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Sample records for anti-malarial drug sensitivity

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

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

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

  2. In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts.

    Science.gov (United States)

    Olasehinde, Grace I; Ojurongbe, Olusola; Adeyeba, Adegboyega O; Fagade, Obasola E; Valecha, Neena; Ayanda, Isaac O; Ajayi, Adesola A; Egwari, Louis O

    2014-02-20

    The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia ('Ejirin') Diospyros monbuttensis ('Egun eja') and Morinda lucida ('Oruwo') was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2 nM) while the lowest was obtained from M. lucida (IC50 = 25 nM). Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs.

  3. Poisoning by anti-malarial drugs

    African Journals Online (AJOL)

    had taken chloroquine: no other anti-malarial drugs were involved [1]. ... and angio-oedema have been described. Itching without a ... 15mg/L the risk of permanent visual damage and cardiac dysrhythmias is ... to use an alternative method.

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

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    Rusk Andria

    2012-08-01

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

  5. 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

  6. 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

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

    Science.gov (United States)

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

    2018-04-03

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

  8. Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay.

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    Linares, María; Viera, Sara; Crespo, Benigno; Franco, Virginia; Gómez-Lorenzo, María G; Jiménez-Díaz, María Belén; Angulo-Barturen, Íñigo; Sanz, Laura María; Gamo, Francisco-Javier

    2015-11-05

    The emergence of Plasmodium falciparum resistance to artemisinins threatens to undermine the effectiveness of artemisinin-based combination anti-malarial therapy. Developing suitable drugs to replace artemisinins requires the identification of new compounds that display rapid parasite killing kinetics. However, no current methods fully meet the requirements to screen large compound libraries for candidates with such properties. This study describes the development and validation of an in vitro parasite viability fast assay for identifying rapidly parasiticidal anti-malarial drugs. Parasite killing kinetics were determined by first culturing unlabelled erythrocytes with P. falciparum in the presence of anti-malarial drugs for 24 or 48 h. After removing the drug, samples were added to erythrocytes pre-labelled with intracellular dye to allow their subsequent identification. The ability of viable parasites to re-establish infection in labelled erythrocytes could then be detected by two-colour flow cytometry after tagging of parasite DNA. Thus, double-stained erythrocytes (with the pre-labelled intracellular dye and the parasite DNA dye) result only after establishment of new infections by surviving parasites. The capacity of the test anti-malarial drugs to eliminate viable parasites within 24 or 48 h could, therefore, be determined. The parasite viability fast assay could be completed within 48 h following drug treatment and distinguished between rapidly parasiticidal anti-malarial drugs versus those acting more slowly. The assay was validated against ten standard anti-malarial agents with known properties and results correlated well with established methods. An abbreviated assay, suitable for adaption to medium-high throughput screening, was validated and applied against a set of 20 compounds retrieved from the publically available Medicines for Malaria Venture 'Malaria Box'. The quantification of new infections to determine parasite viability offers important

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

    NARCIS (Netherlands)

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

    2015-01-01

    Recent studies alluded to the alarming scale of poor anti-malarial drug quality in malaria-endemic countries, but also illustrated the major geographical gaps in data on anti-malarial drug quality from endemic countries. Data are particularly scarce from Central Africa, although it carries the

  10. 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

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

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    Komal Kalani

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

  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...... 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...

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

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    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.

  14. 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

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

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    Antia R

    2003-02-01

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

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

    Science.gov (United States)

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

    2011-10-31

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

  17. 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

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

    Science.gov (United States)

    2011-01-01

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

  19. 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

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

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    Arise Rotimi Olusanya

    2017-09-01

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

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

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    Dondorp Arjen M

    2008-11-01

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

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

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    Olugbenga O. Oluwagbemi

    2018-04-01

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

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

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    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.

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

    Science.gov (United States)

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

    2009-01-01

    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. PMID:19216765

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

    Science.gov (United States)

    Marrelli, Mauro Toledo; Brotto, Marco

    2016-11-02

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

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

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    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.

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

    Science.gov (United States)

    2010-01-01

    Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain) and CY27 (chloroquine-sensitive strain), using the parasite lactate dehydrogenase (pLDH) assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain). Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy), Solanum surattense (Burm.f.) and Prosopis juliflora (Sw.) showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml) and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time. PMID:20462416

  8. Synthesis and exploration of novel curcumin analogues as anti-malarial agents.

    Science.gov (United States)

    Mishra, Satyendra; Karmodiya, Krishanpal; Surolia, Namita; Surolia, Avadhesha

    2008-03-15

    Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.

  9. 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

  10. Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.

    Science.gov (United States)

    Das, Pronay; Babbar, Palak; Malhotra, Nipun; Sharma, Manmohan; Jachak, Gorakhnath R; Gonnade, Rajesh G; Shanmugam, Dhanasekaran; Harlos, Karl; Yogavel, Manickam; Sharma, Amit; Reddy, D Srinivasa

    2018-05-21

    The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332. Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.

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

    Science.gov (United States)

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mwafongo Winfred

    2010-10-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

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    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.

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

    Science.gov (United States)

    Karunamoorthi, Kaliyaperumal

    2014-06-02

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

  16. QSAR models for anti-malarial activity of 4-aminoquinolines.

    Science.gov (United States)

    Masand, Vijay H; Toropov, Andrey A; Toropova, Alla P; Mahajan, Devidas T

    2014-03-01

    In the present study, predictive quantitative structure - activity relationship (QSAR) models for anti-malarial activity of 4-aminoquinolines have been developed. CORAL, which is freely available on internet (http://www.insilico.eu/coral), has been used as a tool of QSAR analysis to establish statistically robust QSAR model of anti-malarial activity of 4-aminoquinolines. Six random splits into the visible sub-system of the training and invisible subsystem of validation were examined. Statistical qualities for these splits vary, but in all these cases, statistical quality of prediction for anti-malarial activity was quite good. The optimal SMILES-based descriptor was used to derive the single descriptor based QSAR model for a data set of 112 aminoquinolones. All the splits had r(2)> 0.85 and r(2)> 0.78 for subtraining and validation sets, respectively. The three parametric multilinear regression (MLR) QSAR model has Q(2) = 0.83, R(2) = 0.84 and F = 190.39. The anti-malarial activity has strong correlation with presence/absence of nitrogen and oxygen at a topological distance of six.

  17. Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria

    OpenAIRE

    Nguetse, Christian N.; Adegnika, Ayola Akim; Agbenyega, Tsiri; Ogutu, Bernhards R.; Krishna, Sanjeev; Kremsner, Peter G.; Velavan, Thirumalaisamy P.

    2017-01-01

    BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped fo...

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

    Science.gov (United States)

    Amuasi, John H; Diap, Graciela; Blay-Nguah, Samuel; Boakye, Isaac; Karikari, Patrick E; Dismas, Baza; Karenzo, Jeanne; Nsabiyumva, Lievin; Louie, Karly S; Kiechel, Jean-René

    2011-02-10

    Malaria is the leading cause of morbidity and mortality in post-conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate-amodiaquine (AS-AQ) as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non-governmental (NGO) retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti-malarials. Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO), a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO) medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment) of AS-AQ, quinine and other anti-malarials were calculated. Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti-malarials were mainly found in the private outlets (38.9%) compared to public (4.2%) and NGO (0%) outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu) for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu). Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu), private and NGO sectors (both US$1.61 or 2,000 FBu). Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors, whereas, it was equivalent to 1.5 days worth

  19. Access to artemisinin-combination therapy (ACT) and other anti-malarials: national policy and markets in Sierra Leone.

    Science.gov (United States)

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

    2012-01-01

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Little is known about how people living with human immunodeficiency virus (HIV) experience malaria and the concomitant use of anti-malarial treatments with anti-retrovirals (ARVs). An understanding of how patients make sense of these experiences is important to consider in planning......, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. CONCLUSIONS: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes...

  1. The effect of mimicking febrile temperature and drug stress on malarial development

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    Adisakwattana Poom

    2009-06-01

    Full Text Available Abstract Background Malaria remains one of the most important tropical diseases of human with 1–2 million deaths annually especially caused by P. falciparum. During malarial life cycle, they exposed to many environmentally stresses including wide temperature fluctuation and pharmacological active molecules. These trigger malarial evolutionarily adaptive responses. The effect of febrile temperature on malarial growth, development and drug susceptibility by mimicking patient in treatment failure before and after drug uptake was examined. Methods Sensitivities of P. falciparum to antimalarial drug (chloroquine, mefloquine, quinine and artesunate were investigated based on the incorporation of [3H] hypoxanthine into parasite nucleic acids or radioisotopic technique. The number of parasites was examined under microscope following Giemsa staining and the parasite development at the end of each phase was counted and comparison of parasite number was made. The proteome was separated, blotted and hybridized with anti-Hsp70s primary antibody. The hybridized proteins were separately digested with trypsin and identified by MALDI-TOF peptide mass fingerprint. Results The results show that febrile temperature is capable of markedly inhibiting the growth of field isolate P. falciparum but not to K1 and 3D7 standard strains. K1 and 3D7 grown under heat shock developed greater and the reinfection rate was increased up to 2-folds when compared to that of non-heat shock group. The IC50 value of K1 toward chloroquine, mefloquine and quinine under heat shock was higher than that of K1 under non-heat shock which is opposite to that of 3D7. Heat shock caused death in field isolated parasite. It was also found that the febrile temperature coped with chloroquine uptake had no effect to the development, drug sensitivity and the parasite number of K1 strain. In the opposite way, heat shock and chloroquine shows extremely effect toward 3D7 and field isolate PF91 as shown

  2. Anti-malarial activity of 6-(8'Z-pentadecenyl-salicylic acid from Viola websteri in mice

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    Park Won-Hwan

    2009-07-01

    Full Text Available Abstract Background Petroleum ether extracts of Viola websteri Hemsl (Violaceae were reported to have anti-plasmodial activity against Plasmodium falciparum in vitro, with this activity being largely attributable to 6-(8'Z-pentadecenyl-salicylic acid (6-SA. Methods The schizontocidal activity of 6-SA on early Plasmodium berghei infections was evaluated in a four-day test. The possible 'repository' activity of 6-SA was assessed using the method described by Peters. The median lethal dose (LD50 of 6-SA, when given intraperitoneally, was also determined using uninfected ICR mice and the method of Lorke. Results In the present study, 6-SA was found to have anti-malarial activity in vivo, when tested against P. berghei in mice. 6-SA at 5, 10 and 25 mg/kg·day exhibited a significant blood schizontocidal activity in four-day early infections, repository evaluations and established infections with a significant mean survival time comparable to that of the standard drug, chloroquine (5 mg/kg·day. Conclusion 6-SA possesses a moderate anti-malarial activity that could be exploited for malaria therapy.

  3. New molecular settings to support in vivo anti-malarial assays.

    Science.gov (United States)

    Bahamontes-Rosa, Noemí; Alejandre, Ane Rodriguez; Gomez, Vanesa; Viera, Sara; Gomez-Lorenzo, María G; Sanz-Alonso, Laura María; Mendoza-Losana, Alfonso

    2016-03-08

    Quantitative real-time PCR (qPCR) is now commonly used as a method to confirm diagnosis of malaria and to differentiate recrudescence from re-infection, especially in clinical trials and in reference laboratories where precise quantification is critical. Although anti-malarial drug discovery is based on in vivo murine efficacy models, use of molecular analysis has been limited. The aim of this study was to develop qPCR as a valid methodology to support pre-clinical anti-malarial models by using filter papers to maintain material for qPCR and to compare this with traditional methods. FTA technology (Whatman) is a rapid and safe method for extracting nucleic acids from blood. Peripheral blood samples from mice infected with Plasmodium berghei, P. yoelii, or P. falciparum were kept as frozen samples or as spots on FTA cards. The extracted genetic material from both types of samples was assessed for quantification by qPCR using sets of specific primers specifically designed for Plasmodium 18S rRNA, LDH, and CytB genes. The optimal conditions for nucleic acid extraction from FTA cards and qPCR amplification were set up, and were confirmed to be suitable for parasite quantification using DNA as template after storage at room temperature for as long as 26 months in the case of P. berghei samples and 52 months for P. falciparum and P. yoelii. The quality of DNA extracted from the FTA cards for gene sequencing and microsatellite amplification was also assessed. This is the first study to report the suitability of FTA cards and qPCR assay to quantify parasite load in samples from in vivo efficacy models to support the drug discovery process.

  4. The association between price, competition, and demand factors on private sector anti-malarial stocking and sales in western Kenya: considerations for the AMFm subsidy

    Science.gov (United States)

    2013-01-01

    Background Households in sub-Saharan Africa are highly reliant on the retail sector for obtaining treatment for malaria fevers and other illnesses. As donors and governments seek to promote the use of artemisinin combination therapy in malaria-endemic areas through subsidized anti-malarials offered in the retail sector, understanding the stocking and pricing decisions of retail outlets is vital. Methods A survey of all medicine retailers serving Bungoma East District in western Kenya was conducted three months after the launch of the AMFm subsidy in Kenya. The survey obtained information on each anti-malarial in stock: brand name, price, sales volume, outlet characteristics and GPS co-ordinates. These data were matched to household-level data from the Webuye Health and Demographic Surveillance System, from which population density and fever prevalence near each shop were determined. Regression analysis was used to identify the factors associated with retailers’ likelihood of stocking subsidized artemether lumefantrine (AL) and the association between price and sales for AL, quinine and sulphadoxine-pyrimethamine (SP). Results Ninety-seven retail outlets in the study area were surveyed; 11% of outlets stocked subsidized AL. Size of the outlet and having a pharmacist on staff were associated with greater likelihood of stocking subsidized AL. In the multivariable model, total volume of anti-malarial sales was associated with greater likelihood of stocking subsidized AL and competition was important; likelihood of stocking subsidized AL was considerably higher if the nearest neighbour stocked subsidized AL. Price was a significant predictor of sales volume for all three types of anti-malarials but the relationship varied, with the largest price sensitivity found for SP drugs. Conclusion The results suggest that helping small outlets overcome the constraints to stocking subsidized AL should be a priority. Competition between retailers and prices can play an important

  5. Mass anti-malarial administration in western Cambodia: a qualitative study of factors affecting coverage.

    Science.gov (United States)

    Pell, Christopher; Tripura, Rupam; Nguon, Chea; Cheah, Phaikyeong; Davoeung, Chan; Heng, Chhouen; Dara, Lim; Sareth, Ma; Dondorp, Arjen; von Seidlein, Lorenz; Peto, Thomas J

    2017-05-19

    Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia. Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities. Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo. Malaria was an important health concern and villagers reported a demand for malaria treatment. This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria. Participants generally understood the overall study aim and were familiar with study activities. Comprehension of the study rationale was however limited. After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as "side effects" contributed to a decrease of coverage in round two. Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings. This contributed to a subsequent increase in coverage. Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement. Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare.

  6. Plasmodium falciparum in vitro continuous culture conditions: A comparison of parasite susceptibility and tolerance to anti-malarial drugs throughout the asexual intra-erythrocytic life cycle.

    Science.gov (United States)

    Duffy, Sandra; Avery, Vicky M

    2017-12-01

    The continuous culture of Plasmodium falciparum is often seen as a means to an end, that end being to probe the biology of the parasite in question, and ultimately for many in the malaria drug discovery arena, to identify means of killing the parasite in order to treat malaria. In vitro continuous culture of Plasmodium falciparum is a fundamental requirement when undertaking malaria research where the primary objectives utilise viable parasites of a desired lifecycle stage. This investigation, and resulting data, compared the impact culturing Plasmodium falciparum long term (4 months) in different environmental conditions had on experimental outcomes and thus conclusions. The example presented here focused specifically on the effect culture conditions had on the in vitro tolerance of Plasmodium falciparum to standard anti-malarial drugs, including artemisinin and lumefantrine. Historical data from an independent experiment for 3D7-ALB (5% O 2 ) was also compared with that obtained from this study. We concluded that parasites cultured for several months in media supplemented with a serum substitute such as Albumax II ® or within hyperoxic conditions (21% O 2 ), demonstrate highly variable responses to artemisinin and lumefantrine but not all anti-malarial drugs, when compared to those cultured in human serum in combination with Albumax II ® under normoxic conditions (5% O 2 ) for the parasite. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  9. 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

  10. Robust prediction of anti-cancer drug sensitivity and sensitivity-specific biomarker.

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    Heewon Park

    Full Text Available The personal genomics era has attracted a large amount of attention for anti-cancer therapy by patient-specific analysis. Patient-specific analysis enables discovery of individual genomic characteristics for each patient, and thus we can effectively predict individual genetic risk of disease and perform personalized anti-cancer therapy. Although the existing methods for patient-specific analysis have successfully uncovered crucial biomarkers, their performance takes a sudden turn for the worst in the presence of outliers, since the methods are based on non-robust manners. In practice, clinical and genomic alterations datasets usually contain outliers from various sources (e.g., experiment error, coding error, etc. and the outliers may significantly affect the result of patient-specific analysis. We propose a robust methodology for patient-specific analysis in line with the NetwrokProfiler. In the proposed method, outliers in high dimensional gene expression levels and drug response datasets are simultaneously controlled by robust Mahalanobis distance in robust principal component space. Thus, we can effectively perform for predicting anti-cancer drug sensitivity and identifying sensitivity-specific biomarkers for individual patients. We observe through Monte Carlo simulations that the proposed robust method produces outstanding performances for predicting response variable in the presence of outliers. We also apply the proposed methodology to the Sanger dataset in order to uncover cancer biomarkers and predict anti-cancer drug sensitivity, and show the effectiveness of our method.

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

    OpenAIRE

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

    2010-01-01

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

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

    Science.gov (United States)

    Massaquoi, Moses B F; Kennedy, Stephen B

    2003-02-01

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

  13. Quality assessment of some selected brands of anti malarial drugs used in Ghana: A case study of Agona West Municipality

    International Nuclear Information System (INIS)

    Asare, Aquisman Ebenezer

    2016-07-01

    The availability of numerous brands of artesunate in our drug market today places clinicians and pharmacists in a difficult situation of choice of a suitable brand or the possibility of alternative use. Fake artesunate could compromise the hope that ACT (artemisinin combination therapy) offers for malaria control in Africa. In this study, quality of some selected brands of anti - malarial drugs used in the communities of Agona west Municipality, Ghana was determined. Blister or packs of antimalarial tablets were randomly sampled. The Protocols of the International Pharmacopeia and Global Pharma Health Fund Minilab were used to assess the quality of antimalarial tablets per blister pack manufactured by Bliss Gvs Pharma Ltd. India, Letap Pharmaceutical Company Ltd. Ghana and Guilin Pharmaceutical Company Ltd. China and sold in chemical sales outlets at the farming communities of Agona West Municipality, Ghana. The identification test was used to confirm the presence of active ingredients in the tablets. A confirmatory test for the active ingredient was achieved with artesunate (ICRS 1302) reference standards and Gsunate reference standard (ICRS4061). The friability test was used to confirm the hardness of the tablets to determine the drug ability to withstand abrasion in packaging, handling and shipping. The disintegration test was used to confirm the time required for the tablets to disintegrate into particles. Titrimetric analysis confirmed the amount of artesunate found in tablets.The results of the study are as follows for Artesunate by GPCL, LPL and Gsunate by BGPL; the identification test confirmed the presence of the active ingredient in all the brands. Based on the International Pharmacopoeia acceptable range of 1 to 15 min for genuine artesunate per tablet, 93.75 % of field selected artesunate blister pack tablets manufactured by GPCL passed the disintegration test and 6.25% failed. Also 85.57% of the sampled artesunate blister pack manufactured by

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

    Science.gov (United States)

    Verbeken, Mathieu; Suleman, Sultan; Baert, Bram; Vangheluwe, Elien; Van Dorpe, Sylvia; Burvenich, Christian; Duchateau, Luc; Jansen, Frans H; De Spiegeleer, Bart

    2011-02-28

    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). 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®. 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. 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.

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

    Directory of Open Access Journals (Sweden)

    Chance Michael L

    2011-08-01

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

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

    Science.gov (United States)

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

    2011-08-21

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

  17. 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

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

    Science.gov (United States)

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

    2016-03-09

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

  19. Flow cytometry for the evaluation of anti-plasmodial activity of drugs on Plasmodium falciparum gametocytes

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    Pipy Bernard

    2010-02-01

    Full Text Available Abstract Background The activity of promising anti-malarial drugs against Plasmodium gametocytes is hard to evaluate even in vitro. This is because visual examination of stained smears, which is commonly used, is not totally convenient. In the current study, flow cytometry has been used to study the effect of established anti-malarial drugs against sexual stages obtained from W2 strain of Plasmodium falciparum. Gametocytes were treated for 48 h with different drug concentrations and the gametocytaemia was then determined by flow cytometry and compared with visual estimation by microscopy. Results and conclusions Initially gametocytaemia was evaluated either using light microscopy or flow cytometry. A direct correlation (r2 = 0.9986 was obtained. Two distinct peaks were observed on cytometry histograms and were attributed to gametocyte populations. The activities of established anti-malarial compounds were then measured by flow cytometry and the results were equivalent to those obtained using light microscopy. Primaquine and artemisinin had IC50 of 17.6 μM and 1.0 μM, respectively. Gametocyte sex was apparently distinguishable by flow cytometry as evaluated after induction of exflagellation by xanthurenic acid. These data form the basis of further studies for developing new methods in drug discovery to decrease malaria transmission.

  20. An ethnobotanical study of anti-malarial plants among indigenous people on the upper Negro River in the Brazilian Amazon.

    Science.gov (United States)

    Frausin, Gina; Hidalgo, Ari de Freitas; Lima, Renata Braga Souza; Kinupp, Valdely Ferreira; Ming, Lin Chau; Pohlit, Adrian Martin; Milliken, William

    2015-11-04

    material available, the patient's age (children and adults) and the local expert. The treatment time varies from a single dose to up to several weeks. Most anti-malarial plants are domesticated or grow spontaneously. They are grown in home gardens, open areas near the communities, clearings and secondary forests, and wild species grow in areas of seasonally flooded wetlands and terra firme ('solid ground') forest, in some cases in locations that are hard to access. Traditional knowledge of plants was found to be falling into disuse presumably as a consequence of the local official health services that treat malaria in the communities using commercial drugs. Despite this, some species are used in the prevention of this disease and also in the recovery after using conventional anti-malarial drugs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Anti-malarial landscape in Myanmar: results from a nationally representative survey among community health workers and the private sector outlets in 2015/2016.

    Science.gov (United States)

    Thein, Si Thu; Khin, Hnin Su Su; Thi, Aung

    2017-04-25

    In 2015/2016, an ACTwatch outlet survey was implemented to assess the anti-malarial and malaria testing landscape in Myanmar across four domains (Eastern, Central, Coastal, Western regions). Indicators provide an important benchmark to guide Myanmar's new National Strategic Plan to eliminate malaria by 2030. This was a cross-sectional survey, which employed stratified cluster-random sampling across four regions in Myanmar. A census of community health workers (CHWs) and private outlets with potential to distribute malaria testing and/or treatment was conducted. An audit was completed for all anti-malarials, malaria rapid diagnostic tests. A total of 28,664 outlets were approached and 4416 met the screening criteria. The anti-malarial market composition comprised CHWs (41.5%), general retailers (27.9%), itinerant drug vendors (11.8%), pharmacies (10.9%), and private for-profit facilities (7.9%). Availability of different anti-malarials and diagnostic testing among anti-malarial-stocking CHWs was as follows: artemisinin-based combination therapy (ACT) (81.3%), chloroquine (67.0%), confirmatory malaria test (77.7%). Less than half of the anti-malarial-stocking private sector had first-line treatment in stock: ACT (41.7%) chloroquine (41.8%), and malaria diagnostic testing was rare (15.4%). Oral artemisinin monotherapy (AMT) was available in 27.7% of private sector outlets (Western, 54.1%; Central, 31.4%; Eastern; 25.0%, Coastal; 15.4%). The private-sector anti-malarial market share comprised ACT (44.0%), chloroquine (26.6%), and oral AMT (19.6%). Among CHW the market share was ACT (71.6%), chloroquine (22.3%); oral AMT (3.8%). More than half of CHWs could correctly state the national first-line treatment for uncomplicated falciparum and vivax malaria (59.2 and 56.9%, respectively) compared to the private sector (15.8 and 13.2%, respectively). Indicators on support and engagement were as follows for CHWs: reportedly received training on malaria diagnosis (60.7%) or

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

    Science.gov (United States)

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

    2015-07-14

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

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

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    Lall Varinder K

    2012-12-01

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

  4. 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

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

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    Bate Roger

    2010-06-01

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

  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. Effects of the anti-malarial compound cryptolepine and its analogues in human lymphocytes and sperm in the Comet assay.

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    Gopalan, Rajendran C; Emerce, Esra; Wright, Colin W; Karahalil, Bensu; Karakaya, Ali E; Anderson, Diana

    2011-12-15

    Malaria is a mosquito-borne infectious disease caused by the genus Plasmodium. It causes one million deaths per year in African children under the age of 5 years. There is an increasing development of resistance of malarial parasites to chloroquine and other currently used anti-malarial drugs. Some plant products such as the indoloquinoline alkaloid cryptolepine have been shown to have potent activity against P. falciparum in vitro. On account of its toxicity, cryptolepine is not suitable for use as an antimalarial drug but a number of analogues of cryptolepine have been synthesised in an attempt to find compounds that have reduced cytotoxicity and these have been investigated in the present study in human sperm and lymphocytes using the Comet assay. The results suggest that cryptolepine and the analogues cause DNA damage in lymphocytes, but appear to have no effect on human sperm at the assessed doses. In the context of antimalarial drug development, the data suggest that all cryptolepine compounds and in particular 2,7-dibromocryptolepine cause DNA damage and therefore may not be suitable for pre clinical development as antimalarial agents. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study

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    Swai Ndeniria

    2011-04-01

    Full Text Available Abstract Background Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs on prescription of anti-malarials in urban Tanzania. Methods The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1 anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2 anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation. Results Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80 in intervention and 32% (9-54 in control HF. For quinine vials, the reduction was 63% (54-72 in intervention and an increase of 2.49 times (1.62-3.35 in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26. The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22% and control HF (60% (Risk ratio 0.30, 95%CI 0.14-0.70. Adherence to test result was excellent since only 7% of negative patients received an anti-malarial. However, antibiotic

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

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    Pybus Brandon S

    2012-08-01

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

  10. Use of a colorimetric (DELI) test for the evaluation of chemoresistance of Plasmodium falciparum and Plasmodium vivax to commonly used anti-plasmodial drugs in the Brazilian Amazon.

