; Elya, Carolyn; Anderson, Johanna; Clark, Julie; Connelly, Michele; Yang, Lei; Min, Jaeki; Sato, Yuko; Guy, R. Kiplin; Landfear, Scott M.

    2015-01-01

    Development of resistance against current antimalarial drugs necessitates the search for novel drugs that interact with different targets and have distinct mechanisms of action. Malaria parasites depend upon high levels of glucose uptake followed by inefficient metabolic utilization via the glycolytic pathway, and the Plasmodium falciparum hexose transporter PfHT, which mediates uptake of glucose, has thus been recognized as a promising drug target. This transporter is highly divergent from mammalian hexose transporters, and it appears to be a permease that is essential for parasite viability in intra-erythrocytic, mosquito, and liver stages of the parasite life cycle. An assay was developed that is appropriate for high throughput screening against PfHT based upon heterologous expression of PfHT in Leishmania mexicana parasites that are null mutants for their endogenous hexose transporters. Screening of two focused libraries of antimalarial compounds identified two such compounds that are high potency selective inhibitors of PfHT compared to human GLUT1. Additionally, 7 other compounds were identified that are lower potency and lower specificity PfHT inhibitors but might nonetheless serve as starting points for identification of analogs with more selective properties. These results further support the potential of PfHT as a novel drug target. PMID:25894322

  9. Development and evaluation of a solid oral dosage form for an artesunate and mefloquine drug combination / Abel Hermanus van der Watt

    OpenAIRE

    Van der Watt, Abel Hermanus

    2014-01-01

    Malaria affects about forty percent of the world’s population. Annually more than 1.5 million fatalities due to malaria occur and parasite resistance to existing antimalarial drugs such as mefloquine has already reached disturbingly high levels in South-East Asia and on the African continent. Consequently, there is a dire need for new drugs or formulations in the prophylaxis and treatment of malaria. Artesunate, an artemisinin derivative, represents a new category of antimalarials that is eff...

  10. High-performance thin layer chromatography for quality control of multicomponent herbal drugs: example of cangzhu xianglian san.

    Science.gov (United States)

    Li, Zhi; Merfort, Irmgard; Reich, Eike

    2010-01-01

    Due to their complexity, multicomponent herbal drugs pose enormous analytical challenges for quality control (QC). Although they may have traditionally been used for hundreds of years, the information about their chemical composition is often still limited. Selecting suitable markers to monitor the identity and potency of the mixture is, therefore, difficult. There is also the possibility of natural variability for each plant. This paper illustrates a pragmatic and practical approach to QC of a multicomponent herbal drug by HPTLC. Cangzhu xianglian xan (CXS), composed of the herbal drugs Coptis rhizome, Aucklandia root, and Atractylodes rhizome (30 + 20 + 60, w/w/w), is used as an example. A characteristic fingerprint can be generated for CXS with toluene-ethyl acetate-methanol-isopropanol-water (60 + 30 + 20 + 15 + 3, v/v/v/v/v) mobile phase on HPTLC silica gel 60 conditioned with ammonia. While the corresponding monograph of the Chinese Veterinary Pharmacopoeia focuses only on the detection of berberine, one of the principal components of Coptis rhizome, the proposed method of identification determines the presence of all three components in the drug after derivatization with anisaldehyde reagent. The same method can also be used to quantitatively determine the content of berberine by scanning densitometry. This paper provides details about the validation of the qualitative and quantitative determinations. PMID:21140648

  11. Longitudinal Changes in Drug Use Severity and Physical Health-Related Quality of Life among Untreated Stimulant Users

    Science.gov (United States)

    Borders, Tyrone F.; Booth, Brenda M.; Falck, Russel S.; Leukefeld, Carl; Wang, Jichuan; Carlson, Robert G.

    2009-01-01

    The primary objective of this study was to investigate whether drug use severity is associated with physical health-related quality of life (HRQL) over time. Data are from a longitudinal, multi-state, natural history community study of users of cocaine and/or methamphetamine who were interviewed at 6-month intervals over 2 years with a 79% follow-up participation rate. Physical HRQL was assessed with the physical component summary (PCS) of the SF-8™ Health Survey and drug, alcohol, and psychiatric severity were all assessed with the Addiction Severity Index (ASI). Random coefficient regression analyses were conducted to test for longitudinal associations between the independent variables and SF-8 PCS scores. Reductions in drug use severity over time were accompanied by only minor improvements in SF-8 PCS scores, underscoring the potential long-term harm of illicit drug use on physical health. Greater psychiatric severity was strongly associated with lower SF-8 PCS scores, suggesting that clinical attention to mental health issues could potentially lead to improvements in perceived physical health as well among stimulant users. PMID:19560873

  12. Non-Sink Dissolution Conditions for Predicting Product Quality and In Vivo Performance of Supersaturating Drug Delivery Systems.

    Science.gov (United States)

    Sun, Dajun D; Wen, Hong; Taylor, Lynne S

    2016-09-01

    With recent advances in the development of supersaturating oral dosage forms for poorly water-soluble drugs, pharmaceutical scientists are increasingly applying in vitro dissolution testing under non-sink conditions for a direct evaluation of their ability to generate and maintain supersaturation as a predictive surrogate for ensuring product quality and in vivo performance. However, the scientific rationale for developing the appropriate non-sink dissolution methodologies has not been extensively debated. This calls for a comprehensive discussion of recent research efforts on theoretical and experimental considerations of amorphous solubility, liquid-liquid phase separation, and phase transitions of drugs in a supersaturated solution when dissolution testing is performed under supersaturated non-sink conditions. In addition, we outline the concept of "sink index" that quantifies the magnitude of deviations from perfect sink dissolution conditions in the sink/non-sink continuum and some considerations of non-sink dissolution testing for marketed drug products. These factors should be carefully considered in recommending an adequately discriminatory dissolution method in the performance assessment of supersaturating drug delivery systems. PMID:27174227

  13. Can pharmacogenomics improve malaria drug policy?

    OpenAIRE

    Roederer, Mary W; McLeod, Howard; Juliano, Jonathan J

    2011-01-01

    Coordinated global efforts to prevent and control malaria have been a tour-de-force for public health, but success appears to have reached a plateau in many parts of the world. While this is a multifaceted problem, policy strategies have largely ignored genetic variations in humans as a factor that influences both selection and dosing of antimalarial drugs. This includes attempts to decrease toxicity, increase effectiveness and reduce the development of drug resistance, thereby lowering healt...

  14. Comparing the Effects of Methadone Maintenance Treatment, Therapeutic Community, and Residential Rehabilitation on Quality of Life and Mental Health of Drug Addicts

    OpenAIRE

    Babaie, Ensiyeh; Razeghi, Nader

    2013-01-01

    Background This study compared the effects of three drug addiction treatment methods on quality of life and mental health of drug addicts. Methods In this study, 227 Iranian male drug addicts were selected from Mazandaran Province (northern Iran). They were randomized to be treated with methadone maintenance treatment, therapeutic community, or residential rehabilitation. The Short Form Health Survey (SF-36) and the General Health Questionnaire (GHQ) were completed by the subjects at the star...

  15. Quality Control Trial for Human Immunodeficiency Virus Type 1 Drug Resistance Testing Using Clinical Samples Reveals Problems with Detecting Minority Species and Interpretation of Test Results

    OpenAIRE

    Korn, Klaus; Reil, Heide; Walter, Hauke; Schmidt, Barbara

    2003-01-01

    Between January and March 2000, a quality control panel for human immunodeficiency virus (HIV) drug resistance testing was analyzed by 20 laboratories in five countries. The panel consisted of three clinical samples with different drug resistance genotypes and phenotypes and one HIV-negative plasma. Participants were asked to report the methods used for amplification and sequencing, a list of drug resistance-associated mutations that were detected in the protease and reverse transcriptase of ...

  16. Novel morpholinoquinoline nucleus clubbed with pyrazoline scaffolds: Synthesis, antibacterial, antitubercular and antimalarial activities.