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    Pratt-Riccio, Lilian R; Chehuan, Yonne F; Siqueira, Maria José; das Graças Alecrim, Maria; Bianco-Junior, Cesare; Druilhe, Pierre; Brasseur, Philippe; de Fátima Ferreira-da-Cruz, Maria; Carvalho, Leonardo J M; Daniel-Ribeiro, Cláudio T

    2013-08-12

    The emergence and spread of Plasmodium falciparum and Plasmodium vivax resistance to available anti-malarial drugs represents a major drawback in the control of malaria and its associated morbidity and mortality. The aim of this study was to evaluate the chemoresistance profile of P. falciparum and P. vivax to commonly used anti-plasmodial drugs in a malaria-endemic area in the Brazilian Amazon. The study was carried out in Manaus (Amazonas state), in the Brazilian Amazon. A total of 88 P. falciparum and 178 P. vivax isolates was collected from 2004 to 2007. The sensitivity of P. falciparum isolates was determined to chloroquine, quinine, mefloquine and artesunate and the sensitivity of P. vivax isolates was determined to chloroquine and mefloquine, by using the colorimetric DELI test. As expected, a high prevalence of P. falciparum isolates resistant to chloroquine (78.1%) was observed. The prevalence of isolates with profile of resistance or decreased sensitivity for quinine, mefloquine and artesunate was 12.7, 21.2 and 11.7%, respectively. In the case of P. vivax, the prevalence of isolates with profile of resistance for chloroquine and mefloquine was 9.8 and 28%, respectively. No differences in the frequencies of isolates with profile of resistance or geometric mean IC50s were seen when comparing the data obtained in 2004, 2005, 2006 and 2007, for all tested anti-malarials. The great majority of P. falciparum isolates in the Brazilian malaria-endemic area remain resistant to chloroquine, and the decreased sensitivity to quinine, mefloquine and artesunate observed in 10-20% of the isolates must be taken with concern, especially for artesunate. Plasmodium vivax isolates also showed a significant proportion of isolates with decreased sensitivity to chloroquine (first-line drug) and mainly to mefloquine. The data presented here also confirm the usefulness of the DELI test to generate results able to impact on public health policies.

  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

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    Phitsinee Thipubon

    2015-11-01

    Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron cstitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

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

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    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

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

    Science.gov (United States)

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

    2012-06-15

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

  14. Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin

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    Mombo-Ngoma Ghyslain

    2010-10-01

    Full Text Available Abstract Background Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (SP is recommended for the prevention of malaria in pregnancy in sub-Saharan Africa. Increasing drug resistance necessitates the urgent evaluation of alternative drugs. Currently, the most promising candidates in clinical development are mefloquine and azithromycin. Besides the anti-malarial activity, SP is also a potent antibiotic and incurs significant anti-microbial activity when given as IPTp - though systematic clinical evaluation of this action is still lacking. Methods In this study, the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay. Results SP was highly active against Staphylococcus aureus and Streptococcus pneumoniae. All tested Gram-positive bacteria, except Enterococcus faecalis, were sensitive to azithromycin. Additionally, azithromycin was active against Neisseria gonorrhoeae. Mefloquine showed good activity against pneumococci but lower in vitro action against all other tested pathogens. Conclusion These data indicate important differences in the spectrum of anti-bacterial activity for the evaluated anti-malarial drugs. Given the large scale use of IPTp in Africa, the need for prospective clinical trials evaluating the impact of antibiotic activity of anti-malarials on maternal and foetal health and on the risk of promoting specific drug resistance of bacterial pathogens is discussed.

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

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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.

  16. 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.

  17. The behavior of chloroquine (a synthesized anti-malaria drug) labeled with 14C in healthy and malarious animals

    International Nuclear Information System (INIS)

    Coulibaly, Kafana

    1972-01-01

    The distribution of 14 C labeled chloroquine is identical in healthy and malarious animals. Fixation (by order of intensity) takes place in the liver, spleen, lungs, lacrimal glands, cerebrospinal fluid, bones, thyroid, and intestinal walls. This was confirmed from quantitative studies and demonstrates the traversing of the blood-brain barrier and the intestinal elimination after biliary excretion. Pharmaco-kinetic studies were undertaken with healthy animals and those afflicted with malaria. After a phase, in which the distribution of chloroquine is identical for both types of animal, a more rapid decrease in the blood level is observed with the malarious animals. The leucocytes contained distinctly more of the tracer than the normal or malarious red corpuscles or the blood plasma. Examination of the urinary elimination revealed a mono-exponential function; nevertheless, the urinary elimination was less regular with the malarious rats. This elimination corresponds to the excretion of unchanged chloroquine accompanied by two metabolites. A third metabolite appeared after a delay period. (author) [fr

  18. Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS) pilot study.

    Science.gov (United States)

    Talisuna, Ambrose O; Daumerie, Penny Grewal; Balyeku, Andrew; Egan, Timothy; Piot, Bram; Coghlan, Renia; Lugand, Maud; Bwire, Godfrey; Rwakimari, John Bosco; Ndyomugyenyi, Richard; Kato, Fred; Byangire, Maria; Kagwa, Paul; Sebisubi, Fred; Nahamya, David; Bonabana, Angela; Mpanga-Mukasa, Susan; Buyungo, Peter; Lukwago, Julius; Batte, Allan; Nakanwagi, Grace; Tibenderana, James; Nayer, Kinny; Reddy, Kishore; Dokwal, Nilesh; Rugumambaju, Sylvester; Kidde, Saul; Banerji, Jaya; Jagoe, George

    2012-10-29

    Artemisinin-based combination therapy (ACT), the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS) pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. Four intervention districts were purposefully selected to receive branded subsidized medicines - "ACT with a leaf", while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention's impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub-optimal anti-malarial. At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, "ACT with a leaf" accounted for 69% of anti-malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2%) at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%). The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4) at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, psupply-side subsidy and an intensive communications campaign significantly increased the uptake and use of ACT in the private sector in Uganda.

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

    Science.gov (United States)

    O'Connell, Kathryn A; Gatakaa, Hellen; Poyer, Stephen; Njogu, Julius; Evance, Illah; Munroe, Erik; Solomon, Tsione; Goodman, Catherine; Hanson, Kara; Zinsou, Cyprien; Akulayi, Louis; Raharinjatovo, Jacky; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Adjibabi, Chérifatou Bello; Agbango, Jean Angbalu; Ramarosandratana, Benjamin Fanomezana; Coker, Babajide; Rubahika, Denis; Hamainza, Busiku; Chapman, Steven; Shewchuk, Tanya; Chavasse, Desmond

    2011-10-31

    Artemisinin-based combination therapy (ACT) is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia. Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets) as compared to first-line quality-assured ACT (sector, first-line quality-assured ACT was available for free in all countries except Benin and the DRC (US$1.29 [Inter Quartile Range (IQR): $1.29-$1.29] and $0.52[IQR: $0.00-$1.29] per adult equivalent dose respectively). In the private sector, first-line quality-assured ACT was 5-24 times more expensive than non-artemisinin therapies. The exception was Madagascar where, due to national social marketing of subsidized ACT, the price of first-line quality-assured ACT ($0.14 [IQR: $0.10, $0.57]) was significantly lower than the most popular treatment (chloroquine, $0.36 [IQR: $0.36, $0.36]). Quality-assured ACT accounted for less than 25% of total anti-malarial volumes; private-sector quality-assured ACT volumes represented less than 6% of the total market share. Most anti-malarials were distributed through the private sector

  20. [Hyper-reactive malarial splenomegaly].

    Science.gov (United States)

    Maazoun, F; Deschamps, O; Barros-Kogel, E; Ngwem, E; Fauchet, N; Buffet, P; Froissart, A

    2015-11-01

    Hyper-reactive malarial splenomegaly is a rare and severe form of chronic malaria. This condition is a common cause of splenomegaly in endemic areas. The pathophysiology of hyper-reactive malarial splenomegaly involves an intense immune reaction (predominantly B cell-driven) to repeated/chronic infections with Plasmodium sp. The diagnosis may be difficult, due to a poorly specific clinical presentation (splenomegaly, fatigue, cytopenias), a long delay between residence in a malaria-endemic area and onset of symptoms, and a frequent absence of parasites on conventional thin and thick blood smears. A strongly contributive laboratory parameter is the presence of high levels of total immunoglobulin M. When the diagnostic of hyper-reactive malarial splenomegaly is considered, search for anti-Plasmodium antibodies and Plasmodium nucleic acids (genus and species) by PCR is useful. Diagnosis of hyper-reactive malarial splenomegaly relies on the simultaneous presence of epidemiological, clinical, biological and follow-up findings. Regression of both splenomegaly and hypersplenism following antimalarial therapy allows the differential diagnosis with splenic lymphoma, a common complication of hyper-reactive malarial splenomegaly. Although rare in Western countries, hyper-reactive malarial splenomegaly deserves increased medical awareness to reduce the incidence of incorrect diagnosis, to prevent progression to splenic lymphoma and to avoid splenectomy. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  1. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission

    NARCIS (Netherlands)

    Baker, D.A.; Stewart, L.B.; Large, J.M.; Bowyer, P.W.; Ansell, K.H.; Jimenez-Diaz, M.B.; Bakkouri, M. El; Birchall, K.; Dechering, K.J.; Bouloc, N.S.; Coombs, P.J.; Whalley, D.; Harding, D.J.; Smiljanic-Hurley, E.; Wheldon, M.C.; Walker, E.M.; Dessens, J.T.; Lafuente, M.J.; Sanz, L.M.; Gamo, F.J.; Ferrer, S.B.; Hui, R.; Bousema, T.; Angulo-Barturen, I.; Merritt, A.T.; Croft, S.L.; Gutteridge, W.E.; Kettleborough, C.A.; Osborne, S.A.

    2017-01-01

    To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase

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

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    Akter Jasmin

    2012-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Hubbard Alan E

    2010-01-01

    Full Text Available Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL vs. dihydroartemisinin-piperaquine (DP performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66 and poor agreement in Apac (kappa = 0.24. Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5. However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03. Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission

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

    Science.gov (United States)

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

    2010-01-15

    Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL) vs. dihydroartemisinin-piperaquine (DP) performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66) and poor agreement in Apac (kappa = 0.24). Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5). However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03). Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission, gel electrophoresis appears adequate to estimate comparative

  5. 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.

  6. Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS pilot study

    Directory of Open Access Journals (Sweden)

    Talisuna Ambrose O

    2012-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT, the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. Methods Four intervention districts were purposefully selected to receive branded subsidized medicines - “ACT with a leaf”, while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention’s impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub-optimal anti-malarial. Results At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, “ACT with a leaf” accounted for 69% of anti-malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2% at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%. The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4 at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, p Conclusions These data demonstrate that a supply-side subsidy and an intensive communications campaign

  7. 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 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.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.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.

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

    International Nuclear Information System (INIS)

    Raza, A.; Beg, M.A.

    2013-01-01

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

  9. Identification and reconstitution of the polyketide synthases responsible for biosynthesis of the anti-malarial agent, cladosporin

    OpenAIRE

    Cochrane, Rachel V. K.; Sanichar, Randy; Lambkin, Gareth R.; Reiz, Béla; Xu, Wei; Tang, Yi; Vederas, John C.

    2015-01-01

    The anti-malarial agent cladosporin is a nanomolar inhibitor of Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood and liver stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it was believed to be biosynthesized by a highly reducing (HR) and non-reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism, and subsequent heterologous expression of these enzymes in Sacchar...

  10. Fascaplysin Sensitizes Anti-Cancer Effects of Drugs Targeting AKT and AMPK

    Directory of Open Access Journals (Sweden)

    Taek-In Oh

    2017-12-01

    Full Text Available Fascaplysin, a natural product isolated from marine sponges, is a potential candidate for the development of anti-cancer drugs. However, the mechanism underlying its therapeutic effect of strengthening anti-cancer efficacy of other drugs is poorly understood. Here, we found that fascaplysin increases phosphorylation of protein kinase B (PKB, also known as AKT, and adenosine monophosphate-activated protein kinase (AMPK, which are considered therapeutic targets for cancer treatment due to their anti-apoptotic or pro-survival functions in cancer. A cell viability assay revealed that pharmacological suppression of AKT using LY294002 enhanced the anti-cancer effect of fascaplysin in various cancer cells. Similarly, fascaplysin was observed to have improved anti-cancer effects in combination with compound C, a selective AMPK inhibitor. Another challenge showed that fascaplysin increased the efficacy of methotrexate (MTX-mediated cancer therapy by suppressing genes related to folate and purine metabolism. Overall, these results suggest that fascaplysin may be useful for improving the anti-cancer efficacy of targeted anti-cancer drugs, such as inhibitors of phosphoinositide 3-kinase AKT signaling, and chemotherapeutic agents, such as MTX.

  11. Alpha-tocopherol transfer protein disruption confers resistance to malarial infection in mice

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    Takeya Motohiro

    2010-04-01

    Full Text Available Abstract Background Various factors impact the severity of malaria, including the nutritional status of the host. Vitamin E, an intra and extracellular anti-oxidant, is one such nutrient whose absence was shown previously to negatively affect Plasmodium development. However, mechanisms of this Plasmodium inhibition, in addition to means by which to exploit this finding as a therapeutic strategy, remain unclear. Methods α-TTP knockout mice were infected with Plasmodium berghei NK65 or Plasmodium yoelii XL-17, parasitaemia, survival rate were monitored. In one part of the experiments mice were fed with a supplemented diet of vitamin E and then infected. In addition, parasite DNA damage was monitored by means of comet assay and 8-OHdG test. Moreover, infected mice were treated with chloroquine and parasitaemia and survival rate were monitored. Results Inhibition of α-tocopherol transfer protein (α-TTP, a determinant of vitamin E concentration in circulation, confers resistance to malarial infection as a result of oxidative damage to the parasites. Furthermore, in combination with the anti-malarial drug chloroquine results were even more dramatic. Conclusion Considering that these knockout mice lack observable negative impacts typical of vitamin E deficiency, these results suggest that inhibition of α-TTP activity in the liver may be a useful strategy in the prevention and treatment of malaria infection. Moreover, a combined strategy of α-TTP inhibition and chloroquine treatment might be effective against drug resistant parasites.

  12. Model-based global sensitivity analysis as applied to identification of anti-cancer drug targets and biomarkers of drug resistance in the ErbB2/3 network

    Science.gov (United States)

    Lebedeva, Galina; Sorokin, Anatoly; Faratian, Dana; Mullen, Peter; Goltsov, Alexey; Langdon, Simon P.; Harrison, David J.; Goryanin, Igor

    2012-01-01

    High levels of variability in cancer-related cellular signalling networks and a lack of parameter identifiability in large-scale network models hamper translation of the results of modelling studies into the process of anti-cancer drug development. Recently global sensitivity analysis (GSA) has been recognised as a useful technique, capable of addressing the uncertainty of the model parameters and generating valid predictions on parametric sensitivities. Here we propose a novel implementation of model-based GSA specially designed to explore how multi-parametric network perturbations affect signal propagation through cancer-related networks. We use area-under-the-curve for time course of changes in phosphorylation of proteins as a characteristic for sensitivity analysis and rank network parameters with regard to their impact on the level of key cancer-related outputs, separating strong inhibitory from stimulatory effects. This allows interpretation of the results in terms which can incorporate the effects of potential anti-cancer drugs on targets and the associated biological markers of cancer. To illustrate the method we applied it to an ErbB signalling network model and explored the sensitivity profile of its key model readout, phosphorylated Akt, in the absence and presence of the ErbB2 inhibitor pertuzumab. The method successfully identified the parameters associated with elevation or suppression of Akt phosphorylation in the ErbB2/3 network. From analysis and comparison of the sensitivity profiles of pAkt in the absence and presence of targeted drugs we derived predictions of drug targets, cancer-related biomarkers and generated hypotheses for combinatorial therapy. Several key predictions have been confirmed in experiments using human ovarian carcinoma cell lines. We also compared GSA-derived predictions with the results of local sensitivity analysis and discuss the applicability of both methods. We propose that the developed GSA procedure can serve as a

  13. In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling

    CSIR Research Space (South Africa)

    Becker, JVW

    2011-10-01

    Full Text Available Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti...

  14. In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling.

    Science.gov (United States)

    Becker, John V W; van der Merwe, Marina M; van Brummelen, Anna C; Pillay, Pamisha; Crampton, Bridget G; Mmutlane, Edwin M; Parkinson, Chris; van Heerden, Fanie R; Crouch, Neil R; Smith, Peter J; Mancama, Dalu T; Maharaj, Vinesh J

    2011-10-11

    Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis. The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 μM against a chloroquine-sensitive strain (D10) of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the α-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that

  15. 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

  16. Sensitivity Pattern of Second Line Anti-Tuberculosis Drugs against Clinical Isolates of Multidrug Resistant Mycobacterium Tuberculosis

    International Nuclear Information System (INIS)

    Ghafoor, T.; Ikram, A.; Abbasi, S. A.; Zaman, G.; Ayyub, M.; Palomino, J. C.; Vandamme, P.; Martin, A.

    2015-01-01

    Objective:To determine the current sensitivity pattern of second line anti-tuberculosis drugs against clinical isolates of Multidrug Resistant Mycobacterium tuberculosis (MDR-TB). Study Design: A cross-sectional study. Place and Duration of Study: Department of Microbiology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from November 2011 to April 2013. Methodology: Samples received during the study period were processed on BACTEC MGIT 960 system for Mycobacterium tuberculosis (MTB) culture followed by first line drugs susceptibility testing of culture proven MTB isolates. On the basis of resistance to rifampicin and isoniazid, 100 clinical isolates of MDR-TB were further subjected to susceptibility testing against amikacin (AMK), capreomycin (CAP), ofloxacin (OFL) and ethionamide (ETH) as per standard BACTEC MGIT 960 instructions. Results: Out of 100 MDR-TB isolates, 62% were from male patients and 38% from female patients. 97% were sensitive to AMK, 53% to OFL, 87% to CAP; and 87% were sensitive to ETH. Conclusion: The majority of the MDR-TB isolates showed excellent sensitivity against AMK, CAP and ETH. However, sensitivity of MDR-TB isolates against fluoroquinolones like OFL was not encouraging. (author)

  17. Working towards consensus on methods used to elicit participant-reported safety data in uncomplicated malaria clinical drug studies: a Delphi technique study.

    Science.gov (United States)

    Mandimika, Nyaradzo; Barnes, Karen I; Chandler, Clare I R; Pace, Cheryl; Allen, Elizabeth N

    2017-01-28

    Eliciting adverse event (AE) and non-study medication data reports from clinical research participants is integral to evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of anti-malarials in vulnerable populations, and their increasing use in healthy, but at-risk individuals, as preventive treatment or to reduce malaria transmission. Experienced and knowledgeable anti-malarial drug clinical researchers were invited to participate in a Delphi technique study, to facilitate consensus on what are considered optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. Of 72 invited, 25, 16 and 10 panellists responded to the first, second and third rounds of the Delphi, respectively. Overall, 68% (68/100) of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed on the utility of a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of specific signs and symptoms questions were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. This study succeeded in reaching consensus within a section of the anti-malarial drug clinical research community about using a general question concept, and structured questions for eliciting data about AEs and non-study medication reports. The concepts and items considered in this Delphi to be

  18. In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae: identification of its main active constituent, structure-activity relationship studies and gene expression profiling

    Directory of Open Access Journals (Sweden)

    van Heerden Fanie R

    2011-10-01

    Full Text Available Abstract Background Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. Methods Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls, followed by oligonucleotide microarray- and data analysis. Results The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 μM against a chloroquine-sensitive strain (D10 of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the α-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action

  19. Postpartum Aplastic Anemia Presenting as Pancytopenia Due to Malarial Infection

    International Nuclear Information System (INIS)

    Shah, M. U.; Sundhu, M. A.; Hussain, M. Z.

    2013-01-01

    Pancytopenia is a condition with decreased numbers of all cell lines. Aplastic anemia is a common cause although malarial infection causing lysis of RBCs may also partly mimic this condition. The infection may also damage the patient's bone marrow resulting in pancytopenia as well. We present the case of a post-partum female patient who reported with fever, body aches and shortness of breath one month after the delivery of her baby. All blood cell counts were decreased and peripheral blood smear showed malarial parasites. Anti-malarial treatment was initiated following which the fever subsided but, despite regular transfusions, the blood counts remained low. Bone marrow biopsy report revealed P. falciparum pigments along with hypocellularity characteristic of severe aplastic anemia. Consequently, bone marrow transplantation was advised as a therapeutic measure. This case report highlights the increased susceptibility of pregnant women to malaria in endemic areas and subsequent aplastic anemia. (author)

  20. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

  1. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    International Nuclear Information System (INIS)

    Li, Xiaoguang; Qian, Hua; Miyamoto, Fusako; Naito, Takeshi; Kawaji, Kumi; Kajiwara, Kazumi; Hattori, Toshio; Matsuoka, Masao; Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka

    2012-01-01

    Highlights: ► We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. ► The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. ► In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1 IIIB and HIV-1 BaL as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1 IIIB activity, whereas fusion inhibitors showed both anti-HIV-1 IIIB and anti-HIV-1 BaL activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, “phenotypic drug evaluation”, may be applicable for the evaluation of various antiviral drugs in vivo.

  2. Phytochemical analysis of essential oil of Anthriscus nemorosa and evaluation of antioxidant and anti-malarial activity

    Directory of Open Access Journals (Sweden)

    S. Naeini

    2017-11-01

    Full Text Available Background and objectives: This investigation was performed in order to analyze the composition of the essential oil (EO of Anthriscus nemorosa and evaluation of its anti-oxidant and anti-malarial activity of its extracts and determination of the total phenolics content (TPC and total flavonoid content (TFC. Methods: One hundred g dried powder of Anthriscus nemorosa was submitted to hydro-distillation and also was extracted (with n-hexane, dichloromethane (DCM and methanol (MeOH, by using Clevenger and Soxhlet apparatus, respectively. Moreover, extracted essential oil (EO was analyzed by GC-MS. Furthermore, the anti-oxidant, anti- malaria, Total phenolics content (TPC and total flavonoid content (TFC of EO and the extracts were investigated by DPPH, cell free -hematin formation, Folin- Ciocalteau and colorimetric methods, respectively. Results: Fifty nine compounds, representing 94% of total oil were identified High content of terpenoids (60.02% were identified in the essential oil with isogeranol (28.86%, crystathenyl acetate  (13.86% and farnesene (10.39% as the most dominant compounds.. Methanol extract demonstrated free radical scavenging activity (RC50 0.192±0.133.Total phenol contents was (325.82±2.72 mg/g. Total flavonoid content was (140.4096±2.4 mg/g. None of the extracts showed anti-malaria effect. Conclusion: Main constituents of A. nemorosa were terpenoids. In comparison with other species of Anthriscus, antioxidant activity of A. nemorosa essential oil was less noticeable.

  3. [Anti-angiogenic drugs].

    Science.gov (United States)

    Sato, Yasufumi

    2010-06-01

    Angiogenesis or neovascularization, the formation of neo-vessels, is a physiological phenomenon endued in vasculature, but is involved in various pathological conditions. Angiogenesis is required for tumor growth and metastasis, and thus constitutes an important target for the control of tumor progression. Indeed, the recent development of bevacizumab, a neutralizing anti-VEGF monoclonal antibody as the first anti-angiogenic drug, legalized the clinical merit of anti-angiogenesis in cancers. Thereafter, various drugs targeting VEGF-mediated signals have been developed to control tumor angiogenesis. Thus, anti-angiogenic drugs are now recognized in the clinic as a major step forward for the treatment of cancers. This review focuses on the current status of antiangiogenesis treatment in cancers.

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

    Science.gov (United States)

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

    2013-10-30

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

  5. Drug use in the management of uncomplicated malaria in public health facilities in the Democratic Republic of the Congo.

    Science.gov (United States)

    Ntamabyaliro, Nsengi Y; Burri, Christian; Nzolo, Didier B; Engo, Aline B; Lula, Yves N; Mampunza, Samuel M; Nsibu, Célestin N; Mesia, Gauthier K; Kayembe, Jean-Marie N; Likwela, Joris L; Kintaudi, Leon M; Tona, Gaston L

    2018-05-03

    Malaria the first causes of death from parasitic infection worldwide. Interventions to reduce the burden of malaria have produced a tremendous drop in malaria morbidity and mortality. However, progress is slower in DRC, which shares with Nigeria 39% of deaths related to malaria globally. Inappropriate use of drugs may be one of the factors of this below-average performance. The aim of this study was to describe the use of drugs in the management of uncomplicated malaria in public health facilities in DRC. A drug use study was carried out in DRC from January to March 2014. In each of the former 11 provinces of DRC, one Rural Health Centre, one Urban Health Centre and one General Hospital were selected. In each of them, 100 patient's files containing prescription of anti-malarials from January to December 2013 were randomly selected. Among them, all of the files with diagnosis of uncomplicated malaria were included in this study. Prescribed anti-malarials, co-prescribed drugs and their indications were collected. Descriptive analyses were performed. A total of 2300 files out of 3300 (69.7%) concerned uncomplicated malaria and were included in analysis. Malaria treatment was initiated after a positive RDT or microscopy in 51.5% of cases, upon suspicion without requesting biological confirmation in 37% and despite negative results in 11%. Twenty-nine (29) different treatment regimens were used. The drugs recommended by the National Malaria Control Programme were used in 54.3% of cases (artesunate-amodiaquine 37.4% or artemether-lumefantrine 16.9%). The second most used anti-malarial was quinine (32.4%). Apart from anti-malarials, an average of 3.1 drugs per patient were prescribed, among which antibiotics (67.9%), analgesics and non-steroidal anti-inflammatory (NSAIDs) (all abbreviations to be explicated on first use) (70.6%), vitamins (29.1%), anaemia drugs, including blood transfusion (9.1%) and corticosteroids (5.7%), In 51.4% of cases there was no indication for

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

    Directory of Open Access Journals (Sweden)

    Barnes Karen I

    2010-12-01

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

  7. 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

  8. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  9. Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection

    NARCIS (Netherlands)

    Nuralitha, Suci; Siregar, Josephine E; Syafruddin, Din; Hoepelman, Andy I M; Marzuki, Sangkot

    2017-01-01

    BACKGROUND: To study within-host selection of resistant parasites, an important factor in the development of resistance to anti-malarial drugs, a mouse model of repeated interrupted malaria treatment (RIT) has been developed. The characteristics of within host selection of resistance to atovaquone

  10. [New concepts in hyperactive malarial splenomegaly].

    Science.gov (United States)

    Moraes, M F; Soares, M; Arroz, M J; Do Rosário, V E; Da Graça, J Pimenta; Abecasis, P

    2003-01-01

    Hyperreactive malarial splenomegaly is thought to represent an immunological dysfunction due to recurrent episodes of malaria. The authors present a case of hyperreactive malarial splenomegaly in a patient from São Tomé e Príncipe and discuss aspects of its differential diagnosis and treatment. A revision is made of recent concepts related to its pathogenesis and relationship with lymphoproliferative disorders. Malarial DNA was found in the absence of parasite forms in the peripheral blood. This may indicate that latent infection plays a role in its pathogenesis.

  11. Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis.

    Science.gov (United States)

    Jain, Vitul; Yogavel, Manickam; Oshima, Yoshiteru; Kikuchi, Haruhisa; Touquet, Bastien; Hakimi, Mohamed-Ali; Sharma, Amit

    2015-05-05

    The Chinese herb Dichroa febrifuga has traditionally treated malaria-associated fever. Its active component febrifugine (FF) and derivatives such as halofuginone (HF) are potent anti-malarials. Here, we show that FF-based derivatives arrest parasite growth by direct interaction with and inhibition of the protein translation enzyme prolyl-tRNA synthetase (PRS). Dual administration of inhibitors that target different tRNA synthetases suggests high utility of these drug targets. We reveal the ternary complex structure of PRS-HF and adenosine 5'-(β,γ-imido)triphosphate where the latter facilitates HF integration into the PRS active site. Structural analyses also highlight spaces within the PRS architecture for HF derivatization of its quinazolinone, but not piperidine, moiety. We also show a remarkable ability of HF to kill the related human parasite Toxoplasma gondii, suggesting wider HF efficacy against parasitic PRSs. Hence, our cell-, enzyme-, and structure-based data on FF-based inhibitors strengthen the case for their inclusion in anti-malarial and anti-toxoplasmosis drug development efforts. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Understanding drugs in breast cancer through drug sensitivity screening.