    Science.gov (United States)

    Karad, Sharad C; Purohit, Vishal B; Thakor, Parth; Thakkar, Vasudev R; Raval, Dipak K

    2016-04-13

    A series of novel morpholinoquinoline based conjugates with pyrazoline moiety were synthesized under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. Most of them exhibited significant antibacterial activity as compared to the first line drugs. Compounds 6a and 9d were found to possess excellent antibacterial activity potency as compared to ampicillin (286 μM), chloramphenicol (154 μM) and ciprofloxacin (150 μM). In antifungal screening, against Candida albicans, compounds 6c, 7c, 8a, 8b, 8c and 9b showed significant activity as compared to griseofulvin (1147 μM). Compounds 8b, 6b, 9d, 6a, 9b, 7b and 8a displayed brilliant activity against P. falciparum strain as compared to chloroquine (IC50 0.062 μM) as well as quinine (IC50 0.826 μM). Compounds 6d, 7b, 8b, 9c and 9d exhibited superior antitubercular activity. Among them 8b was found to be equipotent to rifampicin with 95% inhibition. The cytotoxicity of the synthesized compounds was tested using bioassay of Schizosaccharomyces pombe cells at cellular level. PMID:26900659

  17. Assessment of Antimalarial Activity against Plasmodium falciparum and Phytochemical Screening of Some Yemeni Medicinal Plants

    Directory of Open Access Journals (Sweden)

    Mohammed A. Alshawsh

    2009-01-01

    Full Text Available Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III according to World Health Organization (WHO 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides.

  18. Antimalarial Evaluation of the Chemical Constituents of Hairy Root Culture of Bixa orellana L.

    Directory of Open Access Journals (Sweden)

    Bo Zhai

    2014-01-01

    Full Text Available Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

  19. Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.

    Science.gov (United States)

    Norcross, Neil R; Baragaña, Beatriz; Wilson, Caroline; Hallyburton, Irene; Osuna-Cabello, Maria; Norval, Suzanne; Riley, Jennifer; Stojanovski, Laste; Simeons, Frederick R C; Porzelle, Achim; Grimaldi, Raffaella; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M; Meister, Stephan; Sanz, Laura; Jiménez-Díaz, Belén; Angulo-Barturen, Iñigo; Ferrer, Santiago; Martínez, María Santos; Gamo, Francisco Javier; Frearson, Julie A; Gray, David W; Fairlamb, Alan H; Winzeler, Elizabeth A; Waterson, David; Campbell, Simon F; Willis, Paul; Read, Kevin D; Gilbert, Ian H

    2016-07-14

    In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting. PMID:27314305

  20. New 1-Aryl-3-Substituted Propanol Derivatives as Antimalarial Agents

    Directory of Open Access Journals (Sweden)

    Antonio Monge

    2009-10-01

    Full Text Available This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria.

  1. Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

    Directory of Open Access Journals (Sweden)

    Laurent Calcul

    2013-12-01

    Full Text Available 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 fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds (14–16, 18 were isolated including a new dimeric tetrahydroxanthone, dicerandrol D (14, which was found to display the most favorable bioactivity profile.

  2. Triterpenes from Minquartia guianensis (Olacaceae) and in vitro antimalarial activity

    Energy Technology Data Exchange (ETDEWEB)

    Cursino, Lorena Mayara de Carvalho; Nunez, Cecilia Veronica [Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, AM (Brazil). Lab. de Bioprospeccao e Biotecnologia; Paula, Renata Cristina de; Nascimento, Maria Fernanda Alves do [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Fac. de Farmacia. Dept. de Produtos Farmaceuticos; Santos, Pierre Alexandre dos, E-mail: cecilia@inpa.gov.br [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil). Fac. de Ciencias Farmaceuticas

    2012-07-01

    Minquartia guianensis, popularly known as acariquara, was phytochemically investigated. The following triterpenes were isolated from the dichloromethane extract of leaves: lupen-3-one (1), taraxer-3-one (2) and oleanolic acid (3). The dichloromethane extract of branches yielded the triterpene 3{beta}-methoxy-lup-20(29)-ene (4). The chemical structures were characterized by NMR data. Plant extracts, substance 3, squalene (5) and taraxerol (6), (5 and 6 previously isolated), were evaluated by in vitro assay against chloroquine resistant Plasmodium falciparum. The dichloromethane extract of leaves and the three triterpenes assayed have shown partial activity. Thus, these results demonstrated that new potential antimalarial natural products can be found even in partially active extracts. (author)

  3. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil

    Science.gov (United States)

    A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given...

  4. DETECTION OF PUTATIVE ANTIMALARIAL-RESISTANT PLASMODIUM VIVAX IN ANOPHELES VECTORS AT THAILAND-CAMBODIA AND THAILAND-MYANMAR BORDERS.

    Science.gov (United States)

    Rattaprasert, Pongruj; Chaksangchaichot, Panee; Wihokhoen, Benchawan; Suparach, Nutjaree; Sorosjinda-Nunthawarasilp, Prapa

    2016-03-01

    Monitoring of multidrug-resistant (MDR)falciparum and vivax malaria has recently been included in the Global Plan for Artemisinin Resistance Containment (GPARC) of the Greater Mekong Sub-region, particularly at the Thailand-Cambodia and Thailand-Myanmar borders. In parallel to GPARC, monitoring MDR malaria parasites in anopheline vectors is an ideal augment to entomological surveillance. Employing Plasmodium- and species-specific nested PCR techniques, only P. vivax was detected in 3/109 salivary gland DNA extracts of anopheline vectors collected during a rainy season between 24-26 August 2009 and 22-24 September 2009 and a dry season between 29-31 December 2009 and 16-18 January 2010. Indoor and out- door resting mosquitoes were collected in Thong Pha Phum District, Kanchanaburi Province (border of Thailand-Myanmar) and Bo Rai District, Trat Province (border of Thailand-Cambodia): one sample from Anopheles dirus at the Thailand-Cambodia border and two samples from An. aconitus from Thailand-Myanmar border isolate. Nucleotide sequencing of dihydrofolate reductase gene revealed the presence in all three samples of four mutations known to cause high resistance to antifolate pyrimethamine, but no mutations were found in multidrug resistance transporter 1 gene that are associated with (falciparum) resistance to quinoline antimalarials. Such findings indicate the potential usefulness of this approach in monitoring the prevalence of drug-resistant malaria parasites in geographically regions prone to the development of drug resistance and where screening of human population at risk poses logistical and ethical problems. Keywords: Anopheles spp, Plasmodium vivax, antimalarial resistance, Greater Mekong Sub-region, nested PCR, vector surveillance PMID:27244954

  5. Anti-epileptic drug changes and quality of life in the community

    NARCIS (Netherlands)

    Wassenaar, M.; Leijten, F.S.S.; Sander, J.W.; Uijl, S.G.; Egberts, A.C.G.

    2016-01-01

    Objective: Changes in anti-epileptic drug (AED) regimens may indicate unsatisfactory treatment results such as insufficient seizure control or adverse effects. This inference underlies epilepsy management and research, yet current studies often do not account for AED changes. We assessed AED change

  6. A Review of Quality of Life in Alzheimer's Disease: Part 2: Issues in Assessing Drug Effects

    OpenAIRE

    Sam S. Salek; Melvyn D. Walker; Antony J. Bayer

    1998-01-01

    There are numerous methods available for assessing patients with Alzheimer's disease (AD) or other forms of dementia. Quality-of-life (QOL) assessment is unique among these methods. The subjective nature of quality of life provides healthcare professionals with the opportunity of incorporating the value systems of patients and their carers into their assessments. A systematic review was carried out to assess the published data (and some unpublished data) on QOL assessment tools and instrument...

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

    OpenAIRE

    Nasir Tajure Wabe; Dargicho Ahmed; Mulugeta Tarekegn Angamo

    2012-01-01

    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. ...

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

    Science.gov (United States)

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

    2016-01-01

    Artemisinin resistance in Plasmodium falciparum threatens global efforts in the elimination or eradication of malaria. Several studies have associated mutations in the PfATP6 gene in conjunction with artemisinin resistance, but the underlying molecular mechanism of the resistance remains unexplored. Associated mutations act as a biomarker to measure the artemisinin efficacy. In the proposed work, we have analyzed the binding affinity and efficacy between PfATP6 and artemisinin in the presence of L263D, L263E and L263K mutations. Furthermore, we performed virtual screening to identify potential compounds to inhibit the PfATP6 mutant proteins. In this study, we observed that artemisinin binding affinity with PfATP6 gets affected by L263D, L263E and L263K mutations. This in silico elucidation of artemisinin resistance enhanced the identification of novel compounds (CID: 10595058 and 10625452) which showed good binding affinity and efficacy with L263D, L263E and L263K mutant proteins in molecular docking and molecular dynamics simulations studies. Owing to the high propensity of the parasite to drug resistance the need for new antimalarial drugs will persist until the malarial parasites are eventually eradicated. The two compounds identified in this study can be tested in in vitro and in vivo experiments as possible candidates for the designing of new potential antimalarial drugs. PMID:27471101

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

    Science.gov (United States)

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

    2016-07-01

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

  10. A chemical proteomics approach for the search of pharmacological targets of the antimalarial clinical candidate albitiazolium in Plasmodium falciparum using photocrosslinking and click chemistry.

    Science.gov (United States)

    Penarete-Vargas, Diana Marcela; Boisson, Anaïs; Urbach, Serge; Chantelauze, Hervé; Peyrottes, Suzanne; Fraisse, Laurent; Vial, Henri J

    2014-01-01

    Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an original chemical proteomic approach to identify parasite proteins targeted by albitiazolium during their native interaction in living parasites. We designed a bifunctional albitiazolium-derived compound (photoactivable and clickable) to covalently crosslink drug-interacting parasite proteins in situ followed by their isolation via click chemistry reactions. Mass spectrometry analysis of drug-interacting proteins and subsequent clustering on gene ontology terms revealed parasite proteins involved in lipid metabolic activities and, interestingly, also in lipid binding, transport, and vesicular transport functions. In accordance with this, the albitiazolium-derivative was localized in the endoplasmic reticulum and trans-Golgi network of P. falciparum. Importantly, during competitive assays with albitiazolium, the binding of choline/ethanolamine phosphotransferase (the enzyme involved in the last step of phosphatidylcholine synthesis) was substantially displaced, thus confirming the efficiency of this strategy for searching albitiazolium targets. PMID:25470252

  11. A chemical proteomics approach for the search of pharmacological targets of the antimalarial clinical candidate albitiazolium in Plasmodium falciparum using photocrosslinking and click chemistry.

    Directory of Open Access Journals (Sweden)

    Diana Marcela Penarete-Vargas

    Full Text Available Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an original chemical proteomic approach to identify parasite proteins targeted by albitiazolium during their native interaction in living parasites. We designed a bifunctional albitiazolium-derived compound (photoactivable and clickable to covalently crosslink drug-interacting parasite proteins in situ followed by their isolation via click chemistry reactions. Mass spectrometry analysis of drug-interacting proteins and subsequent clustering on gene ontology terms revealed parasite proteins involved in lipid metabolic activities and, interestingly, also in lipid binding, transport, and vesicular transport functions. In accordance with this, the albitiazolium-derivative was localized in the endoplasmic reticulum and trans-Golgi network of P. falciparum. Importantly, during competitive assays with albitiazolium, the binding of choline/ethanolamine phosphotransferase (the enzyme involved in the last step of phosphatidylcholine synthesis was substantially displaced, thus confirming the efficiency of this strategy for searching albitiazolium targets.

  12. [Hospital pharmacist has a rule for best practice use and French hospital activity tariffs. Example of a pharmaceutical quality control for drugs reimbursed in addition of DRGs].

    Science.gov (United States)

    Hedoux, S; Dode, X; Pivot, C; Couray-Targe, S; Aulagner, G

    2012-07-01

    The best practice contract has given a new objective to the hospital pharmacists for the reimbursement in addition to Diagnosis Related Groups' (DRGs) tariffs. We built our pharmaceutical quality control for the administration traceability follow-up regarding the DRGs and the cost of care, for two reasons: the nominal drugs dispensation in link with the prescription made by pharmacist and the important expenditure of these drugs. Our organization depends on the development level of the informatized drugs circuit and minimizes the risk of financial shortfalls or wrong benefits, possible causes of economic penalties for our hospital. On the basis of this follow-up, we highlighted our activity and identified problems of management and drugs circuit organization. The quality of the administration traceability impacts directly on the quality of the medical records and the reimbursements of the expensive drugs. A better knowledge of prescription software is also required for a better quality and security of the medical data used in the medical informatic systems. The drugs management and the personal treatment in and between the care units need to be improved too. We have to continue and improve our organization with the future financial model for ATU drugs and the FIDES project. The health personnel awareness and the development of best informatic tools are also required. PMID:22818260

  13. Tinospora cordifolia as an adjuvant drug in the treatment of hyper-reactive malarious splenomegaly – case reports

    OpenAIRE

    Ranjan Kumar Singh

    2005-01-01

    Background & objectives: The effect of aqueous extract of Tinospora cordifolia, an immunomodulatorwith antimalarial activity along with chloroquine was studied in the treatment of three cases ofhyper-reactive malarious splenomegaly in District Hospital, Daltonganj town, Jharkhand, India. Thesecases were partial/slow responders to the conventional antimalarial drug chloroquine.Methods: Aqueous extract of T. cordifolia (500 mg) was added to chloroquine (CQ) base (300 mg)weekly and CQ prophylaxi...

  14. Do advertisements for antihypertensive drugs in Australia promote quality prescribing? A cross-sectional study

    OpenAIRE

    Spurling Geoffrey K; Mansfield Peter R; Montgomery Brett D; Ward Alison M

    2008-01-01

    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...

  15. Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana

    Directory of Open Access Journals (Sweden)

    Claudia Simoes-Pires

    2014-12-01

    Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.

  16. Drug-Drug Interaction Analysis of Pyronaridine/Artesunate and Ritonavir in Healthy Volunteers

    OpenAIRE

    Morris, Carrie A; Lopez-Lazaro, Luis; Jung, Donald; Methaneethorn, Janthima; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Pokorny, Rolf; Shin, Chang-Sik; Fleckenstein, Lawrence

    2012-01-01

    A multiple dose, parallel group study was conducted to assess for a drug-drug interaction between the pyronaridine/artesunate (PA) combination antimalarial and ritonavir. Thirty-four healthy adults were randomized (1:1) to receive PA for 3 days or PA with ritonavir (100 mg twice daily for 17 days, PA administered on Days 8–10). Pharmacokinetic parameters for pyronaridine, artesunate, and its active metabolite dihydroartemisinin (DHA) were obtained after the last PA dose and for ritonavir on D...

  17. The interplay between drug resistance and fitness in malaria parasites

    OpenAIRE

    Rosenthal, Philip J.

    2013-01-01

    Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymo...

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

    OpenAIRE

    Shanks G

    2006-01-01

    The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rat...

  19. Clinical pharmacokinetic drug interactions associated with artemisinin derivatives and HIV-antivirals

    OpenAIRE

    Kiang, Tony K.L.; Kyle J Wilby; Ensom, Mary H H

    2014-01-01

    Management of HIV and malaria co-infection is challenging due to potential drug-drug interactions between antimalarial and HIV-antiviral drugs. Little is known of the clinical significance of these drug interactions, and this review provides a comprehensive summary and critical evaluation of the literature. Specifically, drug interactions between WHO-recommended artemisinin combination therapies (ACT) and HIV-antivirals are discussed. An extensive literature search produced eight articles det...

  20. Antimalarial activity of ruthenium(II) and osmium(II) arene complexes with mono- and bidentate chloroquine analogue ligands.