    Science.gov (United States)

    Uhr, Katharina; Prager-van der Smissen, Wendy J C; Heine, Anouk A J; Ozturk, Bahar; Smid, Marcel; Göhlmann, Hinrich W H; Jager, Agnes; Foekens, John A; Martens, John W M

    2015-01-01

    With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

  13. Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.

    Science.gov (United States)

    Shibata, Shoyo; Matsushita, Maiko; Saito, Yoshimasa; Suzuki, Takeshi

    2017-01-01

    The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

  14. Screening the Drug Sensitivity Genes Related to GEM and CDDP in the Lung Cancer Cell-lines

    Directory of Open Access Journals (Sweden)

    Chunyu YANG

    2009-10-01

    Full Text Available Background and objective Screening of small-cell lung cancer (SCLC and non-small cell lung cancer (NSCLC cell lines with gemcitabine hydrochloride (GEM and cisplatin (CDDP related to drug sensitivity gene might clarify the action mechanism of anti-cancer drugs and provide a new clue for overcoming drug resistance and the development of new anti-cancer drugs, and also provide theoretical basis for the clinical treatment of individual. Methods The drug sensitivity of CDDP and GEM in 4 SCLC cell lines and 6 NSCLC cell lines was determined using MTT colorimetric assay, while the cDNA macroarray was applied to detect the gene expression state related to drug sensitivity of 10 lung cancer cell line in 1 291, and the correlation between the two was analysized. Results There were 6 genes showing significant positive correlation (r≥0.632, P < 0.05 with GEM sensitivity; 45 genes positively related to CDDP; another 41 genes related to both GEM and CDDP (r≥± 0.4. Lung cancer with GEM and CDDP sensitivity of two types of drugs significantly related genes were Metallothinein (Signal transduction molecules, Cathepsin B (Organization protease B and TIMP1 (Growth factor; the GEM, CDDP sensitivity associated genes of lung cancer cell lines mainly distributed in Metallothinein, Cathepsin B, growth factor TIMP1 categories. Conclusion There existed drug-related sensitive genes of GEM, CDDP in SCLC and NSCLC cell lines; of these genes, Metallothinein, Cathepsin B and TIMP1 genes presented a significant positive correlation with GEM drug sensitivity, a significant negative correlation with CDDP drug sensitivity.

  15. Automated detection of retinal whitening in malarial retinopathy

    Science.gov (United States)

    Joshi, V.; Agurto, C.; Barriga, S.; Nemeth, S.; Soliz, P.; MacCormick, I.; Taylor, T.; Lewallen, S.; Harding, S.

    2016-03-01

    Cerebral malaria (CM) is a severe neurological complication associated with malarial infection. Malaria affects approximately 200 million people worldwide, and claims 600,000 lives annually, 75% of whom are African children under five years of age. Because most of these mortalities are caused by the high incidence of CM misdiagnosis, there is a need for an accurate diagnostic to confirm the presence of CM. The retinal lesions associated with malarial retinopathy (MR) such as retinal whitening, vessel discoloration, and hemorrhages, are highly specific to CM, and their detection can improve the accuracy of CM diagnosis. This paper will focus on development of an automated method for the detection of retinal whitening which is a unique sign of MR that manifests due to retinal ischemia resulting from CM. We propose to detect the whitening region in retinal color images based on multiple color and textural features. First, we preprocess the image using color and textural features of the CMYK and CIE-XYZ color spaces to minimize camera reflex. Next, we utilize color features of the HSL, CMYK, and CIE-XYZ channels, along with the structural features of difference of Gaussians. A watershed segmentation algorithm is used to assign each image region a probability of being inside the whitening, based on extracted features. The algorithm was applied to a dataset of 54 images (40 with whitening and 14 controls) that resulted in an image-based (binary) classification with an AUC of 0.80. This provides 88% sensitivity at a specificity of 65%. For a clinical application that requires a high specificity setting, the algorithm can be tuned to a specificity of 89% at a sensitivity of 82%. This is the first published method for retinal whitening detection and combining it with the detection methods for vessel discoloration and hemorrhages can further improve the detection accuracy for malarial retinopathy.

  16. Changes in mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs.

    Science.gov (United States)

    Acosta, M Carmen; Berenguer-Ruiz, Leticia; García-Gálvez, Alberto; Perea-Tortosa, David; Gallar, Juana; Belmonte, Carlos

    2005-01-01

    In addition to their well-known anti-inflammatory actions, some of the nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have an analgesic effect. In human subjects, the changes in threshold and intensity of sensations evoked by mechanical, chemical, and thermal stimulation of the cornea induced by topical administration of two commercial NSAIDs, diclofenac sodium (Voltaren; Novartis, Basel, Switzerland) and flurbiprofen (Ocuflur; Allergan, Irvine, CA), were studied. Corneal sensitivity was measured in 10 young, healthy subjects with a gas esthesiometer. Chemical (10%-70% CO2 in air), mechanical (0-264 mL/min), and thermal (corneal temperature changes between -4.5 degrees C and +3 degrees C around the normal value) stimuli were applied to the center of the cornea. The intensity and perceived magnitude of the psychophysical attributes of the evoked sensation were scored at the end of the pulse in a 10-cm, continuous visual analog scale (VAS). The threshold was expressed as the stimulus intensity that evoked a VAS score >0.5. Sensitivity was measured in both eyes of each subject on two separate days, one without treatment and the other 30 minutes after topical application of 0.03% flurbiprofen (seven subjects) or 0.1% diclofenac sodium (six subjects). Diclofenac attenuated significantly all the sensation parameters evoked by high-intensity mechanical, chemical, and thermal stimuli. Flurbiprofen produced a slight reduction of the sensations evoked by mechanical and chemical stimulation that became significant only for the irritation caused by chemical stimuli of maximum intensity (70% CO2). None of the drugs modified significantly the detection threshold of the different stimuli. Flurbiprofen had a very limited effect on sensations evoked by corneal stimulation, whereas diclofenac reduced the intensity of sensations evoked by stimuli of different modality, suggesting a mild local anesthetic effect of this drug on all types of corneal sensory fibers. Such

  17. [Advances of tumor targeting peptides drug delivery system with pH-sensitive activities].

    Science.gov (United States)

    Ma, Yin-yun; Li, Li; Huang, Hai-feng; Gou, San-hu; Ni, Jing-man

    2016-05-01

    The pH-sensitive peptides drug delivery systems, which target to acidic extracellular environment of tumor tissue, have many advantages in drug delivery. They exhibit a high specificity to tumor and low cytotoxicity, which significantly increase the efficacy of traditional anti-cancer drugs. In recent years the systems have received a great attention. The pH-sensitive peptides drug delivery systems can be divided into five types according to the difference in pH-responsive mechanism,type of peptides and carrier materials. This paper summarizes the recent progresses in the field with a focus on the five types of pH-sensitive peptides in drug delivery systems. This may provide a guideline to design and application of tumor targeting drugs.

  18. IN-VITRO EVALUATION OF ANTI-TRICHOMONAL ACTIVITIES OF ...

    African Journals Online (AJOL)

    infective, has shown anti-malarial and antitrypanocidal activities. Therefore using bioactivity guided fractionation, anti-trichomonal activity of E. uniflora leaf was investigated. Anti-trichomonal activities of leaf methanol extract and its fractions against ...

  19. Factors contributing to the development of anaemia in Plasmodium falciparum malaria: what about drug-resistant parasites?

    DEFF Research Database (Denmark)

    Quashie, Neils Ben; Akanmori, Bartholomew D; Ofori-Adjei, David

    2006-01-01

    implicated in its pathogenesis. Since resolution of malaria restores erythropoiesis, we hypothesized that drug-resistant strains of Plasmodium falciparum would increase the risk of severe anaemia developing from initially uncomplicated malaria. Using both in vivo and in vitro drug-sensitivity tests we...... compared the prevalence of drug-resistant malaria between severe malarial anaemia SA and non-anaemic malaria NAM patients. Assessment of treatment outcome using the WHO in vivo criteria showed no significant difference in parasite resistance between the two groups. The mean parasite clearance time was also......-treatment blood levels of chloroquine did not differ much between the two groups. Findings from this study could not therefore implicate drug-resistant parasites in the pathogenesis of severe malarial anaemia....

  20. The challenge to avoid anti-malarial medicine stock-outs in an era of funding partners: the case of Tanzania.

    Science.gov (United States)

    Mikkelsen-Lopez, Inez; Shango, Winna; Barrington, Jim; Ziegler, Rene; Smith, Tom; deSavigny, Don

    2014-05-11

    Between 2007 and 2013, the Tanzanian public sector received 93.1 million doses of first-line anti-malarial artemisinin-based combination therapy (ACT) in the form of artemether-lumefantrine entirely supplied by funding partners. The introduction of a health facility ACT stock monitoring system using SMS technology by the National Malaria Control Programme in mid 2011 revealed a high frequency of stock-outs of ACT in primary care public health facilities. The objective of this study was to determine the pattern of availability of ACT and possible causes of observed stock-outs across public health facilities in Tanzania since mid-2011. Data were collected weekly by the mobile phone reporting tool SMS for Life on ACT availability from over 5,000 public health facilities in Tanzania starting from September 2011 to December 2012. Stock data for all four age-dose levels of ACT across health facilities were summarized and supply of ACT at the national level was also documented. Over the period of 15 months, on average 29% of health facilities in Tanzania were completely stocked out of all four-age dose levels of the first-line anti-malarial with a median duration of total stock-out of six weeks. Patterns of total stock-out by region ranged from a low of 9% to a high of 52%. The ACT stock-outs were most likely caused by: a) insufficient ACT supplies entering Tanzania (e.g. in 2012 Tanzania received 10.9 million ACT doses compared with a forecast demand of 14.4 million doses); and b) irregular pattern of ACT supply (several months with no ACT stock). The reduced ACT availability and irregular pattern of supply were due to cumbersome bureaucratic processes and delays both within the country and from the main donor, the Global Fund to Fight AIDS, Tuberculosis and Malaria. Tanzania should invest in strengthening both the supply system and the health information system using mHealth solutions such as SMS for Life. This will continue to assist in tracking ACT availability across

  1. Anti-VEGF drugs: evidence for effectiveness

    OpenAIRE

    Evans, Jennifer; Virgili, Gianni

    2014-01-01

    Anti-vascular endothelial growth factors (anti-VEGF) are targeted biological drugs (e.g. monoclonal antibodies) that prevent the growth of new vessels by inhibiting VEGF. VEGF is a cytokine (cell-signalling protein) that promotes the growth of, and leakage from, new vessels. Currently there are three anti-VEGF drugs licensed for use in eye disease: pegaptanib, aflibercept, ranibizumab and one that is not licensed but is commonly used off-label (bevacizumab).

  2. Acute allergic reaction to oral quinine for malarial prevention: A case report

    Directory of Open Access Journals (Sweden)

    Sora Yasri

    2016-01-01

    Full Text Available Quinine is a classical antimalarial drug that is used worldwide. It is also used for pre-exposure of malaria before visiting to the jungle in the endemic area of malaria. In this article, the authors reported a case of acute allergic reaction to oral quinine for malarial prevention.

  3. Aluminium per se and in the anti-acid drug sucralfate promotes sensitization via the oral route.

    Science.gov (United States)

    Brunner, R; Wallmann, J; Szalai, K; Karagiannis, P; Altmeppen, H; Riemer, A B; Jensen-Jarolim, E; Pali-Schöll, I

    2009-06-01

    Aluminium (ALUM) is used as experimental and clinical adjuvant for parenteral vaccine formulation. It is also contained in anti-acid drugs like sucralfate (SUC). These anti-acids have been shown to cause sensitization to food proteins via elevation of the gastric pH. The aim of this study was to assess the oral adjuvant properties of ALUM, alone or contained in SUC, in a BALB/c mouse model. Mice were fed SUC plus ovalbumin (OVA) and compared with groups where ALUM or proton pump inhibitors (PPI) were applied as adjuvants. The humoral and cellular immune responses were assessed on antigen-specific antibody and cytokine levels. The in vivo relevance was investigated in skin tests. The highest OVA-specific immunoglobulin G1 (IgG1) and IgE antibody levels were found in mice fed with OVA/SUC, followed by OVA/ALUM-treated animals, indicating a T helper 2 (Th2) shift in both groups. Antibody levels in other groups revealed lower (OVA/PPI-group) or baseline levels (control groups). Positive skin tests confirmed an allergic response in anti-acid or adjuvant-treated animals. Our data show for the first time that ALUM acts as a Th2-adjuvant via the oral route. This suggests that orally applied SUC leads to an enhanced risk for food allergy, not only by inhibiting peptic digestion but also by acting as a Th2-adjuvant by its ALUM content.

  4. Vessel discoloration detection in malarial retinopathy

    Science.gov (United States)

    Agurto, C.; Nemeth, S.; Barriga, S.; Soliz, P.; MacCormick, I.; Taylor, T.; Harding, S.; Lewallen, S.; Joshi, V.

    2016-03-01

    Cerebral malaria (CM) is a life-threatening clinical syndrome associated with malarial infection. It affects approximately 200 million people, mostly sub-Saharan African children under five years of age. Malarial retinopathy (MR) is a condition in which lesions such as whitening and vessel discoloration that are highly specific to CM appear in the retina. Other unrelated diseases can present with symptoms similar to CM, therefore the exact nature of the clinical symptoms must be ascertained in order to avoid misdiagnosis, which can lead to inappropriate treatment and, potentially, death. In this paper we outline the first system to detect the presence of discolored vessels associated with MR as a means to improve the CM diagnosis. We modified and improved our previous vessel segmentation algorithm by incorporating the `a' channel of the CIELab color space and noise reduction. We then divided the segmented vasculature into vessel segments and extracted features at the wall and in the centerline of the segment. Finally, we used a regression classifier to sort the segments into discolored and not-discolored vessel classes. By counting the abnormal vessel segments in each image, we were able to divide the analyzed images into two groups: normal and presence of vessel discoloration due to MR. We achieved an accuracy of 85% with sensitivity of 94% and specificity of 67%. In clinical practice, this algorithm would be combined with other MR retinal pathology detection algorithms. Therefore, a high specificity can be achieved. By choosing a different operating point in the ROC curve, our system achieved sensitivity of 67% with specificity of 100%.

  5. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors

    International Nuclear Information System (INIS)

    Pugach, Pavel; Ketas, Thomas J.; Michael, Elizabeth; Moore, John P.

    2008-01-01

    The small molecule CCR5 inhibitors are a new class of drugs for treating infection by human immunodeficiency virus type 1 (HIV-1). They act by binding to the CCR5 co-receptor and preventing its use during HIV-1-cell fusion. Escape mutants can be raised against CCR5 inhibitors in vitro and will arise when these drugs are used clinically. Here, we have assessed the responses of CCR5 inhibitor-resistant viruses to other anti-retroviral drugs that act by different mechanisms, and their sensitivities to neutralizing antibodies (NAbs). The rationale for the latter study is that the resistance pathway for CCR5 inhibitors involves changes in the HIV-1 envelope glycoproteins (Env), which are also targets for NAbs. The escape mutants CC101.19 and D1/85.16 were selected for resistance to AD101 and vicriviroc (VVC), respectively, from the primary R5 HIV-1 isolate CC1/85. Each escape mutant was cross-resistant to other small molecule CCR5 inhibitors (aplaviroc, maraviroc, VVC, AD101 and CMPD 167), but sensitive to protein ligands of CCR5: the modified chemokine PSC-RANTES and the humanized MAb PRO-140. The resistant viruses also retained wild-type sensitivity to the nucleoside reverse transcriptase inhibitor (RTI) zidovudine, the non-nucleoside RTI nevirapine, the protease inhibitor atazanavir and other attachment and fusion inhibitors that act independently of CCR5 (BMS-806, PRO-542 and enfuvirtide). Of note is that the escape mutants were more sensitive than the parental CC1/85 isolate to a subset of neutralizing monoclonal antibodies and to some sera from HIV-1-infected people, implying that sequence changes in Env that confer resistance to CCR5 inhibitors can increase the accessibility of some NAb epitopes. The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo

  6. Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.

    Directory of Open Access Journals (Sweden)

    Caline G Matar

    2015-05-01

    Full Text Available Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68 infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission.

  7. An ensemble based top performing approach for NCI-DREAM drug sensitivity prediction challenge.

    Directory of Open Access Journals (Sweden)

    Qian Wan

    Full Text Available We consider the problem of predicting sensitivity of cancer cell lines to new drugs based on supervised learning on genomic profiles. The genetic and epigenetic characterization of a cell line provides observations on various aspects of regulation including DNA copy number variations, gene expression, DNA methylation and protein abundance. To extract relevant information from the various data types, we applied a random forest based approach to generate sensitivity predictions from each type of data and combined the predictions in a linear regression model to generate the final drug sensitivity prediction. Our approach when applied to the NCI-DREAM drug sensitivity prediction challenge was a top performer among 47 teams and produced high accuracy predictions. Our results show that the incorporation of multiple genomic characterizations lowered the mean and variance of the estimated bootstrap prediction error. We also applied our approach to the Cancer Cell Line Encyclopedia database for sensitivity prediction and the ability to extract the top targets of an anti-cancer drug. The results illustrate the effectiveness of our approach in predicting drug sensitivity from heterogeneous genomic datasets.

  8. Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

    Directory of Open Access Journals (Sweden)

    Marcel Kaiser

    2013-09-01

    Full Text Available Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2 to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC50 3.1 μM and Plasmodium falciparum (K1 dual drug resistant strain (IC50 3.3 μM while exhibiting low levels of cytotoxicity (L6, IC50 167 μM. A series of C-7 amide and Δ2(3 analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC50 0.62–6.5 μM, and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ2(3-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively, while Δ2(3-phenethylamide 8e (IC50 0.67 μM, SI 78 exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC50 0.34–0.035 μM combined with excellent selectivity (SI 560–4000. In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively.

  9. Use of anti-obesity drugs among college students.

    Science.gov (United States)

    Martins, Maria do Carmo de Carvalho e; Souza Filho, Manoel Dias de; Moura, Felipe Scipião; Carvalho, Juliana de Sousa Ribeiro de; Müller, Marina Costa; Neves, Rebeka Valença; Mousinho, Patrícia Coelho; Lima, Iúri Paz

    2011-01-01

    To evaluate the use of anti-obesity drugs among students attending a public university. This was a cross sectional random study of 664 college students. Drug use, socioeconomic, and anthropometric variables were observed. Body mass index (BMI) and waist circumference (WC) were classified according to World Health Organization criteria. Current or previous use of anti-obesity drugs was reported by 6.8% of students. Amphetamine and sympathomimetic amines (40.5%) were the most commonly used drugs. Among those who reported use of anti-obesity agents, 62.2% were female. Only 31.1% of medications were prescribed by doctors. Mean BMI and WC were higher among students reporting the use of such drugs, but 47% of them were classified as eutrophic by BMI, and 76.5% had normal WC measure. The use of anti-obesity drugs among college students is of concern, particularly due to the high proportion of drug use without indication or prescription.

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

    Directory of Open Access Journals (Sweden)

    Brasseur Philippe

    2012-12-01

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

  11. Context Sensitive Modeling of Cancer Drug Sensitivity.

    Directory of Open Access Journals (Sweden)

    Bo-Juen Chen

    Full Text Available Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression, an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should-and should not-be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features.

  12. Factors determining sensitivity or resistance of tumor cell lines towards artesunate.

    Science.gov (United States)

    Sertel, Serkan; Eichhorn, Tolga; Sieber, Sebastian; Sauer, Alexandra; Weiss, Johanna; Plinkert, Peter K; Efferth, Thomas

    2010-04-15

    Clinical oncology is still challenged by the development of drug resistance of tumors that result in poor prognosis for patients. There is an urgent necessity to understand the molecular mechanisms of resistance and to develop novel therapy strategies. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We first applied a gene-hunting approach using cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles. Among the genes identified by this approach were genes from diverse functional groups such as structural constituents of ribosomes (RPL6, RPL7, RPS12, RPS15A), kinases (CABC1, CCT2, RPL41), transcriptional and translational regulators (SFRS2, TUFM, ZBTB4), signal transducers (FLNA), control of cell growth and proliferation (RPS6), angiogenesis promoting factors (ITGB1), and others (SLC25A19, NCKAP1, BST1, DBH, FZD7, NACA, MTHFD2). Furthermore, we applied a candidate gene approach and tested the role of resistance mechanisms towards established anti-cancer drugs for ART resistance. By using transfected or knockout cell models we found that the tumor suppressor p16(INK4A) and the anti-oxidant protein, catalase, conferred resistance towards ART, while the oncogene HPV-E6 conferred sensitivity towards ART. The tumor suppressor p53 and its downstream protein, p21, as well as the anti-oxidant manganese-dependent superoxide dismutase did not affect cellular response to ART. In conclusion, our pharmacogenomic approach revealed that response of tumor cells towards ART is multi-factorial and is determined by gene expression associated with either ART sensitivity or resistance. At least some of the functional groups of genes (e.g. angiogenesis promoting factors, cell growth and proliferation-associated genes signal transducers and kinases) are also implicated in clinical responsiveness of tumors towards chemotherapy. It merits further investigation, whether ART is responsive in

  13. Biological anti-TNF drugs

    DEFF Research Database (Denmark)

    Prado, Mônica Simon; Bendtzen, Klaus; Andrade, Luis Eduardo Coelho

    2017-01-01

    practice shows a significant percentage of individuals who do not exhibit the desired response. Loss of therapeutic benefit after initial successful response is designated secondary failure. Immune-biological agents are not self-antigens and are therefore potentially immunogenic. Secondary failure...... is frequently caused by antibodies against immune-biologicals, known as anti-drug antibodies (ADA). ADA that neutralize circulating immune-biologicals and/or promote their clearance can reduce treatment efficacy. Furthermore, ADA can induce adverse events by diverse immunological mechanisms. This review...... provides a comprehensive overview of ADA in rheumatoid arthritis patients treated with anti-TNF immune-biologicals, and explores the concept of therapeutic drug monitoring (TDM) as an effective strategy to improve therapeutic management. Expert opinion: Monitoring circulating ADA and therapeutic immune-biological...

  14. Ingenious pH-sensitive dextran/mesoporous silica nanoparticles based drug delivery systems for controlled intracellular drug release.

    Science.gov (United States)

    Zhang, Min; Liu, Jia; Kuang, Ying; Li, Qilin; Zheng, Di-Wei; Song, Qiongfang; Chen, Hui; Chen, Xueqin; Xu, Yanglin; Li, Cao; Jiang, Bingbing

    2017-05-01

    In this work, dextran, a polysaccharide with excellent biocompatibility, is applied as the "gatekeeper" to fabricate the pH-sensitive dextran/mesoporous silica nanoparticles (MSNs) based drug delivery systems for controlled intracellular drug release. Dextran encapsulating on the surface of MSNs is oxidized by NaIO 4 to obtain three kinds of dextran dialdehydes (PADs), which are then coupled with MSNs via pH-sensitive hydrazone bond to fabricate three kinds of drug carriers. At pH 7.4, PADs block the pores to prevent premature release of anti-cancer drug doxorubicin hydrochloride (DOX). However, in the weakly acidic intracellular environment (pH∼5.5) the hydrazone can be ruptured; and the drug can be released from the carriers. The drug loading capacity, entrapment efficiency and release rates of the drug carriers can be adjusted by the amount of NaIO 4 applied in the oxidation reaction. And from which DOX@MSN-NH-N=C-PAD 10 is chosen as the most satisfactory one for the further in vitro cytotoxicity studies and cellular uptake studies. The results demonstrate that DOX@MSN-NH-N=C-PAD 10 with an excellent pH-sensitivity can enter HeLa cells to release DOX intracellular due to the weakly acidic pH intracellular and kill the cells. In our opinion, the ingenious pH-sensitive drug delivery systems have application potentials for cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Hyperreactive malarial splenomegaly in Venezuela.

    Science.gov (United States)

    Torres, J; Noya, O; Mondolfi, A; Peceño, C; Botto, C

    1988-07-01

    A cross-sectional seroepidemiological survey seeking hyperreactive malarial splenomegaly was carried out in isolated Yanomami hamlets in Amazonas Territory in Venezuela. All 110 inhabitants greater than 1 year of age were evaluated clinically and 98 were studied immunologically. The spleen index for individuals greater than 10 years of age was 44%. Only 3 patients had Plasmodium spp. on thick blood smears. All had serological evidence of infection with Plasmodium falciparum and P. vivax. Twenty-three patients were considered to show hyperreactive malarial splenomegaly. Clinical manifestations of the syndrome did not differ from those described in other parts of the world.

  16. Combined antiretroviral and anti- tuberculosis drug resistance ...

    African Journals Online (AJOL)

    these epidemics, many challenges remain.[3] Antiretroviral and anti-TB drug resistance pose considerable threats to the control of these epidemics.[4,5]. The breakdown in HIV/TB control within prisons is another emerging threat.[6,7] We describe one of the first reports of combined antiretroviral and anti-TB drug resistance ...

  17. Thyroid hormone synthesis and anti-thyroid drugs

    Indian Academy of Sciences (India)

    The inhibition of thyroid hormone synthesis is required for the treatment of hyperthyroidism and this can be achieved by one or more anti-thyroid drugs. The most widely used anti-thyroid drug methimazole (MMI) inhibits the production of thyroid hormones by irreversibly inactivating the enzyme TPO. Our studies show that the ...

  18. Synthesis of nir-sensitive Au-Au{sub 2}S nanocolloids for drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Ren, L.; Chow, G.M

    2003-01-15

    Near IR (NIR) sensitive Au-Au{sub 2}S nanocolloids were prepared by mixing HAuCl{sub 4} and Na{sub 2}S in aqueous solutions. An anti-tumor drug, cis-platin, was adsorbed onto Au-Au{sub 2}S nanoparticle surface via the 11-mercaptoundecanoic acid (MUA) layers. The results show that the degree of adsorption of cis-platin onto Au-Au{sub 2}S nanoparticles was controlled by the solution pH value, and the drug release was sensitive to near-infrared irradiation. The cis-platin-loaded Au-Au{sub 2}S nanocolloids can be potentially applied as NIR activated drug delivery carrier.

  19. Direct anti-atherosclerotic therapy; development of natural anti-atherosclerotic drugs preventing cellular cholesterol retention.

    Science.gov (United States)

    Orekhov, Alexander N

    2013-01-01

    The results of numerous clinical trials with statins and other drugs have demonstrated the principal possibility of the prevention and regression of atherosclerosis by pharmacotherapy. This review describes the use of cultured human arterial cells for the mass screening of anti-atherosclerotic substances, the investigation of the mechanisms responsible for their atherosclerosis-related effects, and the optimization of anti-atherosclerotic and anti-atherogenic drug and dietary therapies. Natural products can be considered promising drugs for anti-atherosclerotic therapy. Our basic studies have shown that cellular lipidosis is the principal event in the genesis of atherosclerotic lesions. Using cellular models and natural products, we have developed an approach to prevent lipid accumulation in arterial cells. Based on our knowledge of atherosclerosis, we developed drugs that possess direct anti-atherosclerotic activity. Two-year treatment with allicor (garlic powder) has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Inflaminat (calendula, elder, and violet), which possesses anti-cytokine activity, has been shown to cause the regression of carotid atherosclerosis following the treatment of asymptomatic men for one year. The phytoestrogen-rich drug karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid) prevents the development of carotid atherosclerosis in postmenopausal women. Thus, our basic findings were successfully translated into clinical practice. Because of this translation, a novel approach to antiatherosclerotic therapy was developed. Our clinical trial confirmed the efficacy of both the novel approach and the novel drugs.

  20. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.

    Science.gov (United States)

    Baker, David A; Stewart, Lindsay B; Large, Jonathan M; Bowyer, Paul W; Ansell, Keith H; Jiménez-Díaz, María B; El Bakkouri, Majida; Birchall, Kristian; Dechering, Koen J; Bouloc, Nathalie S; Coombs, Peter J; Whalley, David; Harding, Denise J; Smiljanic-Hurley, Ela; Wheldon, Mary C; Walker, Eloise M; Dessens, Johannes T; Lafuente, María José; Sanz, Laura M; Gamo, Francisco-Javier; Ferrer, Santiago B; Hui, Raymond; Bousema, Teun; Angulo-Barturén, Iñigo; Merritt, Andy T; Croft, Simon L; Gutteridge, Winston E; Kettleborough, Catherine A; Osborne, Simon A

    2017-09-05

    To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC 50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC 50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.

  1. Anti-plasmodial and anti-inflammatory activities of cyclotide-rich ...

    African Journals Online (AJOL)

    2017-09-03

    Sep 3, 2017 ... orthodox anti-malarial treatments, and in search of relief, people living in ... the world today are still derived from natural sources.5. An important role in ..... each assay plate. Effect of CRF on LPS-evoked tumor necrosis factor ..... to contribute to the inflammatory cascade by increasing vascular permeability.

  2. Pharmacognosical evaluation of the bioactive principles of ganiothalmus scortechinii as potential new anti-plasmodials

    Energy Technology Data Exchange (ETDEWEB)

    Siti Najila, M J [Malaysian Inst. for Nuclear Technology Research MINT, Bangi (Malaysia); Noor Rain, A; Teh Hamidah, Z; Rohaya, C; Zakiah, I [Institute of Medical research, Kuala Lumpur (Malaysia). Herbal Medicine Research Centre; Khozirah, S [Universiti Putra Malaysia, Serdang (Malaysia). Natural Product Research Centre

    2002-07-01

    A bioassay guided fractionation of Ganiothalamus scortechinii yielded compounds with promising anti-malarial activity. When subjected to the lactate dehydrogenase calanone, goniothalamine, goniothalenol and pinocembrine, the showed an improved schizonticidal activity with the chloroquine sensitive strain of Plasmodium falciparum, compared to the crude extract of G. scortechinii; whilst only goniothalamine and goniothalanol were active with the resistant strain (Gombak A). The cytotoxicity of each compound were then assessed with the MTT test using MDBK cells. Out of the four compounds only calanone exhibited a safe therapeutic margin, whilst the others are found to be toxic against the cells used. In the attempt to characterise its anti-malarial activity the beta haematin (BH) inhibitory activity of the compounds were determined using the Haematin Polymerisation Inhibitory Assay (HPIA) and the Beta Haematin Inhibitory Assay (BHIA). For each, a better inhibition was observed in the HPIA. However from the low inhibitory values obtained it can be concluded that the inhibition of BH formation is not how the compounds exert their antimalarial activity. (Author)

  3. Pharmacognosical evaluation of the bioactive principles of ganiothalmus scortechinii as potential new anti-plasmodials

    International Nuclear Information System (INIS)

    Siti Najila, M.J.; Noor Rain, A.; Teh Hamidah, Z.; Rohaya, C.; Zakiah, I.; Khozirah, S.

    2002-01-01

    A bioassay guided fractionation of Ganiothalamus scortechinii yielded compounds with promising anti-malarial activity. When subjected to the lactate dehydrogenase calanone, goniothalamine, goniothalenol and pinocembrine, the showed an improved schizonticidal activity with the chloroquine sensitive strain of Plasmodium falciparum, compared to the crude extract of G. scortechinii; whilst only goniothalamine and goniothalanol were active with the resistant strain (Gombak A). The cytotoxicity of each compound were then assessed with the MTT test using MDBK cells. Out of the four compounds only calanone exhibited a safe therapeutic margin, whilst the others are found to be toxic against the cells used. In the attempt to characterise its anti-malarial activity the beta haematin (BH) inhibitory activity of the compounds were determined using the Haematin Polymerisation Inhibitory Assay (HPIA) and the Beta Haematin Inhibitory Assay (BHIA). For each, a better inhibition was observed in the HPIA. However from the low inhibitory values obtained it can be concluded that the inhibition of BH formation is not how the compounds exert their antimalarial activity. (Author)

  4. miR-133b down-regulates ABCC1 and enhances the sensitivity of CRC to anti-tumor drugs.

    Science.gov (United States)

    Chen, Miao; Li, Daojiang; Gong, Ni; Wu, Hao; Su, Chen; Xie, Canbin; Xiang, Hong; Lin, Changwei; Li, Xiaorong

    2017-08-08

    Multidrug resistance (MDR) is the main cause of failed chemotherapy treatments. Therefore, preventing MDR is pivotal in treating colorectal cancer (CRC). In a previous study miR-133b was shown to be a tumor suppressor. Additionally, in CRC cells transfected with miR-133b, ATP-binding cassette (ABC) subfamily C member 1(ABCC1) was shown to be significantly down regulated. Whether miR-133b also enhances the chemosensitivity of drugs used to treat CRC by targeting ABCC1 is still unclear. Here, we utilized flow cytometry and high-performance liquid chromatography (HPLC) analysis to identify the ability of miR-133b to reserve MDR in CRC. We then used a dual-luciferase reporter assay to validate that miR-133b targets ABCC1. Further in vivo experiments were designed to validate the method in which miR-133b reversed MDR in CRC cells. The results demonstrated that the level of miR-133b was down-regulated and the expression of ABCC1 was up-regulated in drug-resistant CRC cells compared to non-drug-resistant CRC cells. The restoration of miR-133b expression in CRC drug-resistant cells in vitro resulted in reduced IC50s to chemotherapeutic drugs, significantly induced G1 accumulation, inhibited growth and promoted necrosis in combination with either 5-fluorouracil (5-FU) or vincristine (VCR), and decreased the expression of ABCC1. The dual-luciferase assay demonstrated that miR-133b directly targets ABCC1. The combination of agomiRNA-133b with chemotherapeutic drugs in vivo inhibited tumor growth induced by CRC drug-resistant cells. A xenograft from the in vivo model resulted in up-regulated levels of miR-133b and down-regulated levels of ABCC1. Therefore, miR-133b enhances the chemosensitivity of CRC cells to anti-tumor drugs by directly down-regulating ABCC1. This discovery provides a therapeutic strategy in which miR-133b is used as a potential sensitizer for drug-resistant CRC.

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

    Directory of Open Access Journals (Sweden)

    Ronn Anita

    2011-08-01

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

  6. Cynaropicrin: a comprehensive research review and therapeutic potential as an anti- hepatitis C virus agent

    Directory of Open Access Journals (Sweden)

    Mahmoud Fahmi Elsebai

    2016-12-01

    Full Text Available The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV. Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway. These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV.

  7. Melatonin effects on Plasmodium life cycle: new avenues for therapeutic approach.

    Science.gov (United States)

    Srinivasan, Venkataramanujam; Ahmad, Asma H; Mohamed, Mahaneem; Zakaria, Rahimah

    2012-05-01

    Malaria remains a global health problem affecting more than 515 million people all over the world including Malaysia. It is on the rise, even within unknown regions that previous to this were free of malaria. Although malaria eradication programs carried out by vector control programs are still effective, anti-malarial drugs are also used extensively for curtailing this disease. But resistance to the use of anti-malarial drugs is also increasing on a daily basis. With an increased understanding of mechanisms that cause growth, differentiation and development of malarial parasites in rodents and humans, new avenues of therapeutic approaches for controlling the growth, synchronization and development of malarial parasites are essential. Within this context, the recent discoveries related to IP3 interconnected signalling pathways, the release of Ca2+ from intracellular stores of Plasmodium, ubiquitin protease systems as a signalling pathway, and melatonin influencing the growth and differentiation of malarial parasites by its effects on these signalling pathways have opened new therapeutic avenues for arresting the growth and differentiation of malarial parasites. Indeed, the use of melatonin antagonist, luzindole, has inhibited the melatonin's effect on these signalling pathways and thereby has effectively reduced the growth and differentiation of malarial parasites. As Plasmodium has effective sensors which detect the nocturnal plasma melatonin concentrations, suppression of plasma melatonin levels with the use of bright light during the night or by anti-melatonergic drugs and by using anti-kinase drugs will help in eradicating malaria on a global level. A number of patients have been admitted with regards to the control and management of malarial growth. Patents related to the discovery of serpentine receptors on Plasmodium, essential for modulating intra parasitic melatonin levels, procedures for effective delivery of bright light to suppress plasma melatonin

  8. Successful drug desensitization in patients with delayed-type allergic reactions to anti-tuberculosis drugs

    Directory of Open Access Journals (Sweden)

    Krittaecho Siripassorn

    2018-03-01

    Full Text Available Objective: To evaluate the outcomes of anti-tuberculosis drug desensitization. Methods: This was a retrospective study. Inclusion criteria were as follows: age >18 years, documented tuberculosis infection, a previous cutaneous allergic reaction to anti-tuberculosis drugs, and having undergone drug desensitization between January 2003 and March 2014. The definition of allergic reaction to anti-tuberculosis drugs included (1 a temporal relationship between drug use and the allergic reaction; (2 improvement in the allergic reaction after drug withdrawal; (3 recurrence of the allergic reaction after reintroduction of only the offending drug; and (4 absence of other causes. Results: A total of 19 desensitization procedures were performed. The drugs used for these procedures were isoniazid (n = 7, rifampicin (n = 6, or ethambutol (n = 6. Of note, severe allergic reactions (Stevens–Johnson syndrome (n = 4, erythema multiforme (n = 3, and drug rash with eosinophilia and systemic syndrome (n = 1 were included. All patients underwent resolution of the previous allergic reactions before desensitization. The median duration of desensitization was 18 days. The success rate was 78.9%. The allergic reactions following failed desensitization were not severe; most were maculopapular rashes. Conclusions: The desensitization protocol for anti-tuberculosis drugs was associated with a high success rate, and the individuals who failed desensitization experienced mild allergic reactions. Keywords: Desensitization, Antituberculosis, Steven-Johnson syndrome, Allergic drug reaction, Tolerance induction, Drug allergy

  9. Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso

    Directory of Open Access Journals (Sweden)

    Diarra Amidou

    2012-03-01

    Full Text Available Abstract Background Patient immune status is thought to affect the efficacy of anti-malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. Methods Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml was obtained from each child to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. Results IgG levels to MSP3 were always higher in the successfully treated group than in the group with treatment failure. The same observation was made for GLURP but the reverse observation was noticed for MSP1-19. Cytophilic and non-cytophilic antibodies were significantly associated with protection against all three antigens, except for IgG4 to MSP1-19 and GLURP. Conclusion Acquired anti-malarial antibodies may play an important role in the efficacy of anti-malarial drugs in younger children more susceptible to the disease.

  10. Pharmacokinetics of Anti-Epileptic Drugs and their Clinical Significance

    Directory of Open Access Journals (Sweden)

    Svein I. Johannessen

    1990-01-01

    Full Text Available The serum concentration achieved and maintained following the administration of a fixed drug dosage is a direct consequence of the interactions of a wide variety of interrelated processes, including drug absorption, distribution, metabolism, and excretion, and the physiological status of the patient. These interrelationships are reviewed with specific reference to the major anti-epileptic drugs, phenobarbitone, phenytoin, sodium valproate, and carbamazepine, as well as a new first-line antiepileptic, oxcarbazepine. Both older drugs, such as phenobarbitone and phenytoin, and newer drugs, such as carbamazepine (CBZ and sodium valproate, have been studied extensively over the past years giving valuable information for drug treatment. An important feature of oxcarbazepine (OXC , which was developed through minimal changes in the structure of CBZ in order to improve on the tolerability of CBZ without sacrificing efficacy, is that its metabolites do not include the 11-epoxide which has been implicated in the side-effects of CBZ. In man, OXC is metabolized to a monohydroxy derivative which has independent anti-epileptic properties. OXC seems to lack several disadavantageous pharmacokinetic properties common to other major anti-epileptic drugs. OXC does not influence its own metabolism after repeated administration, in contrast to the auto-induction displayed by CBZ. The metabolism of OXC is not influenced by anti-epileptic co-medication and does not influence the kinetics of other anti-epileptic drugs – or if it does, then to a lesser extent than CBZ.

  11. Nature is the best source of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity.

    Science.gov (United States)

    Aswad, Miran; Rayan, Mahmoud; Abu-Lafi, Saleh; Falah, Mizied; Raiyn, Jamal; Abdallah, Ziyad; Rayan, Anwar

    2018-01-01

    The aim was to index natural products for less expensive preventive or curative anti-inflammatory therapeutic drugs. A set of 441 anti-inflammatory drugs representing the active domain and 2892 natural products representing the inactive domain was used to construct a predictive model for bioactivity-indexing purposes. The model for indexing the natural products for potential anti-inflammatory activity was constructed using the iterative stochastic elimination algorithm (ISE). ISE is capable of differentiating between active and inactive anti-inflammatory molecules. By applying the prediction model to a mix set of (active/inactive) substances, we managed to capture 38% of the anti-inflammatory drugs in the top 1% of the screened set of chemicals, yielding enrichment factor of 38. Ten natural products that scored highly as potential anti-inflammatory drug candidates are disclosed. Searching the PubMed revealed that only three molecules (Moupinamide, Capsaicin, and Hypaphorine) out of the ten were tested and reported as anti-inflammatory. The other seven phytochemicals await evaluation for their anti-inflammatory activity in wet lab. The proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.

  12. Anti-osteoporosis drug use

    DEFF Research Database (Denmark)

    Hoff, M.; Skurtveit, S.; Meyer, H. E.

    2018-01-01

    Summary: Use of anti-osteoporotic drugs (AODs) was examined in a Norwegian population 50–85 years. Among them with Fracture Risk Assessment Tool (FRAX) score for major osteoporotic fracture ≥ 20, 25% of the women and 17% of the men received AODs. The strongest predictors for AODs were high age in...

  13. Unusual anti-leukemia activity of nanoformulated naproxen and other non-steroidal anti-inflammatory drugs

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Raj [School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005 (India); Advanced Material Research Centre, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005 (India); Siril, Prem Felix, E-mail: prem@iitmandi.ac.in [School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005 (India); Advanced Material Research Centre, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005 (India); Javid, Farideh [School of Applied Science, University of Huddersfield, Queensgate, Huddersfield HD1 3DH (United Kingdom)

    2016-12-01

    The non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used pharmaceuticals worldwide. Interestingly, many of them have significant anticancer properties too. However, the poor water solubility of certain NSAIDs limits their application for cancer treatment. Nanosizing of such drugs can help to improve the solubility and this may result in enhanced anticancer activities too. Moreover, over dosages and the accompanying side effects of NSAIDs can be minimized by improving their solubility and bioavailability. Successful nanoformulation of three NSAIDs: ibuprofen (IBP), ketoprufen (KP) and naproxen (NAP) using a novel evaporation assisted solvent-antisolvent interaction (EASAI) method is reported here. Three water soluble and biocompatible polymers: polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC) were used to stabilize the drug nanoparticles. Particles having spherical morphology with average size below 30 nm were thoroughly characterized using dynamic light scattering and field emission scanning electron microscopy (FESEM) imaging. The nanoformulation resulted in ten to fifteen fold improvements in the solubility and significant enhancement in the in-vitro drug release profiles of the NSAIDs. Anticancer screening of the nanoformulated NSAIDs against five different cancer cell lines such as MCF-7 (Human breast cancer cell line), (Human pancreatic cancer cell line) MIA-PA-CA-2, (Human colon cancer cell line) HT-29, (Human leukemia cell line) Jurkat and (human ovarian carcinoma cell line) A2780 was performed. All the nanoformulated samples showed improved anticancer activity against the Leukemia cancer cell line, out of which NAP-PVP showed the highest anti-cancer activity. The anti-Leukemia activity of NAP-PVP was more than twice that of doxorubicin which is a standard anticancer drug. - Highlights: • Nanoparticles of three non-steroidal anti-inflammatory drugs were prepared. • Particle sizes were

  14. Unusual anti-leukemia activity of nanoformulated naproxen and other non-steroidal anti-inflammatory drugs

    International Nuclear Information System (INIS)

    Kumar, Raj; Siril, Prem Felix; Javid, Farideh

    2016-01-01

    The non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used pharmaceuticals worldwide. Interestingly, many of them have significant anticancer properties too. However, the poor water solubility of certain NSAIDs limits their application for cancer treatment. Nanosizing of such drugs can help to improve the solubility and this may result in enhanced anticancer activities too. Moreover, over dosages and the accompanying side effects of NSAIDs can be minimized by improving their solubility and bioavailability. Successful nanoformulation of three NSAIDs: ibuprofen (IBP), ketoprufen (KP) and naproxen (NAP) using a novel evaporation assisted solvent-antisolvent interaction (EASAI) method is reported here. Three water soluble and biocompatible polymers: polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC) were used to stabilize the drug nanoparticles. Particles having spherical morphology with average size below 30 nm were thoroughly characterized using dynamic light scattering and field emission scanning electron microscopy (FESEM) imaging. The nanoformulation resulted in ten to fifteen fold improvements in the solubility and significant enhancement in the in-vitro drug release profiles of the NSAIDs. Anticancer screening of the nanoformulated NSAIDs against five different cancer cell lines such as MCF-7 (Human breast cancer cell line), (Human pancreatic cancer cell line) MIA-PA-CA-2, (Human colon cancer cell line) HT-29, (Human leukemia cell line) Jurkat and (human ovarian carcinoma cell line) A2780 was performed. All the nanoformulated samples showed improved anticancer activity against the Leukemia cancer cell line, out of which NAP-PVP showed the highest anti-cancer activity. The anti-Leukemia activity of NAP-PVP was more than twice that of doxorubicin which is a standard anticancer drug. - Highlights: • Nanoparticles of three non-steroidal anti-inflammatory drugs were prepared. • Particle sizes were

  15. A biotin-drug extraction and acid dissociation (BEAD) procedure to eliminate matrix and drug interference in a protein complex anti-drug antibody (ADA) isotype specific assay.

    Science.gov (United States)

    Niu, Hongmei; Klem, Thomas; Yang, Jinsong; Qiu, Yongchang; Pan, Luying

    2017-07-01

    Monitoring anti-drug antibody (ADA) responses in patients receiving protein therapeutics treatment is an important safety assessment for regulatory agencies, drug manufacturers, clinicians and patients. Recombinant human IGF-1/IGFBP-3 (rhIGF-1/rhIGFBP-3) is a 1:1 formulation of naturally occurring protein complex. The individual IGF-1 and IGFBP-3 proteins have multiple binding partners in serum matrix with high binding affinity to each other, which presents challenges in ADA assay development. We have developed a biotin-drug extraction with acid dissociation (BEAD) procedure followed by an electrochemiluminescence (ECL) direct assay to overcome matrix and drug interference. The method utilizes two step acid dissociation and excess biotin-drug to extract total ADA, which are further captured by soluble biotin-drug and detected in an ECL semi-homogeneous direct assay format. The pre-treatment method effectively eliminates interference by serum matrix and free drug, and enhances assay sensitivity. The assays passed acceptance criteria for all validation parameters, and have been used for clinical sample Ab testing. This method principle exemplifies a new approach for anti-isotype ADA assays, and could be an effective strategy for neutralizing antibody (NAb), pharmacokinetic (PK) and biomarker analysis in need of overcoming interference factors. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Non-Steroidal Anti Inflammatory Drugs Usage In Orthopaedics And ...

    African Journals Online (AJOL)

    Background: Non steroidal anti-inflammatory drugs NSAIDs) are a group of heterogeneous compounds with nti inflammatory, analgesic and often times anti pyretic roperties. They are weak organic acids and are the most commonly used drugs in Orthopaedic/Trauma practice. hey provide mild to moderate pain relief.

  17. Automated detection of leakage in fluorescein angiography images with application to malarial retinopathy.

    Science.gov (United States)

    Zhao, Yitian; MacCormick, Ian J C; Parry, David G; Leach, Sophie; Beare, Nicholas A V; Harding, Simon P; Zheng, Yalin

    2015-06-01

    The detection and assessment of leakage in retinal fluorescein angiogram images is important for the management of a wide range of retinal diseases. We have developed a framework that can automatically detect three types of leakage (large focal, punctate focal, and vessel segment leakage) and validated it on images from patients with malarial retinopathy. This framework comprises three steps: vessel segmentation, saliency feature generation and leakage detection. We tested the effectiveness of this framework by applying it to images from 20 patients with large focal leak, 10 patients with punctate focal leak, and 5,846 vessel segments from 10 patients with vessel leakage. The sensitivity in detecting large focal, punctate focal and vessel segment leakage are 95%, 82% and 81%, respectively, when compared to manual annotation by expert human observers. Our framework has the potential to become a powerful new tool for studying malarial retinopathy, and other conditions involving retinal leakage.

  18. Observation and Analysis of Anti-cancer Drug Use and Dose ...

    African Journals Online (AJOL)

    As all anti-cancer drugs are of narrow therapeutic window so dose individualization is required to be done. A study was conducted to check the use of anti-cancer drugs in the local anti-cancer facility of Bahawalpur i.e. Bahawalpur Institute of Nuclear Medicine and Oncology (BINO). In this study, the dose individualization ...

  19. Classifying new anti-tuberculosis drugs: rationale and future perspectives

    Directory of Open Access Journals (Sweden)

    Simon Tiberi

    2017-03-01

    Full Text Available The classification of anti-tuberculosis (TB drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR and extensively drug-resistant (XDR TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2–5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed.

  20. Relationships between maternal malaria and malarial immune responses in mothers and neonates

    DEFF Research Database (Denmark)

    Rasheed, F N; Bulmer, J N; De Francisco, A

    1995-01-01

    and schizonts (190L and 190N) were higher in neonates than mothers. There was no clear relationship between maternal malaria and neonatal mean lymphoproliferation to malarial antigens, although fewer neonates responded when mothers were actively infected. Matched maternal and neonatal lymphoproliferation...... responses did not correlate. However, first born neonatal lymphoproliferation to PPD and malarial antigens appeared lower than other neonates, in agreement with lower lymphoproliferation in primigravidae compared with multigravidae. Also in common with mothers, autologous plasma suppressed neonatal...... lymphoproliferation to PPD and malarial antigens, suggesting common immunoregulation. Higher cortisol or other circulating factors in first pregnancies may be implicated. The relevance of cell-mediated malarial immune responses detected at birth remains to be established....

  1. Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection

    OpenAIRE

    Nuralitha, Suci; Siregar, Josephine E; Syafruddin, Din; Hoepelman, Andy I M; Marzuki, Sangkot

    2017-01-01

    BACKGROUND: To study within-host selection of resistant parasites, an important factor in the development of resistance to anti-malarial drugs, a mouse model of repeated interrupted malaria treatment (RIT) has been developed. The characteristics of within host selection of resistance to atovaquone and pyrimethamine in Plasmodium yoelii was examined in such a model. METHODS: Treatment of P. yoelii infected mice, with atovaquone or pyrimethamine, was started at parasitaemia level of 3-5%, inter...

  2. Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

    Science.gov (United States)

    Zhu, Xiali; Xie, Yingxia; Zhang, Yingjie; Huang, Heqing; Huang, Shengnan; Hou, Lin; Zhang, Huijuan; Li, Zhi; Shi, Jinjin; Zhang, Zhenzhong

    2014-11-01

    This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  3. Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease

    NARCIS (Netherlands)

    Hoozemans, Jeroen J. M.; Veerhuis, Robert; Rozemuller, Annemieke J. M.; Eikelenboom, Piet

    2003-01-01

    Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD.

  4. The production and sales of anti-tuberculosis drugs in China.

    Science.gov (United States)

    Huang, Yang-Mu; Zhao, Qi-Peng; Ren, Qiao-Meng; Peng, Dan-Lu; Guo, Yan

    2016-10-04

    Tuberculosis (TB) is a major infectious disease globally. Adequate and proper use of anti-TB drugs is essential for TB control. This study aims to study China's production capacity and sales situation of anti-TB drugs, and to further discuss the potential for China to contribute to global TB control. The production data of anti-TB drugs in China from 2011 to 2013 and the sales data from 2010 to 2014 were extracted from Ministry of Industry and Information Technology database of China and IMS Health database, respectively. The number of drugs was standardized to the molecular level of the key components before calculating. All data were described and analyzed by Microsoft Excel. First-line drugs were the majority in both sales (89.5 %) and production (92.3 %) of anti-TB drugs in China. The production of rifampicin held the majority share in active pharmaceutical ingredients (APIs) and finished products, whilst ethambutol and pyrazinamide were the top two sales in finished products. Fixed-dose combinations only held small percentages in total production and sales weight, though a slight increase was observed. The production and sales of streptomycin showed a tendency of decrease after 2012. The trends and proportion of different anti-TB drugs were similar in production and sales, however, the production weight was much larger than that of sales, especially for rifampicin and isoniazid. First-line drugs were the predominant medicine produced and used in China. While the low production and sales of the second-line TB drugs and FDCs rose concerns for the treatment of multiple drug resistant TB. The redundant production amount, as well as the prompt influence of national policy on drug production and sales, indicated the potential for China to better contribute to global TB control.

  5. Sub-microscopic infections and long-term recrudescence of Plasmodium falciparum in Mozambican pregnant women

    Directory of Open Access Journals (Sweden)

    Mandomando Inacio

    2009-01-01

    Full Text Available Abstract Background Control of malaria in pregnancy remains a public health challenge. Improvements in its correct diagnosis and the adequacy of protocols to evaluate anti-malarial drug efficacy in pregnancy, are essential to achieve this goal. Methods The presence of Plasmodium falciparum was assessed by real-time (RT PCR in 284 blood samples from pregnant women with clinical complaints suggestive of malaria, attending the maternity clinic of a Mozambican rural hospital. Parasite recrudescences in 33 consecutive paired episodes during the same pregnancy were identified by msp1 and msp2 genotyping. Results Prevalence of parasitaemia by microscopy was 5.3% (15/284 and 23.2% (66/284 by RT-PCR. Sensitivity of microscopy, compared to RT-PCR detection, was 22.7%. Risk of maternal anaemia was higher in PCR-positive women than in PCR-negative women (odds ratio [OR] = 1.92, 95% confidence interval [CI] 1.09–3.36. Genotyping confirmed that recrudescence after malaria treatment occurred in 7 (21% out of 33 pregnant women with consecutive episodes during the same pregnancy (time range between recrudescent episodes: 14 to 187 days. Conclusion More accurate and sensitive diagnostic indicators of malaria infection in pregnancy are needed to improve malaria control. Longer follow-up periods than the standard in vivo drug efficacy protocol should be used to assess anti-malarial drug efficacy in pregnancy.