    Science.gov (United States)

    Ekengard, Erik; Glans, Lotta; Cassells, Irwin; Fogeron, Thibault; Govender, Preshendren; Stringer, Tameryn; Chellan, Prinessa; Lisensky, George C; Hersh, William H; Doverbratt, Isa; Lidin, Sven; de Kock, Carmen; Smith, Peter J; Smith, Gregory S; Nordlander, Ebbe

    2015-11-28

    Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(η(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(η(6)-cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(η(6)-cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru-10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes. PMID:26491831

  1. An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients

    Directory of Open Access Journals (Sweden)

    Naumann Terryn

    2004-03-01

    Full Text Available Abstract Background Hospitalization can significantly disrupt sleeping patterns. In consideration of the previous reports of insomnia and apparent widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted a study to assess quality of sleep and hypnotic drug use in our acute care adult patient population. The primary objectives of this study were to assess sleep disturbance and its determinants including the use of drugs with sedating properties. Methods This single-centre prospective study involved an assessment of sleep quality for consenting patients admitted to the general medicine and family practice units of an acute care Canadian hospital. A validated Verran and Snyder-Halpern (VSH Sleep Scale measuring sleep disturbance, sleep effectiveness, and sleep supplementation was completed daily by patients and scores were compared to population statistics. Patients were also asked to identify factors influencing sleep while in hospital, and sedating drug use prior to and during hospitalization was also assessed. Results During the 70-day study period, 100 patients completed at least one sleep questionnaire. There was a relatively even distribution of males versus females, most patients were in their 8th decade of life, retired, and suffered from multiple chronic diseases. The median self-reported pre-admission sleep duration for participants was 8 hours and our review of PharmaNetR profiles revealed that 35 (35% patients had received a dispensed prescription for a hypnotic or antidepressant drug in the 3-month period prior to admission. Benzodiazepines were the most common sedating drugs prescribed. Over 300 sleep disturbance, effective and supplementation scores were completed. Sleep disturbance scores across all study days ranged 16–681, sleep effectiveness scores ranged 54–402, while sleep supplementation scores ranged between 0–358. Patients tended to have worse sleep scores as compared to healthy non

  2. Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Sudipta Das

    2016-05-01

    Full Text Available Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na+ homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na+]i within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na+ influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2, glycosylphosphotidylinositol (GPI-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na+] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na+]i. Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble "rhoptries" and apparent nuclear division. Together these results suggest that [Na+]i disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise.

  3. Drug: D02126 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02126 Drug Primaquine phosphate (USP); Primaquine (TN) C15H21N3O. 2H3PO4 455.1223 ...ICIDES AND REPELLENTS P01 ANTIPROTOZOALS P01B ANTIMALARIALS P01BA Aminoquinolines P01BA03 Primaqui...ne D02126 Primaquine phosphate (USP) USP drug classification [BR:br08302] Antiparasitics Antiprotozoals Primaqui...ne D02126 Primaquine phosphate (USP) Antiinfectives [BR:br08307] Antiparasitics Antmala...rials Others Aminoquinolines Primaquine [ATC:P01BA03] D02126 Primaquine phosphate

  4. Drug: D08420 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08420 Drug Primaquine (INN); Kanaprim (TN) C15H21N3O 259.1685 259.3467 D08420.gif ...oquinolines P01BA03 Primaquine D08420 Primaquine (INN) USP drug classification [BR:br08302] Antiparasitics Antiprotozoals Primaqui...ne D08420 Primaquine (INN) Antiinfectives [BR:br08307] Antiparasitics Antmalarials Oth...ers Aminoquinolines Primaquine [ATC:P01BA03] D08420 Primaquine (INN) CAS: 90-34-6...CTS, INSECTICIDES AND REPELLENTS P01 ANTIPROTOZOALS P01B ANTIMALARIALS P01BA Amin

  5. Malaria treatment in the retail sector: Knowledge and practices of drug sellers in rural Tanzania

    Directory of Open Access Journals (Sweden)

    Makemba Ahmed M

    2008-05-01

    Full Text Available Abstract Background Throughout Africa, the private retail sector has been recognised as an important source of antimalarial treatment, complementing formal health services. However, the quality of advice and treatment at private outlets is a widespread concern, especially with the introduction of artemisinin-based combination therapies (ACTs. As a result, ACTs are often deployed exclusively through public health facilities, potentially leading to poorer access among parts of the population. This research aimed at assessing the performance of the retail sector in rural Tanzania. Such information is urgently required to improve and broaden delivery channels for life-saving drugs. Methods During a comprehensive shop census in the districts of Kilombero and Ulanga, Tanzania, we interviewed 489 shopkeepers about their knowledge of malaria and malaria treatment. A complementary mystery shoppers study was conducted in 118 retail outlets in order to assess the vendors' drug selling practices. Both studies included drug stores as well as general shops. Results Shopkeepers in drug stores were able to name more malaria symptoms and were more knowledgeable about malaria treatment than their peers in general shops. In drug stores, 52% mentioned the correct child-dosage of sulphadoxine-pyrimethamine (SP compared to only 3% in general shops. In drug stores, mystery shoppers were more likely to receive an appropriate treatment (OR = 9.6, but at an approximately seven times higher price. Overall, adults were more often sold an antimalarial than children (OR = 11.3. On the other hand, general shopkeepers were often ready to refer especially children to a higher level if they felt unable to manage the case. Conclusion The quality of malaria case-management in the retail sector is not satisfactory. Drug stores should be supported and empowered to provide correct malaria-treatment with drugs they are allowed to dispense. At the same time, the role of general shops

  6. Malaria treatment in the retail sector: Knowledge and practices of drug sellers in rural Tanzania

    Science.gov (United States)

    Hetzel, Manuel W; Dillip, Angel; Lengeler, Christian; Obrist, Brigit; Msechu, June J; Makemba, Ahmed M; Mshana, Christopher; Schulze, Alexander; Mshinda, Hassan

    2008-01-01

    Background Throughout Africa, the private retail sector has been recognised as an important source of antimalarial treatment, complementing formal health services. However, the quality of advice and treatment at private outlets is a widespread concern, especially with the introduction of artemisinin-based combination therapies (ACTs). As a result, ACTs are often deployed exclusively through public health facilities, potentially leading to poorer access among parts of the population. This research aimed at assessing the performance of the retail sector in rural Tanzania. Such information is urgently required to improve and broaden delivery channels for life-saving drugs. Methods During a comprehensive shop census in the districts of Kilombero and Ulanga, Tanzania, we interviewed 489 shopkeepers about their knowledge of malaria and malaria treatment. A complementary mystery shoppers study was conducted in 118 retail outlets in order to assess the vendors' drug selling practices. Both studies included drug stores as well as general shops. Results Shopkeepers in drug stores were able to name more malaria symptoms and were more knowledgeable about malaria treatment than their peers in general shops. In drug stores, 52% mentioned the correct child-dosage of sulphadoxine-pyrimethamine (SP) compared to only 3% in general shops. In drug stores, mystery shoppers were more likely to receive an appropriate treatment (OR = 9.6), but at an approximately seven times higher price. Overall, adults were more often sold an antimalarial than children (OR = 11.3). On the other hand, general shopkeepers were often ready to refer especially children to a higher level if they felt unable to manage the case. Conclusion The quality of malaria case-management in the retail sector is not satisfactory. Drug stores should be supported and empowered to provide correct malaria-treatment with drugs they are allowed to dispense. At the same time, the role of general shops as first contact points

  7. Adverse Drug Reactions and Quality of Life in Schizophrenia Patients with Chronic Viral Hepatitis

    OpenAIRE

    Vadim A. Akhmedov, PhD, ScD; Olga V. Zadorozhnaya

    2012-01-01

    Schizophrenia patients frequently develop somatic co-morbidity, including chronic viral hepatitis. The study of the quality of life in schizophrenia patients with concomitant viral hepatitis in the context of hospital pharmacotherapy, therefore, becomes an important task. We examined 60 schizophrenia patients with chronic viral hepatitis. Diagnosis was based on clinical, psychopathological, psychometric, clinical and laboratory methods, followed by statistical data processing. The features re...

  8. Comparative study of the pharmacopeial quality and dissolution profiles of generic and other drug forms of sodium metamizole (dipyrone sold in Brazil

    Directory of Open Access Journals (Sweden)

    Morenna Alana Giordani

    2012-08-01

    Full Text Available In Brazil, in order for a pharmaceutical company to register a drug form as generic or ‘similar’ with the Brazilian food and drug agency (Anvisa, it must be proved bioequivalent to its innovatory branded form (reference drug. This requires comparative trials, carried out in conformity with official compendia (Brazilian Pharmacopeia or another officially recognized code. Additionally, according to the Anvisa resolution RDC 31/2010, the dissolution profile of the drug must be tested and compared with that of the branded reference, as a benchmark of quality. The aim of this study was to assess the quality of 500 mg sodium metamizole (dipyrone tablets produced by seven different laboratories in Brazil: three generic drugs (G1, G2, G3, three (branded similar drugs (S1, S2,S3 and their reference branded product (Novalgina®, Sanofi-Aventis, drug R. All tests were carried out by methods specified in the Brazilian Pharmacopeia 4th edition (Farmacopeia Brasileira IV. The following tests were performed: uniformity of mass, friability, disintegration time, hardness, assay, uniformity of dosage units, salicylic acid limit assay, dissolution and identification. The dissolution profile was also recorded, as recommended in RDC 31/2010. Whereas every sample was approved in all the Farmacopeia Brasileira IV tests, the results in the dissolution profile test showed that four of the test drugs (G1, G2, S1 and S2 were notpharmaceutically equivalent to drug R. Thus, only drugs G3 and S3 showed dissolution profiles similar to that of drug R and the other four drugs could not be considered equivalent to it and were not approved.

  9. On the Ideal Quality Control Specification of Compound Prescription -- Taking thought for the New Ingredients Produced in the Single Drugs Combining Process in Compound Prescription

    Institute of Scientific and Technical Information of China (English)

    刘建利

    2002-01-01

    @@ Effectiveness, safety and quality controllability are the three basic and most important premises for evaluating the quality of drugs. Having undergone clinical tests and been verified in thousands of years, the effectiveness and safety of compound prescription, the chief form of medication in TCM, have been proved reliable. Sometimes due to the lack of quality controllability, incorrect drug or method of preparing being used, so poor therapeutic effect can be seen, though diagnosis and prescription are correct. Quality uncontrollability is also one of the important reasons that causes difficulty for TCM preparation to enter international market. In order to ensure the effectiveness and safety of TCM compound prescription and the entering of TCM preparation into international market, strict quality control specifications should be defined. Although wide attention has been paid to this task, how to define the specifications is still under discussion.

  10. The impact of text message reminders on adherence to antimalarial treatment in northern Ghana: a randomized trial.

    Directory of Open Access Journals (Sweden)

    Julia R G Raifman

    Full Text Available BACKGROUND: Low rates of adherence to artemisinin-based combination therapy (ACT regimens increase the risk of treatment failure and may lead to drug resistance, threatening the sustainability of current anti-malarial efforts. We assessed the impact of text message reminders on adherence to ACT regimens. METHODS: Health workers at hospitals, clinics, pharmacies, and other stationary ACT distributors in Tamale, Ghana provided flyers advertising free mobile health information to individuals receiving malaria treatment. The messaging system automatically randomized self-enrolled individuals to the control group or the treatment group with equal probability; those in the treatment group were further randomly assigned to receive a simple text message reminder or the simple reminder plus an additional statement about adherence in 12-hour intervals. The main outcome was self-reported adherence based on follow-up interviews occurring three days after treatment initiation. We estimated the impact of the messages on treatment completion using logistic regression. RESULTS: 1140 individuals enrolled in both the study and the text reminder system. Among individuals in the control group, 61.5% took the full course of treatment. The simple text message reminders increased the odds of adherence (adjusted OR 1.45, 95% CI [1.03 to 2.04], p-value 0.028. Receiving an additional message did not result in a significant change in adherence (adjusted OR 0.77, 95% CI [0.50 to 1.20], p-value 0.252. CONCLUSION: The results of this study suggest that a simple text message reminder can increase adherence to antimalarial treatment and that additional information included in messages does not have a significant impact on completion of ACT treatment. Further research is needed to develop the most effective text message content and frequency. TRIAL REGISTRATION: ClinicalTrials.gov NCT01722734.

  11. Quality

    International Nuclear Information System (INIS)

    What is quality? How do you achieve it? How do you keep it once you have got it. The answer for industry at large is the three-step hierarchy of quality control, quality assurance and Total quality Management. An overview is given of the history of quality movement, illustrated with examples from Schlumberger operations, as well as the oil industry's approach to quality. An introduction of the Schlumberger's quality-associated ClientLink program is presented. 15 figs., 4 ills., 16 refs

  12. New approach for high-throughput screening of drug activity on Plasmodium liver stages.

    NARCIS (Netherlands)

    Gego, A.; Silvie, O.; Franetich, J.F.; Farhati, K.; Hannoun, L.; Luty, A.J.F.; Sauerwein, R.W.; Boucheix, C.; Rubinstein, E.; Mazier, D.

    2006-01-01

    Plasmodium liver stages represent potential targets for antimalarial prophylactic drugs. Nevertheless, there is a lack of molecules active on these stages. We have now developed a new approach for the high-throughput screening of drug activity on Plasmodium liver stages in vitro, based on an infrare

  13. 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...... contrast, the chloroquine-sensitive P. falciparum chloroquine resistance transporter (Pfcrt) CVMNK haplotype increased from 6% to 30% (P < 0.001). The dramatic increase of the triple Pfdhps mutant SGEGA haplotype may endanger the continued use of SP for intermittent presumptive treatment of pregnant women...

  14. Implementation and evaluation of a multisite drug usage evaluation program across Australian hospitals - a quality improvement initiative

    Directory of Open Access Journals (Sweden)

    Robertson Marion B

    2011-08-01

    Full Text Available Abstract Background With the use of medicines being a broad and extensive part of health management, mechanisms to ensure quality use of medicines are essential. Drug usage evaluation (DUE is an evidence-based quality improvement methodology, designed to improve the quality, safety and cost-effectiveness of drug use. The purpose of this paper is to describe a national DUE methodology used to improve health care delivery across the continuum through multi-faceted intervention involving audit and feedback, academic detailing and system change, and a qualitative assessment of the methodology, as illustrated by the Acute Postoperative Pain Management (APOP project. Methods An established methodology, consisting of a baseline audit of inpatient medical records, structured patient interviews and general practitioner surveys, followed by an educational intervention and follow-up audit, is used. Australian hospitals, including private, public, metropolitan and regional, are invited to participate on a voluntary basis. De-identified data collected by hospitals are collated and evaluated nationally to provide descriptive comparative analyses. Hospitals benchmark their practices against state and national results to facilitate change. The educational intervention consists of academic detailing, group education, audit and feedback, point-of-prescribing prompts and system changes. A repeat data collection is undertaken to assess changes in practice. An online qualitative survey was undertaken to evaluate the APOP program. Qualitative assessment of hospitals' perceptions of the effectiveness of the overall DUE methodology and changes in procedure/prescribing/policy/clinical practice which resulted from participation were elicited. Results 62 hospitals participated in the APOP project. Among 23 respondents to the evaluation survey, 18 (78% reported improvements in the documentation of pain scores at their hospital. 15 (65% strongly agreed or agreed that

  15. Chemical and bioassay techniques to authenticate quality of the anti-leishmanial drug miltefosine.

    Science.gov (United States)

    Kaur, Harparkash; Seifert, Karin; Hawkes, Geoffrey E; Coumbarides, Gregory S; Alvar, Jorge; Croft, Simon L

    2015-06-01

    Miltefosine, an effective oral treatment of visceral leishmaniasis (VL), was selected in May 2005, by the governments of India, Nepal, and Bangladesh for the elimination of VL. However, abnormally high treatment failure rates reported in patients in Bangladesh, given a miltefosine generic product ("Miltefos", Popular Pharmaceuticals Ltd.) during 2008, led the World Health Organization (WHO) to procure this formulation for quality testing. Proton ((1)H) and phosphorous ((31)P) nuclear magnetic resonance (NMR) analyses of the Miltefos™ capsules did not give the peaks defined for Impavido®, the quality assured VL treatment product from Aeterna Zentaris. Contents of capsules of Impavido® yielded expected peaks for miltefosine (m/z 408.33 for the protonated parent ion and m/z 183.99 plus m/z 124.8 the fragment ions) that were absent in the Miltefos™ capsules. Furthermore, testing using an in vitro Leishmania donovani intracellular amastigote-macrophage model, yielded EC50 values of between 2.55 and 4.06 μg/mL and 3.02 to 5.92 μg/mL for extracts from the Impavido® capsules and the miltefosine standard, respectively. Lack of significant anti-leishmanial activity of Miltefos™ capsules was identified in this assay even at concentrations up to 100 μg/mL. Capsules of Miltefos™ were classified as falsified (absence of stated active pharmaceutical ingredient) by three methods-NMR and mass spectrometry analysis and bioassay. PMID:25897058