  6. Anti-Aging Drugs - Prospect of Longer Life?

    Science.gov (United States)

    Klimova, Blanka; Novotny, Michal; Kuca, Kamil

    2017-11-29

    Aging is a natural part of human life. However, recent discoveries indicate that pharmacological approaches used for the improvement and possibly, for the delay of the aging process, might shed a new light on this topic. This might obviously contribute to the extension of the active life of older people and maintenance of their quality of life, which could consequently reduce both social and economic burden of each country, especially the developed ones. The purpose of this study is to explore pharmacological discoveries which may help to the delay or improvement of the aging process. More specifically, the authors focus on three anti-aging drugs candidates: metformin, rapamycin and resveratrol and one anti-aging component NAD+ precursors whose randomized control trials on animals have appeared to provide some efficacy in this respect and they seem to be promising in the aging process of human beings. This was done by conducting a literature review of available sources describing the issue of aging process with special focus on those anti-aging drug candidates. The results of this study indicate that promising anti-aging candidates seem to be metformin, especially as far as cardiovascular or cancer mortality is concerned, and NAD+ precursors since they appear to promote better organ function, increased physical resistance, disease resistance and prolonged life expectancy. There is a call for more longitudinal clinical trials, which would prove the efficacy of the promising anti-aging drugs candidates in humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis.

    Science.gov (United States)

    Upadhyay, Seema; Khan, Iliyas; Gothwal, Avinash; Pachouri, Praveen K; Bhaskar, N; Gupta, Umesh D; Chauhan, Devendra S; Gupta, Umesh

    2017-09-01

    First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1 H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

  8. Non-steroidal anti-inflammatory drugs and benign oesophageal stricture.

    Science.gov (United States)

    Heller, S R; Fellows, I W; Ogilvie, A L; Atkinson, M

    1982-01-01

    Drug histories were obtained from 76 patients at the time of initial Eder-Puestow dilatation for benign oesophageal stricture. Six patients had consumed drugs known to cause oesophageal ulceration (emepronium bromide and potassium preparations). Of the remaining 70 patients, 22 had regularly taken a non-steroidal anti-inflammatory drug before the onset of dysphagia compared with 10 patients in a control group matched for age and sex; this difference was significant (p less than 0.02). Non-steroidal anti-inflammatory drugs may have a causative role in the formation of oesophageal stricture in patients with gastro-oesophageal reflux, in whom they should be prescribed with caution. PMID:6807392

  9. Anti-inflammatory drugs and psychosis

    NARCIS (Netherlands)

    Laan, W.

    2008-01-01

    This thesis focuses on the disorder we know as schizophrenia. Although there is treatment for schizophrenia in the form of anti-psychotic drugs, not all patients respond well to this treatment. A large part of patients will have remaining symptoms for the rest of their lives. A number of hypotheses

  10. [Non steroidal anti-inflammatory drugs and rheumatic diseases].

    Science.gov (United States)

    Cossermelli, W; Pastor, E H

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAID) comprise an important class of medicaments that reduced the symptoms of inflamation in rheumatic disease. This article emphasizes similarities and class characteristics of the NSAID, mechanisms of action, and drug-interactions.

  11. Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture

    Directory of Open Access Journals (Sweden)

    Tatsuya Usui

    2018-04-01

    Full Text Available Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61 decreases the cell viability of organoids compared with Notch (YO-01027, DAPT and Wnt (WAV939, Wnt-C59 signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer.

  12. Hemozoin (malarial pigment directly promotes apoptosis of erythroid precursors.

    Directory of Open Access Journals (Sweden)

    Abigail A Lamikanra

    2009-12-01

    Full Text Available Severe malarial anemia is the most common syndrome of severe malaria in endemic areas. The pathophysiology of chronic malaria is characterised by a striking degree of abnormal development of erythroid precursors (dyserythropoiesis and an inadequate erythropoietic response in spite of elevated levels of erythropoietin. The cause of dyserythropoiesis is unclear although it has been suggested that bone-marrow macrophages release cytokines, chemokines or lipo-peroxides after exposure to hemozoin, a crystalloid form of undigested heme moieties from malarial infected erythrocytes, and so inhibit erythropoiesis. However, we have previously shown that hemozoin may directly inhibit erythroid development in vitro and the levels of hemozoin in plasma from patients with malarial anemia and hemozoin within the bone marrow was associated with reduced reticulocyte response. We hypothesized that macrophages may reduce, not enhance, the inhibitory effect of hemozoin on erythropoiesis. In an in vitro model of erythropoiesis, we now show that inhibition of erythroid cell development by hemozoin isolated from P. falciparum is characterised by delayed expression of the erythroid markers and increased apoptosis of progenitor cells. Crucially, macrophages appear to protect erythroid cells from hemozoin, consistent with a direct contribution of hemozoin to the depression of reticulocyte output from the bone marrow in children with malarial anemia. Moreover, hemozoin isolated from P. falciparum in vitro inhibits erythroid development independently of inflammatory mediators by inducing apoptotic pathways that not only involve activation of caspase 8 and cleavage of caspase 3 but also loss of mitochondrial potential. Taken together these data are consistent with a direct effect of hemozoin in inducing apoptosis in developing erythroid cells in malarial anemia. Accumulation of hemozoin in the bone marrow could therefore result in inadequate reticulocytosis in children that

  13. Anti-obesity drugs: past, present and future

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    R. John Rodgers

    2012-09-01

    Full Text Available The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK, peptide YY (PYY and glucagon-like peptide-1 (GLP-1, and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent

  14. Emerging Technologies and Generic Assays for the Detection of Anti-Drug Antibodies

    Directory of Open Access Journals (Sweden)

    Michael A. Partridge

    2016-01-01

    Full Text Available Anti-drug antibodies induced by biologic therapeutics often impact drug pharmacokinetics, pharmacodynamics response, clinical efficacy, and patient safety. It is critical to assess the immunogenicity risk of potential biotherapeutics in producing neutralizing and nonneutralizing anti-drug antibodies, especially in clinical phases of drug development. Different assay methodologies have been used to detect all anti-drug antibodies, including ELISA, radioimmunoassay, surface plasmon resonance, and electrochemiluminescence-based technologies. The most commonly used method is a bridging assay, performed in an ELISA or on the Meso Scale Discovery platform. In this report, we aim to review the emerging new assay technologies that can complement or address challenges associated with the bridging assay format in screening and confirmation of ADAs. We also summarize generic anti-drug antibody assays that do not require drug-specific reagents for nonclinical studies. These generic assays significantly reduce assay development efforts and, therefore, shorten the assay readiness timeline.

  15. BDA-410: a novel synthetic calpain inhibitor active against blood stage malaria.

    Science.gov (United States)

    Li, Xuerong; Chen, Huiqing; Jeong, Jong-Jin; Chishti, Athar H

    2007-09-01

    Falcipains, the papain-family cysteine proteases of the Plasmodium falciparum, are potential drug targets for malaria parasite. Pharmacological inhibition of falcipains can block the hydrolysis of hemoglobin, parasite development, and egress, suggesting that falcipains play a key role at the blood stage of parasite life cycle. In the present study, we evaluated the anti-malarial effects of BDA-410, a novel cysteine protease inhibitor as a potential anti-malarial drug. Recombinant falcipain (MBP-FP-2B) and P. falciparum trophozoite extract containing native falcipains were used for enzyme inhibition studies in vitro. The effect of BDA-410 on the malaria parasite development in vitro as well as its anti-malarial activity in vivo was evaluated using the Plasmodium chabaudi infection rodent model. The 50% inhibitory concentrations of BDA-410 were determined to be 628 and 534nM for recombinant falcipain-2B and parasite extract, respectively. BDA-410 inhibited the malaria parasite growth in vitro with an IC(50) value of 173nM causing irreversible damage to the intracellular parasite. In vivo, the BDA-410 delayed the progression of malaria infection significantly using a mouse model of malaria pathogenesis. The characterization of BDA-410 as a potent inhibitor of P. falciparum cysteine proteases, and the demonstration of its efficacy in blocking parasite growth both in vitro and in vivo assays identifies BDA-410 is an important lead compound for the development of novel anti-malarial drugs.

  16. Various anti-motion sickness drugs and core body temperature changes.

    Science.gov (United States)

    Cheung, Bob; Nakashima, Ann M; Hofer, Kevin D

    2011-04-01

    Blood flow changes and inactivity associated with motion sickness appear to exacerbate the rate of core temperature decrease during subsequent body cooling. We investigated the effects of various classes of anti-motion sickness drugs on core temperature changes. There were 12 healthy male and female subjects (20-35 yr old) who were given selected classes of anti-motion sickness drugs prior to vestibular Coriolis cross coupling induced by graded yaw rotation and periodic pitch-forward head movements in the sagittal plane. All subjects were then immersed in water at 18 degrees C for a maximum of 90 min or until their core temperature reached 35 degrees C. Double-blind randomized trials were administered, including a placebo, a non-immersion control with no drug, and six anti-motion sickness drugs: meclizine, dimenhydrinate, chlorpheniramine, promethazine + dexamphetamine, promethazine + caffeine, and scopolamine + dexamphetamine. A 7-d washout period was observed between trials. Core temperature and the severity of sickness were monitored throughout each trial. A repeated measures design was performed on the severity of sickness and core temperature changes prior to motion provocation, immediately after the motion sickness end point, and throughout the period of cold-water immersion. The most effective anti-motion sickness drugs, promethazine + dexamphetamine (with a sickness score/duration of 0.65 +/- 0.17) and scopolamine + dexamphetamine (with a sickness score/duration of 0.79 +/- 0.17), significantly attenuated the decrease in core temperature. The effect of this attenuation was lower in less effective drugs. Our results suggest that the two most effective anti-motion sickness drugs are also the most effective in attenuating the rate of core temperature decrease.

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

    Directory of Open Access Journals (Sweden)

    Bley Daniel

    2009-07-01

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

  18. Factors influencing anti-asthmatic generic drug consumption in Morocco: 1999-2010.

    Science.gov (United States)

    Ghanname, Imane; Ahid, Samir; Berrada, Ghizlane; Belaiche, Abdelmjid; Hassar, Mohammed; Cherrah, Yahia

    2014-01-01

    The increasing availability of generic drugs (GD) resulted in a remarkable reduction in treatment costs that allowed a better access to health care.The aim of this study is to evaluate the share of anti-asthmatic generic drugs during the period 1999-2010 in Morocco and to look at the factors influencing generic development. In this study, we used Moroccan sales data from IMS Health (Intercontinental Marketing Services). The consumption of the drugs was expressed in DDD/1000 inhabitants/day according to the WHO ATC/DDD methodology. Between 1999 and 2010, anti-asthmatic consumption increased from 3.91 to 14.43 DDD/1000 inhabitants/day. The market of anti-asthmatic generic drugs progressed from 1.83 (47%) to 2.18 (23%) DDD/1000 inhabitants/day from 1999 to 2010. In 2010, inhaled glucocorticosteroids ranked first (0.83 DDD/1000 inhabitants/day), followed by inhaled short acting beta agonists (0.73 DDD/1000 inhabitants/day). The number of brands went from 27 in 1999 to 34 in 2010, with a generic share increasing from 55.55% to 70.59%. The number of anti-asthmatic pharmaceutical preparations increased from 57 to 64 during the same period, of which 31 and 42 were generic preparations. In 2010, the total cost of anti-asthmatic dugs was about 22 million euro, the generics representing 14 million euro. Despite the introduction of a compulsory insurance scheme called "AMO", that allows a refund for 69.5% of anti-asthmatic specialties marketed in Morocco, anti-asthmatic generic drug consumption remains limited. The Moroccan market is still largely dominated by the originator drugs with still valid patents.

  19. Proteomics of anti-cancer drugs

    Czech Academy of Sciences Publication Activity Database

    Kovářová, Hana; Martinková, Jiřina; Hrabáková, Rita; Skalníková, Helena; Novák, Petr; Hajdůch, M.; Gadher, S. J.

    2009-01-01

    Roč. 276, Supplement 1 (2009), s. 84-84 E-ISSN 1742-4658. [34th FEBS Congress. 04.07.2009-09.07.2009, Praha] R&D Projects: GA MŠk LC07017 Institutional research plan: CEZ:AV0Z50450515; CEZ:AV0Z50200510 Keywords : proteomics * anti-cancer drugs * biomarkers Subject RIV: FD - Oncology ; Hematology

  20. Intravenous ferric carboxymaltose accelerates erythropoietic recovery from experimental malarial anemia

    DEFF Research Database (Denmark)

    Maretty, Lasse; Sharp, Rebecca Emilie; Andersson, Mikael

    2012-01-01

    Iron restriction has been proposed as a cause of erythropoietic suppression in malarial anemia; however, the role of iron in malaria remains controversial, because it may increase parasitemia. To investigate the role of iron-restricted erythropoiesis, A/J mice were infected with Plasmodium chabaudi...... use of iron therapy in malaria and show the need for trials of intravenous ferric carboxymaltose as an adjunctive treatment for severe malarial anemia....

  1. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial

    DEFF Research Database (Denmark)

    Massaga, Julius J; Kitua, Andrew Y; Lemnge, Martha M

    2003-01-01

    : Presumptive intermittent treatment for malaria with amodiaquine reduced malarial fevers and anaemia in infants, in an area with high resistance to other antimalarials. Intermittent treatment strategies for malaria in highly endemic areas could be of great benefit to public health.......BACKGROUND: Malaria is a major cause of infant morbidity and mortality in sub-Saharan Africa, and is often complicated by severe anaemia. Resistance of Plasmodium falciparum to most affordable antimalarial drugs is an impediment to intermittent chemotherapy. We investigated the effect...... of presumptive intermittent treatment with amodiaquine and daily iron supplementation in infants on malarial fevers and anaemia, in a holoendemic area of Tanzania where malaria is largely resistant to chloroquine and sulfadoxine/ pyrimethamine. METHODS: 291 infants aged 12-16 weeks who attended three clinics...

  2. Targeted delivery of anti-tuberculosis drugs to macrophages: targeting mannose receptors

    Science.gov (United States)

    Filatova, L. Yu; Klyachko, N. L.; Kudryashova, E. V.

    2018-04-01

    The development of systems for targeted delivery of anti-tuberculosis drugs is a challenge of modern biotechnology. Currently, these drugs are encapsulated in a variety of carriers such as liposomes, polymers, emulsions and so on. Despite successful in vitro testing of these systems, virtually no success was achieved in vivo, because of low accessibility of the foci of infection located in alveolar macrophage cells. A promising strategy for increasing the efficiency of therapeutic action of anti-tuberculosis drugs is to encapsulate the agents into mannosylated carriers targeting the mannose receptors of alveolar macrophages. The review addresses the methods for modification of drug substance carriers, such as liposomes and biodegradable polymers, with mannose residues. The use of mannosylated carriers to deliver anti-tuberculosis agents increases the drug circulation time in the blood stream and increases the drug concentration in alveolar macrophage cells. The bibliography includes 113 references.

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

    OpenAIRE

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2017-03-03

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

  5. Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review.

    Science.gov (United States)

    Van Herwaarden, Noortje; Van Den Bemt, Bart J F; Wientjes, Maike H M; Kramers, Cornelis; Den Broeder, Alfons A

    2017-08-01

    Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient. Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity. Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.

  6. Cytotoxic drug sensitivity of Epstein-Barr virus transformed lymphoblastoid B-cells

    Directory of Open Access Journals (Sweden)

    Olah Eva

    2006-11-01

    Full Text Available Abstract Background Epstein-Barr virus (EBV is the causative agent of immunosuppression associated lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD, AIDS related immunoblastic lymphomas (ARL and immunoblastic lymphomas in X-linked lymphoproliferative syndrome (XLP. The reported overall mortality for PTLD often exceeds 50%. Reducing the immunosuppression in recipients of solid organ transplants (SOT or using highly active antiretroviral therapy in AIDS patients leads to complete remission in 23–50% of the PTLD/ARL cases but will not suffice for recipients of bone marrow grafts. An additional therapeutic alternative is the treatment with anti-CD20 antibodies (Rituximab or EBV-specific cytotoxic T-cells. Chemotherapy is used for the non-responding cases only as the second or third line of treatment. The most frequently used chemotherapy regimens originate from the non-Hodgkin lymphoma protocols and there are no cytotoxic drugs that have been specifically selected against EBV induced lymphoproliferative disorders. Methods As lymphoblastoid cell lines (LCLs are well established in vitro models for PTLD, we have assessed 17 LCLs for cytotoxic drug sensitivity. After three days of incubation, live and dead cells were differentially stained using fluorescent dyes. The precise numbers of live and dead cells were determined using a custom designed automated laser confocal fluorescent microscope. Results Independently of their origin, LCLs showed very similar drug sensitivity patterns against 29 frequently used cytostatic drugs. LCLs were highly sensitive for vincristine, methotrexate, epirubicin and paclitaxel. Conclusion Our data shows that the inclusion of epirubicin and paclitaxel into chemotherapy protocols against PTLD may be justified.

  7. Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

    Science.gov (United States)

    Xu, Yuhui; Wu, Jianan; Liao, Sha; Sun, Zhaogang

    2017-10-03

    Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

  8. Non-steroidal anti-inflammatory drug use and the risk of Parkinson's disease

    DEFF Research Database (Denmark)

    Manthripragada, Angelika D; Schernhammer, Eva S; Qiu, Jiaheng

    2011-01-01

    Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD).......Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD)....

  9. Malaria in South America: a drug discovery perspective.

    Science.gov (United States)

    Cruz, Luiza R; Spangenberg, Thomas; Lacerda, Marcus V G; Wells, Timothy N C

    2013-05-24

    The challenge of controlling and eventually eradicating malaria means that new tools are urgently needed. South America's role in this fight spans both ends of the research and development spectrum: both as a continent capable of discovering and developing new medicines, and also as a continent with significant numbers of malaria patients. This article reviews the contribution of groups in the South American continent to the research and development of new medicines over the last decade. Therefore, the current situation of research targeting malaria control and eradication is discussed, including endemicity, geographical distribution, treatment, drug-resistance and diagnosis. This sets the scene for a review of efforts within South America to discover and optimize compounds with anti-malarial activity.

  10. Self-Assembled Nanocarriers Based on Amphiphilic Natural Polymers for Anti- Cancer Drug Delivery Applications.

    Science.gov (United States)

    Sabra, Sally; Abdelmoneem, Mona; Abdelwakil, Mahmoud; Mabrouk, Moustafa Taha; Anwar, Doaa; Mohamed, Rania; Khattab, Sherine; Bekhit, Adnan; Elkhodairy, Kadria; Freag, May; Elzoghby, Ahmed

    2017-01-01

    Micellization provides numerous merits for the delivery of water insoluble anti-cancer therapeutic agents including a nanosized 'core-shell' drug delivery system. Recently, hydrophobically-modified polysaccharides and proteins are attracting much attention as micelle forming polymers to entrap poorly soluble anti-cancer drugs. By virtue of their small size, the self-assembled micelles can passively target tumor tissues via enhanced permeation and retention effect (EPR). Moreover, the amphiphilic micelles can be exploited for active-targeted drug delivery by attaching specific targeting ligands to the outer micellar hydrophilic surface. Here, we review the conjugation techniques, drug loading methods, physicochemical characteristics of the most important amphiphilic polysaccharides and proteins used as anti-cancer drug delivery systems. Attention focuses on the mechanisms of tumor-targeting and enhanced anti-tumor efficacy of the encapsulated drugs. This review will highlight the remarkable advances of hydrophobized polysaccharide and protein micelles and their potential applications as anti-cancer drug delivery nanosystems. Micellar nanocarriers fabricated from amphiphilic natural polymers hold great promise as vehicles for anti-cancer drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Anti-influenza drugs: the development of sialidase inhibitors.

    Science.gov (United States)

    von Itzstein, Mark; Thomson, Robin

    2009-01-01

    Viruses, particularly those that are harmful to humans, are the 'silent terrorists' of the twenty-first century. Well over four million humans die per annum as a result of viral infections alone. The scourge of influenza virus has plagued mankind throughout the ages. The fact that new viral strains emerge on a regular basis, particularly out of Asia, establishes a continual socio-economic threat to mankind. The arrival of the highly pathogenic avian influenza H5N1 heightened the threat of a potential human pandemic to the point where many countries have put in place 'preparedness plans' to defend against such an outcome. The discovery of the first designer influenza virus sialidase inhibitor and anti-influenza drug Relenza, and subsequently Tamiflu, has now inspired a number of continuing efforts towards the discovery of next generation anti-influenza drugs. Such drugs may act as 'first-line-of-defence' against the spread of influenza infection and buy time for necessary vaccine development particularly in a human pandemic setting. Furthermore, the fact that influenza virus can develop resistance to therapeutics makes these continuing efforts extremely important. An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter.

  12. Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging

    International Nuclear Information System (INIS)

    Flusberg, Deborah A; Sorger, Peter K

    2013-01-01

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell-to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization. (paper)

  13. Nonsteroidal Anti-Inflammatory Drug Hypersensitivity in Preschool Children

    Directory of Open Access Journals (Sweden)

    Kidon Mona

    2007-12-01

    Full Text Available Although extensively studied in adults, nonsteroidal anti-inflammatory drug (NSAID hypersensitivity in children, especially in young children, remains poorly defined. Pediatricians, prescribing antipyretics for children, rarely encounter significant problems, but the few epidemiologic studies performed show conflicting results. Although it is clear that some patients with acetylsalicylic acid (ASA-sensitive asthma have their clinical onset of disease in childhood and bronchoconstriction after ASA challenge is seen in 0 to 22% of asthmatic children so challenged, ibuprofen at antipyretic doses may cause acute respiratory problems only in a very small number of mild to moderate asthmatics. The recently elucidated mechanism of action of acetaminophen may explain some occurrences of adverse reactions in patients with cross-reactive NSAID hypersensitivity on the basis of its inhibitory activity on the newly described enzyme, cyclooxygenase (COX-3. This nonspecific sensitivity to inhibition of COX is most likely genetically determined and shows a remarkable association with atopic disease even in the very young age group and possibly an increased predilection in specific ethnic groups. This review summarizes state-of-the-art published data on NSAID hypersensitivity in preschool children.

  14. Malaria diagnostic testing and treatment practices in three different Plasmodium falciparum transmission settings in Tanzania: before and after a government policy change

    Directory of Open Access Journals (Sweden)

    Bousema Teun

    2011-04-01

    Full Text Available Abstract Background Patterns of decreasing malaria transmission intensity make presumptive treatment of malaria an unjustifiable approach in many African settings. The controlled use of anti-malarials after laboratory confirmed diagnosis is preferable in low endemic areas. Diagnosis may be facilitated by malaria rapid diagnostic tests (RDTs. In this study, the impact of a government policy change, comprising the provision of RDTs and advice to restrict anti-malarial treatment to RDT-positive individuals, was assessed by describing diagnostic behaviour and treatment decision-making in febrile outpatients Methods Prospective data from Biharamulo and Rubya Designated District Hospital (DDH were collected before and after policy change, in Sumve DDH no new policy was implemented. Diagnosis of malaria was confirmed by RDT; transmission intensity was evaluated by a serological marker of malaria exposure in hospital attendees. Results Prior to policy change, there was no evident association between the actual level of transmission intensity and drug-prescribing behaviour. After policy change, there was a substantial decrease in anti-malarial prescription and an increase in prescription of antibiotics. The proportion of parasite-negative individuals who received anti-malarials decreased from 89.1% (244/274 to 38.7% (46/119 in Biharamulo and from 76.9% (190/247 to 10.0% (48/479 in Rubya after policy change. Conclusion This study shows that an official policy change, where RDTs were provided and healthcare providers were advised to adhere to RDT results in prescribing drugs can be followed by more rational drug-prescribing behaviour. The current findings are promising for improving treatment policy in Tanzanian hospitals.

  15. Targeted drug delivery using temperature-sensitive liposomes

    International Nuclear Information System (INIS)

    Magin, R.L.; Niesman, M.R.

    1984-01-01

    Liposomes are receiving considerable attention as vehicles for selective drug delivery. One method of targeting liposomal contents involves the combination of local hyperthermia with temperature-sensitive liposomes. Such liposomes have been used to increase the uptake of methotrexate and cis-platinum into locally heated mouse tumors. However, additional information is needed on the mechanism of liposome drug release and the physiologic deposition of liposomes in vivo before clinical trails are begun. Current research is directed at studying the encapsulation and release of water soluble drugs from temperature-sensitive liposomes. The influence of liposome size, structure, and composition on the rapid release in plasma of cytosine arabinoside, cis-platinum, and the radiation sensitizer SR-2508 are described. These results demonstrate potential applications for temperature-sensitive liposomes in selective drug delivery

  16. Adherence to anti-retroviral drugs in pregnant and lactating HIV ...

    African Journals Online (AJOL)

    Background: Anti-retroviral drugs reduce morbidity and mortality due to HIV and prevent transmission from mother to child. But compliance on anti-retroviral treatment is an essential element for the success of therapeutic goals. Objective: To assess the level of compliance of anti-retroviral treatment in pregnant and lactating ...

  17. The Effects of First-Line Anti-Tuberculosis Drugs on the Actions of Vitamin D in Human Macrophages.

    Science.gov (United States)

    Chesdachai, Supavit; Zughaier, Susu M; Hao, Li; Kempker, Russell R; Blumberg, Henry M; Ziegler, Thomas R; Tangpricha, Vin

    2016-12-01

    Tuberculosis (TB) is a major global health problem. Patients with TB have a high rate of vitamin D deficiency, both at diagnosis and during the course of treatment with anti-tuberculosis drugs. Although data on the efficacy of vitamin D supplementation on Mycobacterium tuberculosis (Mtb) clearance is uncertain from randomized controlled trials (RCTs), vitamin D enhances the expression of the anti-microbial peptide human cathelicidin (hCAP18) in cultured macrophages in vitro. One possible explanation for the mixed (primarily negative) results of RCTs examining vitamin D treatment in TB infection is that anti-TB drugs given to enrolled subjects may impact actions of vitamin D to enhance cathelicidin in macrophages. To address this hypothesis, human macrophage-like monocytic (THP-1) cells were treated with varying doses of first-line anti-tuberculosis drugs in the presence of the active form of vitamin D, 1N1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ). The expression of hCAP18 was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 1,25(OH) 2 D 3 strongly induced expression of hCAP18 mRNA in THP-1 cells (fold-change from control). The combination of the standard 4-drug TB therapy (isoniazid, rifampicin, pyrazinamide and ethambutol) in the cultured THP-1 cells demonstrated a significant decrease of hCAP18 mRNA at the dosage of 10 ug/mL. In 31 subjects with newly diagnosed drug-sensitive TB randomized to either high-dose vitamin D 3 (1.2 million IU over 8 weeks, n=13) versus placebo (n=18), there was no change from baseline to week 8 in hCAP18 mRNA levels in peripheral blood mononuclear cells or in plasma concentrations of LL-37, the protein product of hCAP18.These data suggest that first-line anti-TB drugs may alter the vitamin D-dependent increase in hCAP18 and LL-37 human macrophages.