  16. Prescription for antibiotics at drug shops and strategies to improve quality of care and patient safety: a cross-sectional survey in the private sector in Uganda

    OpenAIRE

    Mbonye, AK; Buregyeya, E.; Rutebemberwa, E.; Clarke, SE; Lal, S; Hansen, KS; Magnussen, P; LaRussa, P

    2016-01-01

    Objectives The main objective of this study was to assess practices of antibiotic prescription at registered drug shops with a focus on upper respiratory tract infections among children in order to provide data for policy discussions aimed at improving quality of care and patient safety in the private health sector in Uganda. Methods A survey was conducted within 57 parishes from August to October 2014 in Mukono District, Uganda. Data was captured on the following variables: drug shop charact...

  17. Nuclear attitudes and reactions: associations with depression, drug use, and quality of life

    International Nuclear Information System (INIS)

    For 40 years the world has lived with the threat of nuclear war and, recently, with the possibility of nuclear power plant accidents. Although virtually every generation must confront various national or international crises, the threat of nuclear war is unprecedented in its destructive potential. This study is an attempt to assess attitudes and amount of distress associated with the ever-present threat of nuclear war and the possibility of accidents at nuclear power plants. The Nuclear Attitudes Questionnaire (NAQ) consists of 15 items and was administered to 722 young adults who have grown up in the nuclear age. The items were found to reflect four latent factors of nuclear concern, nuclear support, fear of the future, and nuclear denial, all of which in turn represent a second-order construct of nuclear anxiety. Women reported significantly more nuclear concern, less nuclear support, more fear of the future, and less nuclear denial than did men. In latent-variable models, nuclear anxiety was found to be significantly associated with less purpose in life, less life satisfaction, more powerlessness, more depression, and more drug use. It is concluded that the threat of nuclear war and accidents is significantly related to psychological distress and may disturb normal maturational development

  18. Intravenous drug use quality management and patient safety%静脉用药质量管理与患者安全用药

    Institute of Scientific and Technical Information of China (English)

    吕红梅; 颜青; 吴永佩

    2014-01-01

    药品质量、药物的合理使用与患者安全用药直接关系到医疗风险和民众健康。通过对静脉药物在临床药物治疗中的地位与风险的分析,认为应严格静脉药物的质量标准,促进合理用药,提高药物治疗水平,疏导民众对静脉药物治疗的心理依赖性,并严格遵循药物治疗的用药途径遴选原则,提出规范静脉用药调配模式,确保静脉输液成品质量,降低静脉用药风险,并简要介绍了药事管理专业委员会下一步工作计划。%Drug quality, rational drug use and patient safety directly related to medical risk and patient's health. Based on the analysis of the importance and risk of intravenous drug use, It needs to strict obeying the quality standard of drug use in intravenous, promoting rational drug use, improving drug treatment capacity and easing the public's dependence of intravenous drug use and strict obeying principles of medication way. Suggestion of standardization intravenous drug allocation mode to assure intravenous drug quality and decrease risk is presented and the further plan of Pharmacy Management Special Committee is also discussed.

  19. Application of quality control circles for improving drug turnover rate%"品管圈"活动在提高药品周转率中的应用

    Institute of Scientific and Technical Information of China (English)

    江红星; 严安定; 许杜娟

    2013-01-01

    Objective To study the effects and experience of quality control circles for the management of drug in pharmacy stores . Methods We set up a " quality control circle " organization, established drug management project, made analysis of the drug turnover rate,and developed appropriate corrective measures for implementing . Results Quality control circle effectively improved the drug turnover rate in pharmacy stores ,and enhanced the awareness of staff in pharmaceutical management and job satisfaction , promoted the staffs enthusiasm,creativity and initiative. Conclusion "Quality control circle" project is effective for improving the turnover rate of drugs .%目的 探索品管圈活动在药库药品管理中的效果与体会.方法 成立"品管圈"组织,确立药品管理项目,对药库药品周转率偏低进行原因分析,制订相应的整改措施并组织实施.结论 提高了药库药品周转率,增强了工作人员参与药品管理的意识和工作满足感,充分地发挥了工作人员的积极性、创造性、主动性.结论 "品管圈"活动在提高药品周转率中取得了较好的效果.

  20. Quality evaluation and pattern recognition analyses of marker compounds from five medicinal drugs of Rutaceae family by HPLC/PDA.

    Science.gov (United States)

    Zhao, Bing Tian; Kim, Eun Jung; Son, Kun Ho; Son, Jong Keun; Min, Byung Sun; Woo, Mi Hee

    2015-08-01

    To establish a standard of quality control and to identify different origins for the Rutaceae family [Citri Unshiu Peel (CU), Citri Unshiu Immature Peel (CI), Ponciri Immature Fructus (PI), Aurantii Immature Fructus (AI), and Aurantii Fructus (AU)], 13 standards including rutin (1), narirutin (2), naringin (3), hesperidin (4), neohesperidin (5), neoponcirin (6), poncirin (7), naringenin (8), isosinensetin (9), sinensetin (10), nobiletin (11), heptamethoxyflavone (12), and tangeretin (13) were determined by high performance liquid chromatography (HPLC)/photo-diode array (PDA) analysis. A YMC ODS C18 (250 × 4.6 mm, 5 µm) column was used and the ratio of mobile phases of water (A) and acetonitrile (B) delivered to the column for gradient elution was applied. This method was fully validated with respect to linearity, accuracy, precision, stability, and robustness. The HPLC/PDA method was applied successfully to quantify 13 major compounds in the extracts of CU, CI, PI, AI, and AU. The pattern recognition analysis combined with LC chromatographic data was performed by repeated analysis of 27 reference samples in the above five Rutaceae oriental medicinal drugs. The established HPLC method was rapid and reliable for quantitative analysis and quality control of multiple components in five Rutaceae species with different origins. PMID:25732613

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

    Directory of Open Access Journals (Sweden)

    Johanna M Porter-Kelley

    2010-08-01

    Full Text Available Johanna M Porter-Kelley1, Joann Cofie2, Sophonie Jean2, Mark E Brooks1, Mia Lassiter1, DC Ghislaine Mayer21Life Sciences Department, ­Winston-Salem State University, Winston Salem, NC, USA; 2Department of Biology, Virginia Commonwealth University, Richmond, VA, USAAbstract: Malaria, a disease of poverty and high morbidity and mortality in the tropical world, has led to a worldwide search for control measures. To that end, good antimalarial chemotherapies have been difficult to find in the global market and those that seem to be most effective are rapidly becoming ineffective due to the emergence and spread of drug resistance. Artemisinin, a very effective yet expensive antimalarial, has quickly become the recommended drug of choice when all other possibilities fail. However, for all its promise as the next great antimalarial, the outlook is bleak. Resistance is developing to artemisinin while another effective antimalarial is not in sight. Malaria endemic areas which are mostly in developing countries must deal with the multifaceted process of changing and implementing new national malaria treatment guidelines. This requires complex interactions between several sectors of the affected society which in some cases take place within the context of political instability. Moreover, the cost associated with preventing and containing the spread of antimalarial resistance is detrimental to economic progress. This review addresses the impact of artemisinin resistance on the socioeconomic structure of malaria endemic countries.Keywords: artemisinin-based drugs, social, economic, malarial parasite resistance

  2. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus

    DEFF Research Database (Denmark)

    Kuhn, A; Sigges, J; Biazar, C;

    2014-01-01

    BACKGROUND: In recent years it has been controversially discussed in the literature if smoking is associated with the activity of cutaneous lupus erythematosus (CLE) and the efficacy of antimalarial agents. OBJECTIVES: To investigate the influence of smoking on disease severity and antimalarial...... treatment in patients with CLE using the Core Set Questionnaire of the European Society of Cutaneous Lupus Erythematosus (EUSCLE). METHODS: A total of 1002 patients (768 female, 234 male) with different CLE subtypes were included in this cross-sectional study, which was performed in 14 different countries....... Smoking behaviour was assessed by the EUSCLE Core Set Questionnaire in 838 patients and statistically analysed using an SPSS database. The results were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the efficacy of antimalarial treatment. RESULTS: A high...