  18. A short history of anti-rheumatic therapy. III. Non steroidal anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    P. Marson

    2011-06-01

    Full Text Available The chemical advances of the 20th century led to the synthesis of non steroidal anti-inflammatory drugs (NSAIDs, beginning from phenylbutazone and indomethacin and continuing with other new drugs, including ibuprofen, diclofenac, naproxen, piroxicam and, more recently, the highly selective COX-2 inhibitors (coxibs. This progress derived from the discovery of the mechanism of action of these drugs: the inhibition of synthesis of prostaglandins due to the cycloxigenase enzyme system, according to the experimental contributions of John R. Vane.

  19. Remission of Grave's disease after oral anti-thyroid drug treatment.

    Science.gov (United States)

    Ishtiaq, Osama; Waseem, Sabiha; Haque, M Naeemul; Islam, Najmul; Jabbar, Abdul

    2009-11-01

    To evaluate remission rate of anti-thyroid drug treatment in patients with Grave's disease, and to study the factors associated with remission. A cross sectional study. The Endocrine Department of the Aga Khan University Hospital, Karachi from 1999 to 2000. Seventy four patients of Grave's disease were recruited who were prescribed medical treatment. Grave's disease was diagnosed in the presence of clinical and biochemical hyperthyroidism along with anti-microsomal (AMA) and anti-thyroglobulin antibodies (ATA) and thyroid scan. These patients were prescribed oral anti-thyroid drugs using titration regime and followed at 3, 6, 12 and 18 months. Patients were categorized into two groups: "remission group" and "treatment failure group" and results were compared using a chi-square test, t-test and logistic regression model with significance at p disease on initial presentation.

  20. The anti-hepatitis drug use effect and inventory management optimization from the perspective of hospital drug supply chain.

    Science.gov (United States)

    Liu, Zhanyu

    2017-09-01

    By analyzing the current hospital anti hepatitis drug use, dosage, indications and drug resistance, this article studied the drug inventory management and cost optimization. The author used drug utilization evaluation method, analyzed the amount and kind distribution of anti hepatitis drugs and made dynamic monitoring of inventory. At the same time, the author puts forward an effective scheme of drug classification management, uses the ABC classification method to classify the drugs according to the average daily dose of drugs, and implements the automatic replenishment plan. The design of pharmaceutical services supply chain includes drug procurement platform, warehouse management system and connect to the hospital system through data exchange. Through the statistical analysis of drug inventory, we put forward the countermeasures of drug logistics optimization. The results showed that drug replenishment plan can effectively improve drugs inventory efficiency.

  1. Suppression of gastric acid increases the risk of developing immunoglobulin E-mediated drug hypersensitivity: human diclofenac sensitization and a murine sensitization model.

    Science.gov (United States)

    Riemer, A B; Gruber, S; Pali-Schöll, I; Kinaciyan, T; Untersmayr, E; Jensen-Jarolim, E

    2010-03-01

    Hypersensitivity reactions towards non-steroidal anti-inflammatory drugs (NSAID) are common, although true allergies are detectable only in a subgroup of patients. The current study was prompted by a case observation, where a patient experienced generalized urticaria following his second course of diclofenac and proton pump inhibitor medication, and was found to have diclofenac-specific IgE. During recent years, our group has been investigating the importance of gastric digestion in the development of food allergies, demonstrating anti-acid medication as a risk factor for sensitization against food proteins. Here, we aimed to investigate whether the mechanism of food allergy induction described can also be causative in NSAID allergy, using diclofenac as a paradigm. We subjected BALB/c mice to several oral immunization regimens modelled after the patient's medication intake. Diclofenac was applied with or without gastric acid suppression, in various doses, alone or covalently coupled to albumin, a protein abundant in gastric juices. Immune responses were assessed on the antibody level, and functionally examined by in vitro and in vivo crosslinking assays. Only mice receiving albumin-coupled diclofenac under gastric acid suppression developed anti-diclofenac IgG1 and IgE, whereas no immune responses were induced by the drug alone or without gastric acid suppression. Antibody induction was dose dependent with the group receiving the higher dose of the drug showing sustained anti-diclofenac titres. The antibodies induced triggered basophil degranulation in vitro and positive skin tests in vivo. Gastric acid suppression was found to be a causative mechanism in the induction of IgE-mediated diclofenac allergy.

  2. Anti-topoisomerase drugs as potent inducers of chromosomal aberrations

    Directory of Open Access Journals (Sweden)

    Loredana Bassi

    2000-12-01

    Full Text Available DNA topoisomerases catalyze topological changes in DNA that are essential for normal cell cycle progression and therefore they are a preferential target for the development of anticancer drugs. Anti-topoisomerase drugs can be divided into two main classes: "cleavable complex" poisons and catalytic inhibitors. The "cleavable complex" poisons are very effective as anticancer drugs but are also potent inducers of chromosome aberrations so they can cause secondary malignancies. Catalytic inhibitors are cytotoxic but they do not induce chromosome aberrations. Knowledge about the mechanism of action of topoisomerase inhibitors is important to determine the best anti-topoisomerase combinations, with a reduced risk of induction of secondary malignancies.As topoisomerases de DNA catalisam alterações topológicas no DNA que são essenciais para a progressão do ciclo celular normal e, portanto, são um alvo preferencial para o desenvolvimento de drogas anticâncer. Drogas anti-topoisomerases podem ser divididas em duas classes principais: drogas anti-"complexos cliváveis" e inibidores catalíticos. As drogas anti-"complexos cliváveis" são muito eficazes como drogas anticancerígenas, mas são também potentes indutores de aberrações cromossômicas, podendo causar neoplasias malignas secundárias. Inibidores catalíticos são citotóxicos mas não induzem aberrações cromossômicas. Conhecimento a respeito do mecanismo de ação de inibidores de topoisomerases é importante para determinar as melhores combinações anti-topoisomerases, com um reduzido risco de indução de neoplasias malignas secundárias.

  3. Glycaemic adverse drug reactions from anti-neoplastics used in ...

    African Journals Online (AJOL)

    235625 records ... Glycaemic adverse drug reactions from anti-neoplastics used in treating pancreatic cancer. ... Based on the emphasized nine antineoplastic drugs with high hyperglycemic ADR incidence, we found: fluorouracil, sorafenib and pemetrexed with high ADR record of metabolism and nutrition disorders; ...

  4. Macrolide Hybrid Compounds: Drug Discovery Opportunities in Anti- Infective and Anti-inflammatory Area.

    Science.gov (United States)

    Paljetak, Hana Cipcic; Tomaskovic, Linda; Matijasic, Mario; Bukvic, Mirjana; Fajdetic, Andrea; Verbanac, Donatella; Peric, Mihaela

    2017-01-01

    Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Aspirin and its related non-steroidal anti-inflammatory drugs

    African Journals Online (AJOL)

    Aspirin and its related non-steroidal anti-inflammatory drugs. Aspirin or acetylsalicylic acid has been utilised by physicians for hundreds of years as an analgesic, anti-inflammatory and antipyretic (1). Derived from plant sources, such as the willow tree, it has the ability to induce apoptosis in cancer cells and stimulate.

  6. A pilot study on quality of artesunate and amodiaquine tablets used in the fishing community of Tema, Ghana.

    Science.gov (United States)

    Affum, Andrews O; Lowor, Samuel; Osae, Shiloh D; Dickson, Adomako; Gyan, Benjamin A; Tulasi, Delali

    2013-06-28

    The ineffectiveness of artesunate and amodiaquine tablets in malaria treatment remains a health burden to WHO and governments of malaria-endemic countries, including Ghana. The proliferation of illegitimate anti-malarial drugs and its use by patients is of primary concern to international and local drug regulatory agencies because such drugs are known to contribute to the development of the malaria-resistant parasites in humans. No data exist on quality of these drugs in the fishing village communities in Ghana although the villagers are likely users of such drugs. A pilot study on the quality of anti-malarial tablets in circulation during the major fishing season at a malarious fishing village located along the coast of Tema in southern Ghana was determined. Blisterpacks of anti-malarial tablets were randomly sampled. The International Pharmacopoeia and Global Pharma Health Fund Minilab protocols were used to assess the quality of anti-malarial tablets per blisterpacks allegedly manufactured by Guilin Pharmaceutical Co Ltd, China (GPCL) and Letap Pharmaceuticals Ltd, Ghana (LPL) and sold in chemical sales outlets at Kpone-on-Sea. Ferric chloride and cobaltous thiocyanate tests confirmed the presence of active ingredients in the tablets. A confirmatory test for the active ingredient was achieved with artesunate (ICRS1409) and amodiaquine (ICRS0209) reference standards. A high performance liquid chromatography analysis confirmed the amount of artesunate found in tablets. Based on the International Pharmacopoeia acceptable range of 96/98 to 102% for genuine artesunate per tablet, 10% [relative standard deviation (RSD): 3.2%] of field-selected artesunate blisterpack per tablets manufactured by GPCL, and 50% (RSD: 5.1%) of a similar package per tablet by LPL, passed the titrimetric test. However, 100% (RSD: 2.2%) of amodiaquine blisterpack per tablet by GPCL were found to be within the International Pharmacopeia acceptable range of 90 to 110% for genuine amodiaquine in

  7. 77 FR 12063 - Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Nonprescription Drugs...

    Science.gov (United States)

    2012-02-28

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice announces a forthcoming meeting of a public...

  8. Stockpiling anti-viral drugs for a pandemic: the role of Manufacturer Reserve Programs.

    Science.gov (United States)

    Harrington, Joseph E; Hsu, Edbert B

    2010-05-01

    To promote stockpiling of anti-viral drugs by non-government organizations such as hospitals, drug manufacturers have introduced Manufacturer Reserve Programs which, for an annual fee, provide the right to buy in the event of a severe outbreak of influenza. We show that these programs enhance drug manufacturer profits but could either increase or decrease the amount of pre-pandemic stockpiling of anti-viral drugs.

  9. Sir Ronald Ross and the Malarial Parasite

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 7. Sir Ronald Ross and the Malarial Parasite - Discovery of its Route - From Man to Mosquito and Back. Shobhona Sharma. General Article Volume 11 Issue 7 July 2006 pp 4-13 ...

  10. Osteoarthritis guidelines: a progressive role for topical nonsteroidal anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Stanos SP

    2013-04-01

    Full Text Available Steven P Stanos Rehabilitation Institute of Chicago, Center for Pain Management, Chicago, IL, USA Abstract: Current treatment guidelines for the treatment of chronic pain associated with osteoarthritis reflect the collective clinical knowledge of international experts in weighing the benefits of pharmacologic therapy options while striving to minimize the negative effects associated with them. Consideration of disease progression, pattern of flares, level of functional impairment or disability, response to treatment, coexisting conditions such as cardiovascular disease or gastrointestinal disorders, and concomitant prescription medication use should be considered when creating a therapeutic plan for a patient with osteoarthritis. Although topical nonsteroidal anti-inflammatory drugs historically have not been prevalent in many of the guidelines for osteoarthritis treatment, recent evidence-based medicine and new guidelines now support their use as a viable option for the clinician seeking alternatives to typical oral formulations. This article provides a qualitative review of these treatment guidelines and the emerging role of topical nonsteroidal anti-inflammatory drugs as a therapy option for patients with localized symptoms of osteoarthritis who may be at risk for oral nonsteroidal anti-inflammatory drug-related serious adverse events. Keywords: osteoarthritis, nonsteroidal anti-inflammatory drugs, guidelines, topical analgesics, diclofenac

  11. Price Sensitivity of Demand for Prescription Drugs

    DEFF Research Database (Denmark)

    Skipper, Lars; Simonsen, Marianne; Skipper, Niels

    This paper investigates price sensitivity of demand for prescription drugs using drug purchase records for at 20% random sample of the Danish population. We identify price responsiveness by exploiting exogenous variation in prices caused by kinked reimbursement schemes and implement a regression ...... education and income are, however, more responsive to the price. Also, essential drugs that prevent deterioration in health and prolong life have lower associated average price sensitivity....

  12. Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

    Science.gov (United States)

    Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

    2016-08-01

    Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

  13. Use of nonsteroidal anti-inflammatory drugs among healthy people and specific cerebrovascular safety

    DEFF Research Database (Denmark)

    Fosbøl, Emil L; Olsen, Anne-Marie Schjerning; Olesen, Jonas Bjerring

    2014-01-01

    BACKGROUND: Nonsteroidal anti-inflammatory drugs can increase bleeding and thrombosis, but little is known about the cerebrovascular safety of these drugs, especially among healthy people. AIMS: The aim of this study was to examine the risk of ischemic and hemorrhagic stroke associated with the use...... stroke). RESULTS: We selected 1,028,437 healthy individuals (median age 39 years). At least one nonsteroidal anti-inflammatory drug was claimed by 44·7% of the study population, and the drugs were generally used for a short period of time and in low doses. High-dose ibuprofen and diclofenac were......·35-3·42)]. CONCLUSIONS: In healthy individuals, use of commonly available nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac, and naproxen was associated with increased risk of stroke....

  14. Improved consistency in dosing anti-tuberculosis drugs in Taipei, Taiwan.

    Science.gov (United States)

    Chiang, Chen-Yuan; Yu, Ming-Chih; Shih, Hsiu-Chen; Yen, Muh-Yong; Hsu, Yu-Ling; Yang, Shiang-Lin; Lin, Tao-Ping; Bai, Kuan-Jen

    2012-01-01

    It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (pTaipei City has remarkably improved after health authorities implemented a series of interventions.

  15. Exploiting Large-Scale Drug-Protein Interaction Information for Computational Drug Repurposing

    Science.gov (United States)

    2014-06-20

    studies that have reported antimalarial activities of azole compounds [39-43] lend support to our model predictions. The highest-scored non-malarial...Table 4, verapamil and cimetidine, do not have antimal- arial activities themselves but exhibit synergism when used in combination with antimalarial ... activators . Because of their high frequencies among the antimalarial drugs, according to Eq. 3, the drug-protein interactions contributing most to the

  16. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

    DEFF Research Database (Denmark)

    De Bruin, M L; Pettersson, M; Meyboom, R H B

    2005-01-01

    AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS...... defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value......, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. CONCLUSION: Anti-HERG activity is associated...

  17. Electrochemical studies of ropinirole, an anti-Parkinson's disease drug

    Indian Academy of Sciences (India)

    The oxidation behaviour of a potent anti-Parkinson's disease drug ropinirole hydrochloride was investigated over a wide pH range in aqueous solution at glassy carbon electrode using cyclic and square-wave voltammetry. The oxidation of drug is a pH dependent irreversible process and occurs in two steps.

  18. Pharmacogenetics of Anti-Diabetes Drugs

    Directory of Open Access Journals (Sweden)

    Johanna K. DiStefano

    2010-08-01

    Full Text Available A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D. In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs, meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4 inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of ‘response’ can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for “individualized medicine” for patients with T2D.

  19. Return of chloroquine sensitivity to Africa? Surveillance of African Plasmodium falciparum chloroquine resistance through malaria imported to China.

    Science.gov (United States)

    Lu, Feng; Zhang, Meihua; Culleton, Richard L; Xu, Sui; Tang, Jianxia; Zhou, Huayun; Zhu, Guoding; Gu, Yaping; Zhang, Chao; Liu, Yaobao; Wang, Weiming; Cao, Yuanyuan; Li, Julin; He, Xinlong; Cao, Jun; Gao, Qi

    2017-07-26

    Chloroquine (CQ) was the cornerstone of anti-malarial treatment in Africa for almost 50 years, but has been widely withdrawn due to the emergence and spread of resistance. Recent reports have suggested that CQ-susceptibility may return following the cessation of CQ usage. Here, we monitor CQ sensitivity and determine the prevalence of genetic polymorphisms in the CQ resistance transporter gene (pfcrt) of Plasmodium falciparum isolates recently imported from Africa to China. Blood samples were collected from falciparum malaria patients returning to China from various countries in Africa. Isolates were tested for their sensitivity to CQ using the SYBR Green I test ex vivo, and for a subset of samples, in vitro following culture adaptation. Mutations at positions 72-76 and codon 220 of the pfcrt gene were analyzed by sequencing and confirmed by PCR-RFLP. Correlations between drug sensitivity and pfcrt polymorphisms were investigated. Of 32 culture adapted isolates assayed, 17 (53.1%), 6 (18.8%) and 9 (28.1%) were classified as sensitive, moderately resistant, and highly resistant, respectively. In vitro CQ susceptibility was related to point mutations in the pfcrt gene, the results indicating a strong association between pfcrt genotype and drug sensitivity. A total of 292 isolates were typed at the pfcrt locus, and the prevalence of the wild type (CQ sensitive) haplotype CVMNK in isolates from East, South, North, West and Central Africa were 91.4%, 80.0%, 73.3%, 53.3% and 51.7%, respectively. The only mutant haplotype observed was CVIET, and this was almost always linked to an additional mutation at A220S. Our results suggest that a reduction in drug pressure following withdrawal of CQ as a first-line drug may lead to a resurgence in CQ sensitive parasites. The prevalence of wild-type pfcrt CQ sensitive parasites from East, South and North Africa was higher than from the West and Central areas, but this varied greatly between countries. Further surveillance is

  20. Depressive disorders and anti-parkinson drug treatment

    DEFF Research Database (Denmark)

    Brandt-Christensen, M; Lopez, A G; Nilsson, F M

    2007-01-01

    OBJECTIVE: To estimate the rate of treatment with anti-parkinson drugs (APD) among patients with depression. METHOD: In a nationwide case register linkage study, all persons with a main diagnosis of depression during 5 years were identified. A control group of persons with diagnoses of osteoarthr...... that prescription of APD reflects the presence of Parkinson's disease, results support a positive statistical association between depressive disorders and Parkinson's disease.......OBJECTIVE: To estimate the rate of treatment with anti-parkinson drugs (APD) among patients with depression. METHOD: In a nationwide case register linkage study, all persons with a main diagnosis of depression during 5 years were identified. A control group of persons with diagnoses...... of osteoarthritis was included. The subsequent risk of getting treatment with APD was estimated for the two groups. Statistical analyses involved Poisson's regression and competing risk models. RESULTS: A total of 14 991 persons were included. The rate of getting APD was 2.57 (95% CI: 1.46-4.52) times higher...

  1. Anti-inflammatory drugs in the 21st century.

    Science.gov (United States)

    Rainsford, K D

    2007-01-01

    Historically, anti-inflammatory drugs had their origins in the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., this enabled these compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was developed. Likewise, the chemical advances of the 19th-20th centuries lead to development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were discovered. There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays. In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to

  2. Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis.

    Science.gov (United States)

    Gandini, Sara; Palli, Domenico; Spadola, Giuseppe; Bendinelli, Benedetta; Cocorocchio, Emilia; Stanganelli, Ignazio; Miligi, Lucia; Masala, Giovanna; Caini, Saverio

    2018-02-01

    Several anti-hypertensive drugs have photosensitizing properties, however it remains unclear whether long-term users of these drugs are also at increased risk of skin malignancies. We conducted a literature review and meta-analysis on the association between use of anti-hypertensive drugs and the risk of cutaneous melanoma and non-melanoma skin cancer (NMSC). We searched PubMed, EMBASE, Google Scholar and the Cochrane Library, and included observational and experimental epidemiological studies published until February 28th, 2017. We calculated summary relative risk (SRR) and 95% confidence intervals (95% CI) through random effect models to estimate the risk of skin malignancies among users of the following classes of anti-hypertensive drugs: thiazide diuretics, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB) and β-blockers. We conducted sub-group and sensitivity analysis to explore causes of between-studies heterogeneity, and assessed publication bias using a funnel-plot based approach. Nineteen independent studies were included in the meta-analysis. CCB users were at increased skin cancer risk (SRR 1.14, 95% CI 1.07-1.21), and β-blockers users were at increased risk of developing cutaneous melanoma (SRR 1.21, 95% CI 1.05-1.40), with acceptable between-studies heterogeneity (I 2  skin cancer risk. We found no evidence of publication bias affecting the results. Family doctors and clinicians should inform their patients about the increased risk of skin cancer associated with the use of CCB and β-blockers and instruct them to perform periodic skin self-examination. Further studies are warranted to elucidate the observed associations. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Assessment of Anti-inflammatory Activity of Taxus Baccata Linn. Bark Extract.

    Science.gov (United States)

    Dutta, Satyajit; Mariappan, G; Sarkar, Dipankar; Sarkar, Piyali

    2010-01-01

    Taxus baccata (L) known as Sthauneyaka in Sanskrit(1) has wide range of biological activities including analgesic, anti-malarial, anti-rheumatic, sedative, anti-spasmodic, aphrodisiac and anti-asthmatic. In the present study, the dried and powdered bark of Taxus baccata (L) was extracted with 95% ethanol and ether at room temperature and screened for their anti--inflammatory activity by Carrageenan-induced paw edema method in rat. 95% ethanol extract exhibits potent anti-inflammatory activity at 200mg/kg four hours after administration in comparison with ether extract, as well reference standard, Aspirin. The observed pharmacological activities provide a scientific basis for the folklore use of the plant in treating acute inflammation.

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

    International Nuclear Information System (INIS)

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

    2003-01-01

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

  5. Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs)

    DEFF Research Database (Denmark)

    Nissen, Christoffer V; Bindslev-Jensen, Carsten; Mørtz, Charlotte G

    2015-01-01

    BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are reported to be the second most common cause of drug hypersensitivity. In 2011, experts from the EAACI/ENDA group and GA(2)LEN proposed a new classification system for NSAID hypersensitivity. The aim of this study was to classify...... responders reacted to non-pyrazolone drugs. Only one patient could not be classified according to the EAACI/ENDA system. An overlap between respiratory and cutaneous symptoms was found in 15/39 (38%) of patients. CONCLUSIONS: All but one of our patients could be classified according to the EAACI...

  6. Novel approaches in anti-arenaviral drug development

    International Nuclear Information System (INIS)

    Lee, Andrew M.; Pasquato, Antonella; Kunz, Stefan

    2011-01-01

    Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant efforts have been undertaken to identify novel potent inhibitors of arenavirus infection. High throughput screening of small molecule libraries employing pseudotype platforms led to the discovery of several potent and broadly active inhibitors of arenavirus cell entry that are effective against the major hemorrhagic arenaviruses. Mechanistic studies revealed that these novel entry inhibitors block arenavirus membrane fusion and provided novel insights into the unusual mechanism of this process. The success of these approaches highlights the power of small molecule screens in antiviral drug discovery and establishes arenavirus membrane fusion as a robust drug target. These broad screenings have been complemented by strategies targeting cellular factors involved in productive arenavirus infection. Approaches targeting the cellular protease implicated in maturation of the fusion-active viral envelope glycoprotein identified the proteolytic processing of the arenavirus glycoprotein precursor as a novel and promising target for anti-arenaviral strategies.

  7. Availability, price and affordability of anti-tuberculosis drugs in Europe: a TBNET survey

    NARCIS (Netherlands)

    Günther, Gunar; Gomez, Gabriela B.; Lange, Christoph; Rupert, Stephan; van Leth, Frank; Andrejak, Claire; Pieridou-Bagatzouni, Despo; Anderson, Aase Bengard; Bojovic, Olivera; Bothamley, Graham; Bruchfeld, Judith; Codecasa, Luigi R.; Danilovits, Manfred; Davidaviciene, Edita; Dalemo, Paulina; Dimopoulos, Giorgos; Duarte, Raquel; Hafizi, Hasan; Horvath, Ildiko; Eyuboglu, Fusun; Ibraim, Elmira; Jankovic, Mateja; Kan, Boris; Kopecka, Emilia; Kruczak, Katarzyna; Kutsyna, Galyna; de lange, Wiel; Leimane, Vaira; Mack, Ulrich; Manzano, Juan Ruiz; Markova, Roumania; McDonald, Colm; McLaughlin, Anne-Marie; Mulliqi, Gjyle; Muylle, Inge; Pesut, Dragica; Polcova, Veronika; Rumetshofer, Rudolf; Rusu, Doina; Skrahina, Alena; Spiric, Nicolina; Solovic, Ivan; Svetina-Sorli, Petra; Vasakova, Martina; Vasankari, Tuula; Viiklepp, Piret; Wirz, Gil; Zakoska, Maja; Zellweger, Jean-Pierre

    2015-01-01

    Data on availability and cost of anti-tuberculosis (TB) drugs in relation to affordability at national level are scarce. We performed a cross-sectional study on availability and cost of anti-TB drugs at major TB-reference centres in 37 European countries. Costs of standardised treatment regimens

  8. Electrocatalytic oxidation of some anti-inflammatory drugs on a nickel hydroxide-modified nickel electrode

    Energy Technology Data Exchange (ETDEWEB)

    Hajjizadeh, M. [Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran (Iran, Islamic Republic of); Jabbari, A. [Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran (Iran, Islamic Republic of)], E-mail: jabbari@kntu.ac.ir; Heli, H.; Moosavi-Movahedi, A.A. [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Haghgoo, S. [Center of Quality Control of Drug, Tehran (Iran, Islamic Republic of)

    2007-12-31

    The electrocatalytic oxidation of several anti-inflammatory drugs (mefenamic acid, diclofenac and indomethacin) was investigated on a nickel hydroxide-modified nickel (NHMN) electrode in alkaline solution. This oxidation process and its kinetics were studied using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques. Voltammetric studies indicated that in the presence of drugs, the anodic peak current of low-valence nickel species increases, followed by a decrease in the corresponding cathodic current. This pattern indicates that drugs were oxidized on the redox mediator immobilized on the electrode surface via an electrocatalytic mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by drugs was also investigated. The corresponding rate law under the control of charge transfer was developed and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of drugs and the electron-transfer coefficients are reported. A sensitive, simple and time-saving amperometric procedure was developed for the analysis of these drugs in bulk form and for the direct assay of tablets, using the NHMN electrode.

  9. Electrocatalytic oxidation of some anti-inflammatory drugs on a nickel hydroxide-modified nickel electrode

    International Nuclear Information System (INIS)

    Hajjizadeh, M.; Jabbari, A.; Heli, H.; Moosavi-Movahedi, A.A.; Haghgoo, S.

    2007-01-01

    The electrocatalytic oxidation of several anti-inflammatory drugs (mefenamic acid, diclofenac and indomethacin) was investigated on a nickel hydroxide-modified nickel (NHMN) electrode in alkaline solution. This oxidation process and its kinetics were studied using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy techniques. Voltammetric studies indicated that in the presence of drugs, the anodic peak current of low-valence nickel species increases, followed by a decrease in the corresponding cathodic current. This pattern indicates that drugs were oxidized on the redox mediator immobilized on the electrode surface via an electrocatalytic mechanism. A mechanism based on the electrochemical generation of Ni(III) active sites and their subsequent consumption by drugs was also investigated. The corresponding rate law under the control of charge transfer was developed and kinetic parameters were derived. In this context, the charge-transfer resistance accessible both theoretically and through impedancemetry was used as a criterion. The rate constants of the catalytic oxidation of drugs and the electron-transfer coefficients are reported. A sensitive, simple and time-saving amperometric procedure was developed for the analysis of these drugs in bulk form and for the direct assay of tablets, using the NHMN electrode

  10. Quorum sensing Inhibitors as anti-pathogenic drugs

    DEFF Research Database (Denmark)

    Rasmussen, Thomas Bovbjerg; Givskov, Michael Christian

    2006-01-01

    as well as elevated tolerance to the activity of the innate immune system. Gram-negative bacteria commonly use N-acyl homoserine lactones (AHL) as QS signal molecules. The use of signal molecule based drugs to attenuate bacterial pathogenecity rather than bacterial growth is attractive for several reasons......, particularly considering the emergence of increasingly antibiotic-resistant bacteria. Compounds capable of this type of interference have been termed anti-pathogenic drugs. A large variety of synthetic AHL analogues and natural products libraries have been screened and a number of QS inhibitors (QSI) have been...

  11. Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

    Science.gov (United States)

    Michinaga, Shotaro; Koyama, Yutaka

    2015-01-01

    Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vasogenic or cytotoxic edema. Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB) and extravasations of serum proteins, while cytotoxic edema is characterized by cell swelling caused by intracellular accumulation of fluid. Various experimental animal models are often used to investigate mechanisms underlying brain edema. Many soluble factors and functional molecules have been confirmed to induce BBB disruption or cell swelling and drugs targeted to these factors are expected to have anti-edema effects. In this review, we discuss the mechanisms and involvement of factors that induce brain edema formation, and the possibility of anti-edema drugs targeting them. PMID:25941935

  12. Ethnobotany and ethnopharmacy--their role for anti-cancer drug development.

    Science.gov (United States)

    Heinrich, Michael; Bremner, Paul

    2006-03-01

    Local and traditional knowledge has been the starting point for many successful drug development projects over the last decades. Here we discuss some examples of anti-cancer drugs which have had enormous impact as anti-cancer agents (camptothecan, taxol and derivatives) and a few examples of drugs currently under various stages of preclinical development. Ethnobotanists investigate the relationship between humans and plants in all its complexity, and such research is generally based on a detailed observation and study of the use a society makes of plants. The requirements of modern research on natural products as, for example, outlined in the Convention on Biological Diversity (Rio Convention) and the overall approach in ethnobotanical research are also discussed. Selected phytochemical-pharmacological studies based on traditional plant use are used to highlight the potential of ethnobotany driven anti-cancer research. The link between traditionally used plants and targets of the NF-kappaB pathway is discussed using on an EU-funded, multidisciplinary project as an example. Lastly the potential of chemopreventive agents derived from traditional food plants is briefly addressed.

  13. Determination of Four Anti-epileptic Drugs in Plasma Using Ultra Performance Liquid Chromatography with Mass Detection Technique.

    Science.gov (United States)

    Hassib, Sonia T; Hashem, Hanaa M A; Mahrouse, Marianne A; Mostafa, Eman A

    2018-04-10

    Status epilepticus (SE) is considered the second most frequent neurologic emergency. Its therapeutic management is performed using sequential anti-epileptic drug regimens. Diazepam (DIA), midazolam (MID), phenytoin (PHT) and phenobarbital (PB) are four drugs of different classes used sequentially in the management of SE. A sensitive, selective, accurate and precise method was developed and validated for simultaneous determination of the four anti-epileptic drugs in human plasma. Their separation and quantification were achieved using ultra performance liquid chromatography (UPLC) with mass detection using carbamazepine as internal standard (IS). For the first three drugs and IS, UPLC-MS/MS with electrospray ionization working in multiple reaction monitoring mode was used at the following transitions: m/z 285→193 for DIA, m/z 326→291 for MID, m/z 253→182 for PHT and m/z 237→194, 237→192 for IS. For the fourth drug (PB), molecular ion peak of PB [M+H] + at m/z 233 was used for its quantitation. The method was linear over concentration ranges of 5-500 ng/ml for DIA and MID and 0.25-20 μg/ml for PHT and PB, respectively. Bio-analytical validation of the developed method was carried out according to European Medicines Agency guidelines. The developed method can be applied for routine drug analysis, therapeutic drug monitoring and bioequivalence studies. This article is protected by copyright. All rights reserved.

  14. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.

    Science.gov (United States)

    Trelle, Sven; Reichenbach, Stephan; Wandel, Simon; Hildebrand, Pius; Tschannen, Beatrice; Villiger, Peter M; Egger, Matthias; Jüni, Peter

    2011-01-11

    To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Network meta-analysis. Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

  15. Zur Verbreitung von Phaethornis malaris (Nordmann) (Aves, Trochilidae)

    NARCIS (Netherlands)

    Mees, G.F.

    1977-01-01

    Obwohl der Kolibri Phaethornis malaris (Nordmann) der Wissenschaft wahrscheinlich schon vor Ausgang des XVIII. Jahrhunderts bekannt war (eine Abbildung findet sich in Audebert & Vieillot, 1802: 37, T. 17) und 1835 die wissenschaftliche Benennung erfolgte (Nordmann, 1835), war er nur aus einem

  16. pH- and ion-sensitive polymers for drug delivery

    Science.gov (United States)

    Yoshida, Takayuki; Lai, Tsz Chung; Kwon, Glen S; Sako, Kazuhiro

    2013-01-01

    Introduction Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. Areas covered Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. Expert opinion Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients. PMID:23930949

  17. pH- and ion-sensitive polymers for drug delivery.

    Science.gov (United States)

    Yoshida, Takayuki; Lai, Tsz Chung; Kwon, Glen S; Sako, Kazuhiro

    2013-11-01

    Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.

  18. The heme biosynthetic pathway of the obligate Wolbachia endosymbiont of Brugia malayi as a potential anti-filarial drug target.

    Directory of Open Access Journals (Sweden)

    Bo Wu

    2009-07-01

    Full Text Available Filarial parasites (e.g., Brugia malayi, Onchocerca volvulus, and Wuchereria bancrofti are causative agents of lymphatic filariasis and onchocerciasis, which are among the most disabling of neglected tropical diseases. There is an urgent need to develop macro-filaricidal drugs, as current anti-filarial chemotherapy (e.g., diethylcarbamazine [DEC], ivermectin and albendazole can interrupt transmission predominantly by killing microfilariae (mf larvae, but is less effective on adult worms, which can live for decades in the human host. All medically relevant human filarial parasites appear to contain an obligate endosymbiotic bacterium, Wolbachia. This alpha-proteobacterial mutualist has been recognized as a potential target for filarial nematode life cycle intervention, as antibiotic treatments of filarial worms harboring Wolbachia result in the loss of worm fertility and viability upon antibiotic treatments both in vitro and in vivo. Human trials have confirmed this approach, although the length of treatments, high doses required and medical counter-indications for young children and pregnant women warrant the identification of additional anti-Wolbachia drugs.Genome sequence analysis indicated that enzymes involved in heme biosynthesis might constitute a potential anti-Wolbachia target set. We tested different heme biosynthetic pathway inhibitors in ex vivo B. malayi viability assays and report a specific effect of N-methyl mesoporphyrin (NMMP, which targets ferrochelatase (FC, the last step. Our phylogenetic analysis indicates evolutionarily significant divergence between Wolbachia heme genes and their human homologues. We therefore undertook the cloning, overexpression and analysis of several enzymes of this pathway alongside their human homologues, and prepared proteins for drug targeting. In vitro enzyme assays revealed a approximately 600-fold difference in drug sensitivities to succinyl acetone (SA between Wolbachia and human 5

  19. Treatment of imported malaria in adults: a multicentre study in France.

    Science.gov (United States)

    Ranque, S; Marchou, B; Malvy, D; Adehossi, E; Laganier, R; Tissot-Dupont, H; Lotte, A; Dydymsky, S; Durant, J; Stahl, J-P; Bosseray, A; Gaillat, J; Sotto, A; Cazorla, C; Ragneau, J-M; Brouqui, P; Delmont, J

    2005-10-01

    Data about anti-malarial drugs prescription practices in Europe and the safety of imported malaria treatments are scanty. In 1999, a French consensus development conference published guidelines for the prevention and treatment of imported P. falciparum malaria. The impact of these guidelines has not been evaluated. To investigate the impact of these guidelines on the prescription of anti-malarials, and to evaluate the incidence of acute drug events (ADEs) leading to discontinuation of treatment. Cross-sectional survey. Members of the medical staff in 14 French infectious and tropical disease wards completed a standardized form for each patient treated for imported malaria in 2001. A propensity score matching technique was used to estimate the risk of ADEs leading to discontinuation of the regimen. In the 474 patients studied, quinine was the first-line anti-malarial most often prescribed. Only 3% of patients received halofantrine. Mefloquine was associated with a RR of 4.9 (95%CI 3.2-7.4, p guidelines have been taken into account. Mefloquine was associated with a substantial risk of discontinuing the treatment because of ADEs. This is a serious limitation for the use of mefloquine in the treatment of out-patients with imported malaria.

  20. In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.

    Directory of Open Access Journals (Sweden)

    Xi-Nan Shi

    Full Text Available Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related deaths worldwide. Surgical resection and conventional chemotherapy and radiotherapy ultimately fail due to tumor recurrence and HCC's resistance. The development of novel therapies against HCC is thus urgently required. The cyclin-dependent kinase (CDK pathways are important and well-established targets for cancer treatment. In particular, CDK2 is a key factor regulating the cell cycle G1 to S transition and a hallmark for cancers. In this study, we utilized our free and open-source protein-ligand docking software, idock, prospectively to identify potential CDK2 inhibitors from 4,311 FDA-approved small molecule drugs using a repurposing strategy and an ensemble docking methodology. Sorted by average idock score, nine compounds were purchased and tested in vitro. Among them, the anti-psychotic drug fluspirilene exhibited the highest anti-proliferative effect in human hepatocellular carcinoma HepG2 and Huh7 cells. We demonstrated for the first time that fluspirilene treatment significantly increased the percentage of cells in G1 phase, and decreased the expressions of CDK2, cyclin E and Rb, as well as the phosphorylations of CDK2 on Thr160 and Rb on Ser795. We also examined the anti-cancer effect of fluspirilene in vivo in BALB/C nude mice subcutaneously xenografted with human hepatocellular carcinoma Huh7 cells. Our results showed that oral fluspirilene treatment significantly inhibited tumor growth. Fluspirilene (15 mg/kg exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil (10 mg/kg. Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect. These results suggested for the first time that fluspirilene is a potential CDK2 inhibitor and a candidate anti-cancer drug for the treatment of human hepatocellular carcinoma. In view of the fact that fluspirilene has a long history

  1. Smart stimuli sensitive nanogels in cancer drug delivery and imaging: a review.

    Science.gov (United States)

    Maya, S; Sarmento, Bruno; Nair, Amrita; Rejinold, N Sanoj; Nair, Shantikumar V; Jayakumar, R

    2013-01-01

    Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail.

  2. The fourth national anti-tuberculosis drug resistance survey in Viet Nam.

    Science.gov (United States)

    Nhung, N V; Hoa, N B; Sy, D N; Hennig, C M; Dean, A S

    2015-06-01

    Viet Nam's Fourth National Anti-Tuberculosis Drug Resistance Survey was conducted in 2011. To determine the prevalence of resistance to the four main first-line anti-tuberculosis drugs in Viet Nam. Eighty clusters were selected using a probability proportion to size approach. Drug susceptibility testing (DST) against the four main first-line anti-tuberculosis drugs was performed. A total of 1629 smear-positive tuberculosis (TB) patients were eligible for culture. Of these, DST results were available for 1312 patients, including 1105 new TB cases, 195 previously treated TB cases and 12 cases with an unknown treatment history. The proportion of cases with resistance to any drug was 32.7% (95%CI 29.1-36.5) among new cases and 54.2% (95%CI 44.3-63.7) among previously treated cases. The proportion of multidrug-resistant TB (MDR-TB) cases was 4.0% (95%CI 2.5-5.4) in new cases and 23.3 (95%CI 16.7-29.9) in previously treated cases. The fourth drug resistance survey in Viet Nam found that the proportion of MDR-TB among new and previously treated cases was not significantly different from that in the 2005 survey. The National TB Programme should prioritise the detection and treatment of MDR-TB to reduce transmission of MDR-TB in the community.

  3. National anti-tuberculosis drug resistance study in Tanzania

    NARCIS (Netherlands)

    Chonde, T. M.; Basra, D.; Mfinanga, S. G. M.; Range, N.; Lwilla, F.; Shirima, R. P.; van Deun, A.; Zignol, M.; Cobelens, F. G.; Egwaga, S. M.; van Leth, F.

    2010-01-01

    OBJECTIVE: To assess the prevalence of anti-tuberculosis drug resistance in a national representative sample of tuberculosis (TB) patients in Tanzania according to recommended methodology. DESIGN: Cluster survey, with 40 clusters sampled proportional to size, of notified TB patients from all

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

    African Journals Online (AJOL)

    DR. AMINU

    MATERIALS AND METHODS. Study Design. The study was a cross ... Muhammadu Sanusi General Hospital (SMSGH) and ... regimens, guided focus group presentations and one .... to the optimal theoretical value of 17.2% proposed in.

  5. Use of biomarkers in the discovery of novel anti-schizophrenia drugs

    DEFF Research Database (Denmark)

    Mikkelsen, Jens D; Thomsen, Morten S; Hansen, Henrik H

    2010-01-01

    Schizophrenia is characterized by a diverse symptomatology that often includes positive, cognitive and negative symptoms. Current anti-schizophrenic drugs act at multiple receptors, but little is known about how each of these receptors contributes to their mechanisms of action. Screening of novel...... anti-schizophrenic drug candidates targeting single receptors will be based on biomarker assays that measure signalling pathways, transcriptional factors, epigenetic mechanisms and synaptic function and translate these effects to behavioural effects in animals and humans. This review discusses current...

  6. Investigation of Susceptibility of Mycobacterium tuberculosis Complex Strains Isolated from Clinical Samples Against the First and Second-Line Anti-tuberculosis Drugs by the Sensititre MycoTB Plate Method

    Directory of Open Access Journals (Sweden)

    Figen KAYSERİLİ ORHAN

    2018-03-01

    Full Text Available Introduction: Phenotypic methods for drug susceptibility testing of Mycobacterium tuberculosis complex (MTC to second-line drugs are not yet standardized. The Sensititre MycoTB Plate is a microtiter plate containing lyophilized antibiotics and configured for determination of MIC to first and second-line anti-tuberculosis drugs. The purpose of this study is to detect the susceptibility rates of MTC strains isolated from patients’ specimens for first and second-line anti-tuberculosis drugs. Materials and Methods: This study included 50 MTC strains isolated from various clinical specimens. Out of the 50 strains, 38 were isolated from sputum, three from cerebrospinal fluid, three from bronchoalveolar lavage, and six from other samples in this study. The susceptibility of strains to anti-tuberculosis drugs were determined by the Sensititre MycoTB Plate Method. Thawed isolates were subcultured, and dilutions were inoculated into MycoTB wells. The results were read at days 7, 14 and 21. Results: At the end of study, out of 50 MTC isolates, 7 (14% showed resistance to Isoniazid (INH, 5 (10% to streptomycin (SM, 4 (8% to ethambutol (EMB, 4 (8% to ethionamide (ETH, 3 (6% to rifampicin (RIF, 3 (6% to rifabutin (RFB, 2 (4% to kanamycin (KAN, 2 (4% to ofloxacin (OFL, 2 (4% to P-aminosalicyclic acid (PAS, 1 (2% to moxiflocacin (MOX, and 1 (2% to cycloserine (CYC. All strains were found sensitive to amikacin while 2 strains (4% were identified as multidrug-resistant tuberculosis (MDR-TB. Thirty-five strains (70% were sensitive to all drugs. Extensively drug resistant tuberculosis (XDR-TB was not determined in this study. Conclusion: This is the first study that tests second line anti-tuberculosis drugs in our location and provides us valuable data regarding MDR-TB and XDR-TB rates. The Sensititre MycoTB Plate Method is a fast, reliable and practical method and can be used to determine the susceptibility of first and second-line anti-tuberculosis drugs.

  7. Management of severe malarial anaemia in Gambian children

    NARCIS (Netherlands)

    Bojang, K. A.; Palmer, A.; Boele van Hensbroek, M.; Banya, W. A.; Greenwood, B. M.

    1997-01-01

    The optimum management of children with severe malarial anaemia is still uncertain. Hence, we have undertaken a study to determine whether iron treatment is as effective at restoring haemoglobin levels one month after presentation as blood transfusion without iron treatment in children with

  8. Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso

    DEFF Research Database (Denmark)

    Diarra, Amidou; Nebie, Issa; Tiono, Alfred

    2012-01-01

    ABSTRACT: BACKGROUND: Patient immune status is thought to affect the efficacy of anti-malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment...... of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. METHODS: Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml) was obtained from each child...... to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. RESULTS: IgG levels to MSP3 were always higher in the successfully treated...

  9. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

    Science.gov (United States)

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-05-26

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery.

  10. Identification of active Plasmodium falciparum calpain to establish screening system for Pf-calpain-based drug development

    Directory of Open Access Journals (Sweden)

    Soh Byoung

    2013-02-01

    Full Text Available Abstract Background With the increasing resistance of malaria parasites to available drugs, there is an urgent demand to develop new anti-malarial drugs. Calpain inhibitor, ALLN, is proposed to inhibit parasite proliferation by suppressing haemoglobin degradation. This provides Plasmodium calpain as a potential target for drug development. Pf-calpain, a cysteine protease of Plasmodium falciparum, belongs to calpain-7 family, which is an atypical calpain not harboring Ca2+-binding regulatory motifs. In this present study, in order to establish the screening system for Pf-calpain specific inhibitors, the active form of Pf-calpain was first identified. Methods Recombinant Pf-calpain including catalytic subdomain IIa (rPfcal-IIa was heterologously expressed and purified. Enzymatic activity was determined by both fluorogenic substrate assay and gelatin zymography. Molecular homology modeling was carried out to address the activation mode of Pf-calpain in the aspect of structural moiety. Results Based on the measurement of enzymatic activity and protease inhibitor assay, it was found that the active form of Pf-calpain only contains the catalytic subdomain IIa, suggesting that Pf-calpain may function as a monomeric form. The sequence prediction indicates that the catalytic subdomain IIa contains all amino acid residues necessary for catalytic triad (Cys-His-Asn formation. Molecular modeling suggests that the Pf-calpain subdomain IIa makes an active site, holding the catalytic triad residues in their appropriate orientation for catalysis. The mutation analysis further supports that those amino acid residues are functional and have enzymatic activity. Conclusion The identified active form of Pf-calpain could be utilized to establish high-throughput screening system for Pf-calpain inhibitors. Due to its unique monomeric structural property, Pf-calpain could be served as a novel anti-malarial drug target, which has a high specificity for malaria parasite

  11. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs.

    Science.gov (United States)

    Agrawal, Mukta; Saraf, Swarnlata; Saraf, Shailendra; Antimisiaris, Sophia G; Chougule, Mahavir Bhupal; Shoyele, Sunday A; Alexander, Amit

    2018-05-23

    According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found

  12. Military Medical Research in Support of National Instruments of Power

    Science.gov (United States)

    2009-03-26

    diseases. Military sponsored research in the U.S. and abroad has produced antibiotic cures for typhoid and scrub typhus, new anti-malarial drugs, and...ARV drugs to Kenyan tea plantation workers has directly resulted in the reduction of absenteeism , maintenance of highly developed skill sets

  13. Microencapsulation of anti-tumor, antibiotic and thrombolytic drugs in microgravity

    Science.gov (United States)

    Morrison, Dennis R.; Mosier, Benjamin; Cassanto, John

    1994-01-01

    Encapsulation of cytotoxic or labile drugs enables targeted delivery and sustained release kinetics that are not available with intravenous injection. A new liquid-liquid diffusion process has been developed for forming unique microcapsules that contain both aqueous and hydrocarbon soluble drugs. Microgravity experiments, on sounding rockets (1989-92) and Shuttle missions STS-52 (1992) and STS-56 (1993) using an automated Materials Dispersion Apparatus, produced multi-lamellar microcapsules containing both Cis-platinum (anti-tumor drug) and iodinated poppy seed oil (a radiocontrast medium), surrounded by a polyglyceride skin. Microcapsules formed with amoxicillin (antibiotic) or urokinase (a clot dissolving enzyme), co-encapsulated with IPO, are still intact after two years. Microcapsules were formed with the drug so concentrated that crystals formed inside. Multi-layered microspheres, with both hydrophobic drug compartments, can enable diffusion of complementary drugs from the same microcapsule, e.g. antibiotics and immuno-stimulants to treat resistant infections or multiple fibrinolytic drugs to dissolve emboli. Co-encapsulation of enough radio-contrast medium enables oncologists to monitor the delivery of anti-tumor microcapsules to target tumors using computerized tomography and radiography that would track the distribution of microcapsules after release from the intra-arterial catheter. These microcapsules could have important applications in chemotheraphy of certain liver, kidney, brain and other tumors.

  14. Systems analysis of chaperone networks in the malarial parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Soundara Raghavan Pavithra

    2007-09-01

    Full Text Available Molecular chaperones participate in the maintenance of cellular protein homeostasis, cell growth and differentiation, signal transduction, and development. Although a vast body of information is available regarding individual chaperones, few studies have attempted a systems level analysis of chaperone function. In this paper, we have constructed a chaperone interaction network for the malarial parasite, Plasmodium falciparum. P. falciparum is responsible for several million deaths every year, and understanding the biology of the parasite is a top priority. The parasite regularly experiences heat shock as part of its life cycle, and chaperones have often been implicated in parasite survival and growth. To better understand the participation of chaperones in cellular processes, we created a parasite chaperone network by combining experimental interactome data with in silico analysis. We used interolog mapping to predict protein-protein interactions for parasite chaperones based on the interactions of corresponding human chaperones. This data was then combined with information derived from existing high-throughput yeast two-hybrid assays. Analysis of the network reveals the broad range of functions regulated by chaperones. The network predicts involvement of chaperones in chromatin remodeling, protein trafficking, and cytoadherence. Importantly, it allows us to make predictions regarding the functions of hypothetical proteins based on their interactions. It allows us to make specific predictions about Hsp70-Hsp40 interactions in the parasite and assign functions to members of the Hsp90 and Hsp100 families. Analysis of the network provides a rational basis for the anti-malarial activity of geldanamycin, a well-known Hsp90 inhibitor. Finally, analysis of the network provides a theoretical basis for further experiments designed toward understanding the involvement of this important class of molecules in parasite biology.

  15. prevalence of malarial parasites in pregnant women attending sir

    African Journals Online (AJOL)

    DR. AMINU

    Keyword: Prevalence, Malarial Parasite, Pregnant Women, Kano. INTRODUCTION ... protective semi-immunity against plasmodium falciparum is acquired during the first 10-. 15 years of life and .... hiding place for the mosquito? It is therefore ...

  16. Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients

    NARCIS (Netherlands)

    Bloem, Karien; van Leeuwen, Astrid; Verbeek, Gerrit; Nurmohamed, Michael T.; Wolbink, Gerrit Jan; van der Kleij, Desiree; Rispens, Theo

    2015-01-01

    Drug interference complicates assessment of immunogenicity of biologicals and results in an underestimation of anti-drug antibody (ADA) formation. Drug-tolerant assays have the potential to overcome such limitations. However, to which extent drug-tolerant assays provide an unbiased picture of the

  17. Apomorphine conditioning and sensitization: the paired/unpaired treatment order as a new major determinant of drug conditioned and sensitization effects.

    Science.gov (United States)

    de Matos, Liana Wermelinger; Carey, Robert J; Carrera, Marinete Pinheiro

    2010-09-01

    Repeated treatments with psychostimulant drugs generate behavioral sensitization. In the present study we employed a paired/unpaired protocol to assess the effects of repeated apomorphine (2.0 mg/kg) treatments upon locomotion behavior. In the first experiment we assessed the effects of conditioning upon apomorphine sensitization. Neither the extinction of the conditioned response nor a counter-conditioning procedure in which we paired an inhibitory treatment (apomorphine 0.05 mg/kg) with the previously established conditioned stimulus modified the sensitization response. In the second experiment, we administered the paired/unpaired protocol in two phases. In the second phase, we reversed the paired/unpaired protocol. Following the first phase, the paired group alone exhibited conditioned locomotion in the vehicle test and a sensitization response. In the second phase, the initial unpaired group which received 5 paired apomorphine trials during the reversal phase did not develop a conditioned response but developed a potentiated sensitization response. This disassociation of the conditioned response from the sensitization response is attributed to an apomorphine anti-habituation effect that can generate a false positive Pavlovian conditioned response effect. The potentiated sensitization response induced by the treatment reversal protocol points to an important role for the sequential experience of the paired/unpaired protocol in behavioral sensitization. 2010 Elsevier Inc. All rights reserved.

  18. Metabolic Engineering

    Indian Academy of Sciences (India)

    IAS Admin

    Considering its advantages over the other chemical synthesis routes ... such as an anti-malarial drug (artemesinin), chemicals required as the raw ... Assistant Professor at. Symbiosis ... research interests are in ... Synthetic biology, commodity.

  19. Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

    Directory of Open Access Journals (Sweden)

    Shotaro Michinaga

    2015-04-01

    Full Text Available Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vasogenic or cytotoxic edema. Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB and extravasations of serum proteins, while cytotoxic edema is characterized by cell swelling caused by intracellular accumulation of fluid. Various experimental animal models are often used to investigate mechanisms underlying brain edema. Many soluble factors and functional molecules have been confirmed to induce BBB disruption or cell swelling and drugs targeted to these factors are expected to have anti-edema effects. In this review, we discuss the mechanisms and involvement of factors that induce brain edema formation, and the possibility of anti-edema drugs targeting them.

  20. Chloroquine induced pruritus - questionnaire based epidemiological ...

    African Journals Online (AJOL)

    Chloroquine (CQ) is a very useful drug with a broad spectrum of uses (as anti malarial, anti amoebiasis and for connective tissue diseases). A major side effect preventing or limiting its utilization in blacks is chloroquine induced pruritus (CP). A descriptive cross sectional questionnaire based epidemiological study of ...

  1. 49 CFR 655.12 - Required elements of an anti-drug use and alcohol misuse program.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 7 2010-10-01 2010-10-01 false Required elements of an anti-drug use and alcohol... and alcohol misuse program. An anti-drug use and alcohol misuse program shall include the following: (a) A statement describing the employer's policy on prohibited drug use and alcohol misuse in the...

  2. Development of anti-inflammatory drugs - the research and development process.

    Science.gov (United States)

    Knowles, Richard Graham

    2014-01-01

    The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

  3. [Anti-inflammatory, analgesic and anti-pyretic activities of a non-steroidal anti-inflammatory drug, etofenamate, in experimental animals].

    Science.gov (United States)

    Nakamura, H; Motoyoshi, S; Imazu, C; Ishii, K; Yokoyama, Y; Seto, Y; Kadokawa, T; Shimizu, M

    1982-08-01

    Anti-inflammatory, analgesic, and anti-pyretic activities of orally administered etofenamate, the diethylene glycol ester of flufenamic acid, were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice and ultra-violet light-induced erythema in guinea pigs, etofenamate produced a dose related inhibition at doses of 40--320 mg/kg and 5--20 mg/kg, respectively. In rats, felt-pellet-induced granuloma formation and adjuvant-induced arthritis were significantly inhibited by repeated administration of etofenamate at doses of 20 mg/kg/day for 5 days and 40 mg/kg/day for 21 days, respectively. Etofenamate showed an inhibitory activity on the squeak response caused by flexing and extending the silver nitrate-induced arthritic joint in rats; and it produced a dose related anti-writhing activity at doses of 50--300 mg/kg and 10--80 mg/kg in mice and rats, respectively, in the acetic acid-induced writhing test. Etofenamate showed a significant anti-pyretic activity at doses of 0.2 mg/kg or more. These potencies of etofenamate were 0.5 to 1.6 times those of flufenamic acid. In particular, the anti-erythema, anti-arthritis, and anti-pyretic activities of etofenamate were approximately equivalent to or superior to those of flufenamic acid. From these results, it was suggested that etofenamate given orally, like other non-steroidal anti-inflammatory drugs, showed anti-inflammatory, analgesic, and anti-pyretic activities in experimental animals.