  3. Environmental, pharmacological and genetic influences on the spread of drug-resistant malaria

    OpenAIRE

    Antao, Tiago; Hastings, Ian M.

    2010-01-01

    Plasmodium falciparum malaria is subject to artificial selection from antimalarial drugs that select for drug-resistant parasites. We describe and apply a flexible new approach to investigate how epistasis, inbreeding, selection heterogeneity and multiple simultaneous drug deployments interact to influence the spread of drug-resistant malaria. This framework recognizes that different human ‘environments’ within which treatment may occur (such as semi- and non-immune humans taking full or part...

  4. Treatment of fevers prior to introducing rapid diagnostic tests for malaria in registered drug shops in Uganda

    OpenAIRE

    Mbonye, AK; Lal, S; Cundill, B; Hansen, KS; Clarke, S.; Magnussen, P

    2013-01-01

    Background: Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of...

  5. Introducing malaria rapid diagnostic tests at registered drug shops in Uganda: Limitations of diagnostic testing in the reality of diagnosis.

    OpenAIRE

    Chandler, Clare IR; Hall-Clifford, Rachel; Asaph, Turinde; Magnussen, Pascal; Clarke, Siân; Mbonye, Anthony K.

    2011-01-01

    In Uganda, around two thirds of medicines are procured from the private sector, mostly from drug shops. The introduction of malaria rapid diagnostic tests (RDTs) at drug shops therefore has the potential to make a significant contribution to targeting antimalarial drugs to those with malaria parasites. We undertook formative research in a district in Uganda in preparation for a randomised trial of RDTs in drug shops. In May to July 2009, we interviewed 9 drug shop workers, 5 health workers an...

  6. Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

    OpenAIRE

    Timothy J. Hubin; Amoyaw, Prince N. -A.; Roewe, Kimberly D.; Simpson, Natalie C.; Maples, Randall D.; Carder Freeman, TaRynn N.; Amy N. Cain; Le, Justin G.; Stephen J Archibald; Khan, Shabana I.; Tekwani, Babu L.; Khan, M. O. Faruk

    2014-01-01

    Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal comple...

  7. Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

    Science.gov (United States)

    Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

    2013-09-01

    Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone. PMID:23597248

  8. The Impact of Experiencing Adverse Drug Reactions on the Patient's Quality of Life : A Retrospective Cross-Sectional Study in the Netherlands

    NARCIS (Netherlands)

    Rolfes, Leàn; van Hunsel, Florence; Taxis, Katja; van Puijenbroek, Eugène

    2016-01-01

    INTRODUCTION: There is little information as to what extent adverse drug reactions (ADRs) influence patients' health-related quality of life (HR-QOL). From a pharmacovigilance perspective, capturing and making the best use of this information remains a challenge. The Netherlands Pharmacovigilance Ce

  9. A simultaneous determination of related substances by high performance liquid chromatography in a drug product using quality by design approach.

    Science.gov (United States)

    Tol, Trupti; Kadam, Nilesh; Raotole, Nilesh; Desai, Anita; Samanta, Gautam

    2016-02-01

    The combination of Abacavir, Lamivudine and Dolutegravir is an anti-retroviral formulation that displays high efficacy and superiority in comparison to other anti-retroviral combinations. Analysis of related substances in this combination drug product was very challenging due to the presence of nearly thirty peaks including the three active pharmaceutical ingredients (APIs), eleven known impurities and other pharmaceutical excipients. Objective of this study was to develop a single, selective, and robust high performance liquid chromatography method for the efficient separation of all peaks. Initially, one-factor-at-a-time (OFAT) approach was adopted to develop the method. But, it could not resolve all the critical peaks in such complex matrix. This led to the advent of two different HPLC methods for the determination of related substances, one for Abacavir and Lamivudine and the other for Dolutegravir. But, since analysis of a single sample using two methods instead of one is time and resource consuming and thus expensive, an attempt was made to develop a single and robust method by adopting quality by design (QbD) principles. Design of Experiments (DoE) was applied as a tool to achieve the optimum conditions through Response surface methodology with three method variables, pH, temperature, and mobile phase composition. As the study progressed, it was discovered that establishment of the design space was not viable due to the completely distant pH requirements of the two responses, i.e. (i) retention time for Lamivudine carboxylic acid and (ii) resolution between Abacavir impurity B and unknown impurity. Eventually, neglecting one of these two responses each time, two distinguished design spaces have been established and verified. Edge of failures at both design spaces indicate high probability of failure. It therefore, becomes very important to identify the most robust zone or normal operating range (NOR) within the design space with low risk of failure and high

  10. ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity.

    Science.gov (United States)

    Maignan, Jordany R; Lichorowic, Cynthia L; Giarrusso, James; Blake, Lynn D; Casandra, Debora; Mutka, Tina S; LaCrue, Alexis N; Burrows, Jeremy N; Willis, Paul A; Kyle, Dennis E; Manetsch, Roman

    2016-07-28

    Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days. PMID:27291102

  11. 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

    Institute of Scientific and Technical Information of China (English)

    Phitsinee; Thipubon; Wachiraporn; Tipsuwan; Chairat; Uthaipibull; Sineenart; Santitherakul; Somdet; Srichiratanakool

    2015-01-01

    Objective: To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one(CM1) iron chelator and green tea extract(GTE) as anti-malarial activity in Plasmodium berghei(P. berghei) infected mice.Methods: The CM1(0–100 mg/kg/day) and GTE(0–100 mg(-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells(PRBC) were enumerated by using Giemsa staining microscopic method.Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine(PYR)(ED50= 0.76 mg/kg).GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity.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.

  12. 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

    Institute of Scientific and Technical Information of China (English)

    Phitsinee Thipubon; Wachiraporn Tipsuwan; Chairat Uthaipibull; Sineenart Santitherakul; Somdet Srichiratanakool

    2015-01-01

    Objective:To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) iron chelator and green tea extract (GTE) as anti-malarial activity in Plasmodium berghei (P. berghei ) infected mice. Methods:The CM1 (0–100 mg/kg/day) and GTE (0–100 mg (-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells (PRBC) were enumerated by using Giemsa staining microscopic method. Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine (PYR) (ED50=0.76 mg/kg). GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity. 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 constitutive 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.

  13. Drug-Resistant Malaria: The Era of ACT

    OpenAIRE

    Lin, Jessica T.; Juliano, Jonathan J; Wongsrichanalai, Chansuda

    2010-01-01

    As drug-resistant falciparum malaria has continued to evolve and spread worldwide, artemisinin-based combination therapies (ACT) have become the centerpiece of global malaria control over the past decade. This review discusses how advances in antimalarial drug resistance monitoring and rational use of the array of ACTs now available can maximize the impact of this highly efficacious therapy, even as resistance to artemisinins is emerging in Southeast Asia.

  14. Quality assurance and quality improvement using supportive supervision in a large-scale STI intervention with sex workers, men who have sex with men/transgenders and injecting-drug users in India

    NARCIS (Netherlands)

    V. Mogasale; T.C. Wi; A. Das; S. Kane; A.K. Singh; B. George; R. Steen

    2010-01-01

    Background Documentation of the long-term impact of supportive supervision using a monitoring tool in STI intervention with sex workers, men who have sex with men and injection-drug users is limited. The authors report methods and results of continued quality monitoring in a large-scale STI services

  15. Application of a colorimetric technique in quality control for printed pediatric orodispersible drug delivery systems containing propranolol hydrochloride.

    Science.gov (United States)

    Vakili, Hossein; Nyman, Johan O; Genina, Natalja; Preis, Maren; Sandler, Niklas

    2016-09-10

    The feasibility of a colorimetric technique was investigated in CIELAB color space as an analytical quality control method for content uniformity of printed orodispersible pediatric delivery systems. Inkjet printing was utilized to fabricate orodispersibe film formulations containing propranolol hydrochloride in a colored ink base using three different edible substrates. A thin sweetener coating layer of saccharin was successfully included in the final dosage forms for palatability purposes using a casting knife. Optical microscopy, scanning electron microscopy and scanning white light interferometry analyses were conducted to study the effect of printing on the surface morphology and topography of the substrates. Differential scanning calorimetry and attenuated total reflectance infrared spectroscopy were used to study the solid state properties and possible interactions between the drug and the excipients. The inkjet printing technique deposited precise and uniform escalating doses (0.08-3.16mg) of the active pharmaceutical ingredient onto the substrates (R(2)≥0.9934). A disintegration test with clear end-point detection confirmed that all the substrates meet the requirements of the Ph. Eur. to disintegrate within 180s. The colorimetric technique proved to be a reliable method to distinguish the small color differences between formulations containing an escalating dose of propranolol hydrochloride. PMID:27444550

  16. The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability.

    Science.gov (United States)

    Waterman, Kenneth Craig

    2011-09-01

    An isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a fixed degradant level, is shown to compensate for the complex, non-single order kinetics of solid drug products. A humidity-corrected Arrhenius equation provides reliable estimates for temperature and relative humidity effects on degradation rates. A statistical protocol is employed to determine best fits for chemical stability data, which in turn allows for accurate estimations of shelf life (with appropriate confidence intervals) at any storage condition including inside packaging (based on the moisture vapor transmission rate of the packaging and moisture sorption isotherms of the internal components). These methodologies provide both faster results and far better predictions of chemical stability limited shelf life (expiry) than previously possible. Precise shelf-life estimations are generally determined using a 2-week, product-specific protocol. Once the model for a product is developed, it can play a critical role in providing the product understanding necessary for a quality by design (QbD) filing for product approval and enable rational control strategies to assure product stability. Moreover, this Accelerated Stability Assessment Program (ASAP) enables the coupling of product attributes (e.g., moisture content, packaging options) to allow for flexibility in how control strategies are implemented to provide a balance of cost, speed, and other factors while maintaining adequate stability. PMID:21748541

  17. Investigation of the quality of the drug Enalapril commercialized by pharmacies of manipulation in Belo Horizonte, Brazil

    International Nuclear Information System (INIS)

    Samples of Enalapril (C20H28N2O5), a drug largely used to treat hypertension commercialized in Belo Horizonte, Brazil, were analysed applying the k0-method of neutron activation analysis (k0-INAA). Medicines prepared according to personalized medical prescription are called manipulated medicines. These analyses aimed at to obtaining complementary data about the quality of the manipulated Enalapril to a survey carried out by the State Health Surveillance Agency of Minas Gerais, Brazil and to determining the presence of impurities in order to perform a preliminary study of the heterogeneity of the samples from each pharmacy. Due to operational reasons, the institutes Centre for Development of Nuclear Technology/Brazilian Commission for Nuclear Energy in Brazil, and Jozef Stefan Institute in Slovenia analysed different set of samples. The results pointed out the presence of: Al, As, Au, Br, Ce, Cl, Co, Cr, Hf, La, Sb, Sc, Sm, Th and Zn. These elements may be originated from the raw material, imported from other countries. Elements such as Cl, Fe, K, Mg and Na could be expected in this kind of samples because they are normally present in the substances used as excipients in the preparation of the medicines. The results for the impurities through the analyses using k 0-INAA method can also be used to verify the heterogeneity of the capsules of the medicines contained in each bottle. (author)

  18. Drug quality analysis through high performance liquid chromatography of isometamidium chloride hydrochloride and diminazene diaceturate purchased from official and unofficial sources in Northern Togo.

    Science.gov (United States)

    Tchamdja, E; Kulo, A E; Akoda, K; Teko-Agbo, A; Assoumy, A M; Niang, E M M; Batawui, K; Adomefa, K; Bankolé, A A; Kombiagou, K; Hoppenheit, A; Clausen, P-H; Mattioli, R C; Peter, R; Napier, G B; De Deken, R; Marcotty, T; Van Den Abbeele, J; Delespaux, V

    2016-04-01

    Trypanocidal drugs remain the most accessible and thus commonly used means of controlling tsetse transmitted animal African trypanosomosis. In Togo, trypanocides are sold on official as well as unofficial markets, but the quality of these trypanocides is undocumented so a drug quality assessment study was conducted from May 2013 to June 2014. Trypanocides supplied by European, Indian and Chinese pharmaceutical companies and sold on official and unofficial markets in Togo were purchased. In total fifty-two trypanocides were obtained, 24 of these samples from official markets and 28 from unofficial markets made up of a total of 36 diminazene diaceturate and 16 isometamidium chloride hydrochloride samples. The samples were analysed in the reference laboratory of the OIE (World Organisation for Animal Health), Laboratory for the Control of Veterinary Medicines (LACOMEV) in Dakar which uses galenic testing and high performance liquid chromatography (HPLC) testing as standard reference analysis methods. The results revealed a high proportion of trypanocides of sub-standard quality on the Togolese market: 40% were non-compliant to these quality reference standards. All of the HPLC non-compliant samples contained lower amounts of active ingredient compared to the concentration specified on the packaging. Non-compliance was higher in samples from the unofficial (53.57%) than from the official markets (25%; p=0.04).The main drug manufacturers, mostly of French origin in the study area, supply quality drugs through the official legal distribution circuit. Products of other origins mostly found on illegal markets present a significantly lower quality. PMID:26907208

  19. Analysis of Gap in Service Quality in Drug Addiction Treatment Centers of Kerman, Iran, Using SERVQUAL Model

    OpenAIRE

    Naqavi, Mohammad Reza; Refaiee, Raheleh; Baneshi, Mohammad Reza; NAKHAEE, Nouzar

    2014-01-01

    Background Treatment of drug addicts is one of the main strategies of drug control in Iran. Client satisfaction strongly influences the success of any treatment program. This study aimed to explore the difference between customer expectations and perceptions in drug addiction treatment centers of Kerman, Iran, using SERVQUAL model. Methods Using a cross-sectional design 260 clients referring to drug addiction treatment centers of Kerman, were enrolled in 2012. From among 84 clinics, 20 center...

  20. Benefits of a new Metropolis-Hasting based algorithm, in non-linear regression for estimation of ex vivo antimalarial sensitivity in patients infected with two strains.

    Science.gov (United States)

    Bauer, Rebecca; Mentré, France; Kaddouri, Halima; Le Bras, Jacques; Le Nagard, Hervé

    2014-12-01

    Malaria is one of the world׳s most widespread parasitic diseases. The parasitic protozoans of the genus Plasmodium have developed resistance to several antimalarial drugs. Some patients are therefore infected by two or more strains with different levels of antimalarial drug sensitivity. We previously developed a model to estimate the drug concentration (IC50) that inhibits 50% of the growth of the parasite isolated from a patient infected with one strain. We propose here a new Two-Slopes model for patients infected by two strains. This model involves four parameters: the proportion of each strain and their IC50, and the sigmoidicity parameter. To estimate the parameters of this model, we have developed a new algorithm called PGBO (Population Genetics-Based Optimizer). It is based on the Metropolis-Hasting algorithm and is implemented in the statistical software R. We performed a simulation study and defined three evaluation criteria to evaluate its properties and compare it with three other algorithms (Gauss-Newton, Levenberg-Marquardt, and a simulated annealing). We also evaluated it using in vitro data and three ex vivo datasets from the French Malaria Reference Center. Our evaluation criteria in the simulation show that PGBO gives good estimates of the parameters even if the concentration design is poor. Moreover, our algorithm is less sensitive than Gauss-Newton algorithms to initial values. Although parameter estimation is good, interpretation of the results can be difficult if the proportion of the second strain is close to 0 or 1. For these reasons, this approach cannot yet be implemented routinely. PMID:25450214