  4. Cross-talk between malarial cysteine proteases and falstatin: the BC loop as a hot-spot target.

    Directory of Open Access Journals (Sweden)

    Srinivasan Sundararaj

    Full Text Available Cysteine proteases play a crucial role in the development of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Our earlier studies demonstrated that these enzymes are equipped with specific domains for defined functions and further suggested the mechanism of activation of cysteine proteases. The activities of these proteases are regulated by a new class of endogenous inhibitors of cysteine proteases (ICPs. Structural studies of the ICPs of Trypanosoma cruzi (chagasin and Plasmodium berghei (PbICP indicated that three loops (termed BC, DE, and FG are crucial for binding to target proteases. Falstatin, an ICP of P. falciparum, appears to play a crucial role in invasion of erythrocytes and hepatocytes. However, the mechanism of inhibition of cysteine proteases by falstatin has not been established. Our study suggests that falstatin is the first known ICP to function as a multimeric protein. Using site-directed mutagenesis, hemoglobin hydrolysis assays and peptide inhibition studies, we demonstrate that the BC loop, but not the DE or FG loops, inhibits cysteine proteases of P. falciparum and P. vivax via hydrogen bonds. These results suggest that the BC loop of falstatin acts as a hot-spot target for inhibiting malarial cysteine proteases. This finding suggests new strategies for the development of anti-malarial agents based on protease-inhibitor interactions.

  5. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

    Science.gov (United States)

    Devarbhavi, Harshad; Andrade, Raúl J

    2014-05-01

    Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  6. Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs

    Science.gov (United States)

    McGettigan, Patricia; Roderick, Peter; Mahajan, Rushikesh; Kadam, Abhay; Pollock, Allyson M.

    2015-01-01

    Background In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states’ powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). Methods and Findings This was an ecologic study with a time-trend analysis of FDC sales volumes (2007–2012) and a cross-sectional examination of 2011–2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval (“approved” and “unapproved”), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011–2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved

  7. Therapeutic Potential of Plants as Anti-Microbials for Drug Discovery

    Directory of Open Access Journals (Sweden)

    Ramar Perumal Samy

    2010-01-01

    Full Text Available The uses of traditional medicinal plants for primary health care have steadily increased worldwide in recent years. Scientists are in search of new phytochemicals that could be developed as useful anti-microbials for treatment of infectious diseases. Currently, out of 80% of pharmaceuticals derived from plants, very few are now being used as anti-microbials. Plants are rich in a wide variety of secondary metabolites that have found anti-microbial properties. This review highlights the current status of traditional medicine, its contribution to modern medicine, recent trends in the evaluation of anti-microbials with a special emphasis upon some tribal medicine, in vitro and in vivo experimental design for screening, and therapeutic efficacy in safety and human clinical trails for commercial outlet. Many of these commercially available compounds are crude preparations administered without performing human clinical trials. Recent methods are useful to standardize the extraction for scientific investigation of new phytochemicals and anti-microbials of traditionally used plants. It is concluded that once the local ethnomedical preparations of traditional sources are scientifically evaluated before dispensing they should replace existing drugs commonly used for the therapeutic treatment of infection. This method should be put into practice for future investigations in the field of ethnopharmacology, phytochemistry, ethnobotany and other biological fields for drug discovery.

  8. Automatic detection and classification of malarial retinopathy- associated retinal whitening in digital retinal images

    International Nuclear Information System (INIS)

    Akram, M.U.; Alvi, A.B.N.; Khan, S.A.

    2017-01-01

    Malarial retinopathy addresses diseases that are characterized by abnormalities in retinal fundus imaging. Macular whitening is one of the distinct signs of cerebral malaria but has hardly been explored as a critical bio-marker. The paper proposes a computerized detection and classification method for malarial retinopathy using retinal whitening as a bio-marker. The paper combines various statistical and color based features to form a sound feature set for accurate detection of retinal whitening. All features are extracted at image level and feature selection is performed to detect most discriminate features. A new method for macula location is also presented. The detected macula location is further used for grading of whitening as macular or peripheral whitening. Support vector machine along with radial basis function is used for classification of normal and malarial retinopathy patients. The evaluation is performed using a locally gathered dataset from malarial patients and it achieves an accuracy of 95% for detection of retinal whitening and 100% accuracy for grading of retinal whitening as macular or non-macular. One of the major contributions of proposed method is grading of retinal whitening into macular or peripheral whitening. (author)

  9. Pharmacokinetic aspects of the anti-epileptic drug substance vigabatrin

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Frølund, Sidsel; Holm, René

    2014-01-01

    are discussed in detail. Special focus is on the contribution of the proton-coupled amino acid transporter 1 (PAT1) for intestinal vigabatrin absorption. Furthermore, the review gives an overview of the pharmacokinetic parameters of vigabatrin across different species and drug-food and drug-drug interactions......Drug transporters in various tissues, such as intestine, kidney, liver and brain, are recognized as important mediators of absorption, distribution, metabolism and excretion of drug substances. This review gives a current status on the transporter(s) mediating the absorption, distribution......, metabolism and excretion properties of the anti-epileptic drug substance vigabatrin. For orally administered drugs, like vigabatrin, the absorption from the intestine is a prerequisite for the bioavailability. Therefore, transporter(s) involved in the intestinal absorption of vigabatrin in vitro and in vivo...

  10. Photo-translocation of anti-HIV-1 drugs into TZM-bl cells

    CSIR Research Space (South Africa)

    Khanyile, T

    2013-04-01

    Full Text Available Targeted drug delivery into HIV-1 infected cells offers a reduction in toxicity and side effect. Using a femtosecond (fs) laser of different beam shapes anti-HIV-1 drugs are efficiently delivered into TZM-bl cells....

  11. AtriplaR/anti-TB combination in TB/HIV patients. Drug in focus

    Directory of Open Access Journals (Sweden)

    Semvua Hadija H

    2011-11-01

    Full Text Available Abstract Background Co-administration of anti-tuberculosis and antiretroviral therapy is often inevitable in high-burden countries where tuberculosis is the most common opportunistic infection associated with HIV/AIDS. Concurrent use of rifampicin and several antiretroviral drugs is complicated by pharmacokinetic drug-drug interaction. Method Pubmed and Google search following the key words tuberculosis, HIV, emtricitabine, tenofovir efavirenz, interaction were used to find relevant information on each drug of the fixed dose combination AtriplaR Results Information on generic name, trade name, pharmacokinetic parameter, metabolism and the pharmacokinetic interaction with Anti-TB drugs of emtricitabine, tenofovir, and efavirenz was obtained. Conclusion Fixed dose combination of emtricitabine/tenofovir/efavirenz (ATRIPLAR which has been approved by Food and Drug Administration shows promising results as far as safety and efficacy is concerned in TB/HIV co-infection patients, hence can be considered effective and safe antiretroviral drug in TB/HIV management for adult and children above 3 years of age.

  12. Effects of Ethanolic Extract of Hyptis Suavoelens on the Food, Water ...

    African Journals Online (AJOL)

    ... of Plasmodium(P.) species to hitherto widely used anti-malarial drugs such as chloroquine and more recently quinine. Resistance to these drugs which occurs with increasing frequency consequently underlies the necessity to develop new agents for malaria chemotherapy, (family Labiatae) a plant traditionally used in the ...

  13. Characterization of Nanodiamond-based anti-HIV drug Delivery to the Brain.

    Science.gov (United States)

    Roy, Upal; Drozd, Vadym; Durygin, Andriy; Rodriguez, Jesse; Barber, Paul; Atluri, Venkata; Liu, Xiaohua; Voss, Thomas G; Saxena, Surendra; Nair, Madhavan

    2018-01-25

    Human Immunodeficiency Virus Type 1 (HIV-1) remains one of the leading causes of death worldwide. Present combination antiretroviral therapy has substantially improved HIV-1 related pathology. However, delivery of therapeutic agents to the HIV reservoir organ like Central nervous system (CNS) remains a major challenge primarily due to the ineffective transmigration of drugs through Blood Brain Barrier (BBB). The recent advent of nanomedicine-based drug delivery has stimulated the development of innovative systems for drug delivery. In this regard, particular focus has been given to nanodiamond due to its natural biocompatibility and non-toxic nature-making it a more efficient drug carrier than other carbon-based materials. Considering its potential and importance, we have characterized unmodified and surface-modified (-COOH and -NH 2 ) nanodiamond for its capacity to load the anti-HIV-1 drug efavirenz and cytotoxicity, in vitro. Overall, our study has established that unmodified nanodiamond conjugated drug formulation has significantly higher drug loading capacity than surface-modified nanodiamond with minimum toxicity. Further, this nanodrug formulation was characterized by its drug dissolution profile, transmigration through the BBB, and its therapeutic efficacy. The present biological characterizations provide a foundation for further study of in-vivo pharmacokinetics and pharmacodynamics of nanodiamond-based anti-HIV drugs.

  14. 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

  15. Anticancer Effect of AntiMalarial Artemisinin Compounds | Das ...

    African Journals Online (AJOL)

    A PubMed search of about 127 papers on anti‑cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. ... Keywords: Anticancer agents, Antimalarials, Antitumor activity, Artemisinins, Novel chemotherapy ...

  16. Prevalence of drug resistant tuberculosis in Arsi Zone, Ethiopia ...

    African Journals Online (AJOL)

    Background: Wide spread of occurrence of multi-drug resistance tuberculosis is becoming a major challenge to effective tuberculosis control. Thus, it is imperative to monitor the sensitivity of anti-TB drugs regularly. Objective: To determine the prevalence resistance to anti-TB drugs in a well established control program area ...

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

    Science.gov (United States)

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

    2016-06-22

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

  18. Osteoarthritis guidelines: a progressive role for topical nonsteroidal anti-inflammatory drugs.

    Science.gov (United States)

    Stanos, Steven P

    2013-01-01

    Current treatment guidelines for the treatment of chronic pain associated with osteoarthritis reflect the collective clinical knowledge of international experts in weighing the benefits of pharmacologic therapy options while striving to minimize the negative effects associated with them. Consideration of disease progression, pattern of flares, level of functional impairment or disability, response to treatment, coexisting conditions such as cardiovascular disease or gastrointestinal disorders, and concomitant prescription medication use should be considered when creating a therapeutic plan for a patient with osteoarthritis. Although topical nonsteroidal anti-inflammatory drugs historically have not been prevalent in many of the guidelines for osteoarthritis treatment, recent evidence-based medicine and new guidelines now support their use as a viable option for the clinician seeking alternatives to typical oral formulations. This article provides a qualitative review of these treatment guidelines and the emerging role of topical nonsteroidal anti-inflammatory drugs as a therapy option for patients with localized symptoms of osteoarthritis who may be at risk for oral nonsteroidal anti-inflammatory drug-related serious adverse events.

  19. Cost-effectiveness of dihydroartemisinin-piperaquine compared with artemether-lumefantrine for treating uncomplicated malaria in children at a district hospital in Tanzania.

    Science.gov (United States)

    Mori, Amani T; Ngalesoni, Frida; Norheim, Ole F; Robberstad, Bjarne

    2014-09-15

    Dihydroartemisinin-piperaquine (DhP) is highly recommended for the treatment of uncomplicated malaria. This study aims to compare the costs, health benefits and cost-effectiveness of DhP and artemether-lumefantrine (AL) alongside "do-nothing" as a baseline comparator in order to consider the appropriateness of DhP as a first-line anti-malarial drug for children in Tanzania. A cost-effectiveness analysis was performed using a Markov decision model, from a provider's perspective. The study used cost data from Tanzania and secondary effectiveness data from a review of articles from sub-Saharan Africa. Probabilistic sensitivity analysis was used to incorporate uncertainties in the model parameters. In addition, sensitivity analyses were used to test plausible variations of key parameters and the key assumptions were tested in scenario analyses. The model predicts that DhP is more cost-effective than AL, with an incremental cost-effectiveness ratio (ICER) of US$ 12.40 per DALY averted. This result relies on the assumption that compliance to treatment with DhP is higher than that with AL due to its relatively simple once-a-day dosage regimen. When compliance was assumed to be identical for the two drugs, AL was more cost-effective than DhP with an ICER of US$ 12.54 per DALY averted. DhP is, however, slightly more likely to be cost-effective compared to a willingness-to-pay threshold of US$ 150 per DALY averted. Dihydroartemisinin-piperaquine is a very cost-effective anti-malarial drug. The findings support its use as an alternative first-line drug for treatment of uncomplicated malaria in children in Tanzania and other sub-Saharan African countries with similar healthcare infrastructures and epidemiology of malaria.

  20. [Development of anti-Alzheimer's disease drug based on beta-amyloid hypothesis].

    Science.gov (United States)

    Sugimoto, Hachiro

    2010-04-01

    Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of beta-amyloid is the fundamental cause. This theory suggests that beta-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the beta-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.

  1. Animal models for testing anti-prion drugs.

    Science.gov (United States)

    Fernández-Borges, Natalia; Elezgarai, Saioa R; Eraña, Hasier; Castilla, Joaquín

    2013-01-01

    Prion diseases belong to a group of fatal infectious diseases with no effective therapies available. Throughout the last 35 years, less than 50 different drugs have been tested in different experimental animal models without hopeful results. An important limitation when searching for new drugs is the existence of appropriate models of the disease. The three different possible origins of prion diseases require the existence of different animal models for testing anti-prion compounds. Wild type, over-expressing transgenic mice and other more sophisticated animal models have been used to evaluate a diversity of compounds which some of them were previously tested in different in vitro experimental models. The complexity of prion diseases will require more pre-screening studies, reliable sporadic (or spontaneous) animal models and accurate chemical modifications of the selected compounds before having an effective therapy against human prion diseases. This review is intended to put on display the more relevant animal models that have been used in the search of new antiprion therapies and describe some possible procedures when handling chemical compounds presumed to have anti-prion activity prior to testing them in animal models.

  2. [Drug eruptions caused by noncorticoid anti-inflammatory agents].

    Science.gov (United States)

    Roujeau, J C; Guillaume, J C; Revuz, J; Touraine, R

    1984-01-01

    Non-steroidal anti-inflammatory drugs (NSAI) may elicit various kinds of cutaneous side effects. The commonest ones are non-specific erythematous eruptions, sometimes with a phototoxic distribution, and urticaria. Vasculitis and severe bullous eruptions (Stevens-Johnson's syndrome and Toxic Epidermal Necrolysis) are rare but may have severe outcomes. The overall incidence of cutaneous reactions is about the same for all NSAI, 1 to 3 p. 100, during the clinical studies performed before marketing the drug, but this increases afterwards (up to 45 p. 100 for Benoxaprofen). Drugs with long half-lives may carry a higher risk for severe cutaneous reactions. NSAI are now the main cause of drug induced TEN. Urticarial reactions seem related to pharmacological phenomena while the pathogenic events leading to other kinds of skin reactions remain unknown. An hypersensitivity reaction is postulated. The therapeutic value of corticosteroids for the severe cutaneous side effects of drugs is still controversial.

  3. Effects of non-steroidal anti-inflammatory drugs on cyanobacteria and algae in laboratory strains and in natural algal assemblages.

    Science.gov (United States)

    Bácsi, István; B-Béres, Viktória; Kókai, Zsuzsanna; Gonda, Sándor; Novák, Zoltán; Nagy, Sándor Alex; Vasas, Gábor

    2016-05-01

    In recent years measurable concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) have been shown in the aquatic environment as a result of increasing human consumption. Effects of five frequently used non-steroidal anti-inflammatory drugs (diclofenac, diflunisal, ibuprofen, mefenamic acid and piroxicam in 0.1 mg ml(-1) concentration) in batch cultures of cyanobacteria (Synechococcus elongatus, Microcystis aeruginosa, Cylindrospermopsis raciborskii), and eukaryotic algae (Desmodesmus communis, Haematococcus pluvialis, Cryptomonas ovata) were studied. Furthermore, the effects of the same concentrations of NSAIDs were investigated in natural algal assemblages in microcosms. According to the changes of chlorophyll-a content, unicellular cyanobacteria seemed to be more tolerant to NSAIDs than eukaryotic algae in laboratory experiments. Growth of eukaryotic algae was reduced by all drugs, the cryptomonad C. ovata was the most sensitive to NSAIDs, while the flagellated green alga H. pluvialis was more sensitive than the non-motile green alga D. communis. NSAID treatments had weaker impact in the natural assemblages dominated by cyanobacteria than in the ones dominated by eukaryotic algae, confirming the results of laboratory experiments. Diversity and number of functional groups did not change notably in cyanobacteria dominated assemblages, while they decreased significantly in eukaryotic algae dominated ones compared to controls. The results highlight that cyanobacteria (especially unicellular ones) are less sensitive to the studied, mostly hardly degradable NSAIDs, which suggest that their accumulation in water bodies may contribute to the expansion of cyanobacterial mass productions in appropriate environmental circumstances by pushing back eukaryotic algae. Thus, these contaminants require special attention during wastewater treatment and monitoring of surface waters. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Anti-trypanosomal activity of pentacyclic triterpenes isolated from Austroplenckia populnea (Celastraceae).

    Science.gov (United States)

    Duarte, Lucienir Pains; Vieira Filho, Sidney Augusto; Silva, Grácia Divina de Fátima; de Sousa, José Rego; Pinto, Artur da Silveira

    2002-01-01

    Four pentacyclic triterpenes isolated from Austroplenckia populnea and four compounds of known anti T. cruzi or anti-malarial activity were tested. Of those triterpenes tested 20alpha-hydroxy-tingenone showed high activity, epikatonic acid was less active, while populnilic and populninic acids were inactive against the trypanosome of the subgenus Schizotrypanum tested. Benzonidazole, nifurtimox, ketoconazole and primaquine presented a remarkable dose-dependent inhibitory effect reaching practically to a total growth inhibition of the parasite at the end of incubation time. The trypanosome tested appear to be a suitable model for preliminary screen for anti T. (S.) cruzi compounds.

  5. Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson disease.

    Science.gov (United States)

    Hancock, Dana B; Martin, Eden R; Stajich, Jeffrey M; Jewett, Rita; Stacy, Mark A; Scott, Burton L; Vance, Jeffery M; Scott, William K

    2007-04-01

    To assess associations between Parkinson disease (PD) and putatively protective factors-smoking, caffeine (coffee, tea, and soft drinks), and nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, and naproxen). Family-based case-control study. Academic medical center clinic. A total of 356 case subjects and 317 family controls who self-reported environmental exposures. Associations between PD and environmental measures (history, status, dosage, duration, and intensity) of smoking, coffee, caffeine, nonsteroidal anti-inflammatory drugs, and non-aspirin nonsteroidal anti-inflammatory drugs were examined using generalized estimating equations with an independent correlation matrix while controlling for age and sex. Individuals with PD were significantly less likely to report ever smoking (odds ratio = 0.56; 95% confidence interval, 0.41-0.78). Additional measures of smoking revealed significant inverse associations with PD (Pcoffee drinking was inversely associated with PD (test for trend P = .05). Increasing dosage (trend P = .009) and intensity (trend P = .01) of total caffeine consumption were also inversely associated, with high dosage presenting a significant inverse association for PD (odds ratio = 0.58; 95% confidence interval, 0.34-0.99). There were no significant associations between nonsteroidal anti-inflammatory drugs and PD. Inverse associations of smoking and caffeine were corroborated using families with PD, thus emphasizing smoking and caffeine as important covariates to consider in genetic studies of PD.

  6. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention.

    NARCIS (Netherlands)

    Vonkeman, Harald Erwin; van de Laar, Mart A F J

    2010-01-01

    Objectives: To discuss nonsteroidal anti-inflammatory drugs (NSAIDs), their history, development, mode of action, toxicities, strategies for the prevention of toxicity, and future developments. - Methods: Medline search for articles published up to 2007, using the keywords acetylsalicylic acid,

  7. Nanotech revolution for the anti-cancer drug delivery through blood-brain barrier.

    Science.gov (United States)

    Caraglia, M; De Rosa, G; Salzano, G; Santini, D; Lamberti, M; Sperlongano, P; Lombardi, A; Abbruzzese, A; Addeo, R

    2012-03-01

    Nanotechnology-based drug delivery was born as a chance for pharmaceutical weapons to be delivered in the body sites where drug action is required. Specifically, the incorporation of anti-cancer agents in nanodevices of 100-300 nm allows their delivery in tissues that have a fenestrated vasculature and a reduced lymphatic drainage. These two features are typical of neoplastic tissues and, therefore, allow the accumulation of nanostructured devices in tumours. An important issue of anti-cancer pharmacological strategies is the overcoming of anatomical barriers such as the bloodbrain- barrier (BBB) that protects brain from toxicological injuries but, at the same time, makes impossible for most of the pharmacological agents with anti-cancer activity to reach tumour cells placed in the brain and derived from either primary tumours or metastases. In fact, only highly lipophilic molecules can passively diffuse through BBB to reach central nervous system (CNS). Another possibility is to use nanotechnological approaches as powerful tools to across BBB, by both prolonging the plasma half-life of the drugs and crossing fenestrations of BBB damaged by brain metastases. Moreover, modifications of nanocarrier surface with specific endogenous or exogenous ligands can promote the crossing of intact BBB as in the case of primary brain tumours. This aim can be achieved through the binding of the nanodevices to carriers or receptors expressed by the endothelial cells of BBB and that can favour the internalization of the nanostructured devices delivering anti-cancer drugs. This review summarizes the most meaningful advances in the field of nanotechnologies for brain delivery of drugs.

  8. In vivo antiplasmodial and toxicological effect of crude ethanol extract of Echinops kebericho traditionally used in treatment of malaria in Ethiopia.

    Science.gov (United States)

    Toma, Alemayehu; Deyno, Serawit; Fikru, Abrham; Eyado, Amalework; Beale, Andrew

    2015-05-10

    Medicinal plants have contributed significantly to current malaria treatment. Emergence of resistance to currently available drugs has necessitated the search for new plant-based anti-malarial agents and several plant-based, pharmacologically active anti-malarial compounds have been isolated. This study was conducted to validate the traditional usage of Echinops kebericho for treating malaria in the traditional health care system of Ethiopia. The roots of E. kebericho were collected from Masha Woreda, Sheka Zone. After collection, the plant materials were identified by a taxonomist, dried under shade and crushed to powder for extraction. The powdered roots were extracted by maceration using 70 % ethanol. Acute toxicity study of the crude extract was carried out in Swiss albino mice. The in vivo anti-malarial activity of plant extract (200, 350 and 500 mg/kg) of E. kebericho roots against a chloroquine (CQ) sensitive strain of Plasmodium berghei strain ANKA was assessed using the four-day suppressive test procedure. Parameters such as parasitaemia, packed cell volume, body weight and survival time were then determined using standard tests. Oral administration of the ethanol extract showed significant (P<0.001) parasitaemia suppression at dose levels of 350 and 500 mg/kg in dose-related manner compared with the negative control. Five hundred mg/kg showed the highest (57.29±1.76 %) parasitaemia suppression. The survival times of P. berghei-infected mice were also increased in a dose-dependent manner but the test material did not prevent weight loss associated with increased parasitaemia. The result also showed the plant material prevented the loss in packed cell volume associated with increased parasitaemia. Its oral LD50 was found to be greater than 5,000 mg/kg, indicating its wider safety margin in mice. The result revealed the ethanol extract of E. kebericho roots has anti-malarial activity against P. berghei in an animal model and lends support to the use of the

  9. A targeted proteomics approach to the quantitative analysis of ERK/Bcl-2-mediated anti-apoptosis and multi-drug resistance in breast cancer.

    Science.gov (United States)

    Yang, Ting; Xu, Feifei; Sheng, Yuan; Zhang, Wen; Chen, Yun

    2016-10-01

    Apoptosis suppression caused by overexpression of anti-apoptotic proteins is a central factor to the acquisition of multi-drug resistance (MDR) in breast cancer. As a highly conserved anti-apoptotic protein, Bcl-2 can initiate an anti-apoptosis response via an ERK1/2-mediated pathway. However, the details therein are still far from completely understood and a quantitative description of the associated proteins in the biological context may provide more insights into this process. Following our previous attempts in the quantitative analysis of MDR mechanisms, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics was continually employed here to describe ERK/Bcl-2-mediated anti-apoptosis. A targeted proteomics assay was developed and validated first for the simultaneous quantification of ERK1/2 and Bcl-2. In particular, ERK isoforms (i.e., ERK1 and ERK2) and their differential phosphorylated forms including isobaric ones were distinguished. Using this assay, differential protein levels and site-specific phosphorylation stoichiometry were observed in parental drug-sensitive MCF-7/WT cancer cells and drug-resistant MCF-7/ADR cancer cells and breast tissue samples from two groups of patients who were either suspected or diagnosed to have drug resistance. In addition, quantitative analysis of the time course of both ERK1/2 and Bcl-2 in doxorubicin (DOX)-treated MCF-7/WT cells confirmed these findings. Overall, we propose that targeted proteomics can be used generally to resolve more complex cellular events.

  10. Nonsteroidal anti-inflammatory drugs for treatment of acute gout

    NARCIS (Netherlands)

    van Durme, Caroline M. P. G.; Wechalekar, Mihir D.; Landewé, Robert B. M.

    2015-01-01

    Are nonsteroidal anti-inflammatory drugs (NSAIDs) associated with better outcomes than cyclooxygenase inhibitors, glucocorticoids, IL-1 inhibitors or placebo in the treatment of acute gout? NSAIDs are not significantly associated with a difference in pain reduction compared with cyclooxygenase

  11. In silico approaches and chemical space of anti-P-type ATPase compounds for discovering new antituberculous drugs.

    Science.gov (United States)

    Santos, Paola; López-Vallejo, Fabian; Soto, Carlos-Y

    2017-08-01

    Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti-TB targets. In this context, P-type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti-TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti-TB and anti-P-type ATPase activity is discussed. The chemical space distribution compared to public compound libraries demonstrates that natural product libraries are a source of novel chemical scaffolds with potential anti-P-type ATPase activity. Furthermore, compounds that experimentally display anti-P-type ATPase activity belong to a chemical space of molecular properties comparable to that occupied by those approved for oral use, suggesting that these kinds of molecules have a good pharmacokinetic profile (drug-like) for evaluation as potential anti-TB drugs. © 2017 John Wiley & Sons A/S.

  12. The Multi-Billion Dollar Drug-Sensitive Spending Opportunity.

    Science.gov (United States)

    Easter, Jon C; Thorpe, Kenneth

    2018-01-01

    Chronic diseases increase utilization and avoidable drug-sensitive spending, but little is done to optimize medication use and drive value. Value-based approaches to health care financing should shift focus to drug-sensitive spending to balance patient access and quality improvement with cost containment. ©2018 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.

  13. Anti-diabetic drug utilization of pregnant diabetic women in us managed care.

    Science.gov (United States)

    Knox, Caitlin A; Delaney, Joseph A C; Winterstein, Almut G

    2014-01-17

    With the increasing prevalence of type 2 diabetes in young adulthood, treatment of diabetes in pregnancy faces new challenges. Anti-diabetic drug utilization patterns of pregnant women with pre-existing diabetes are poorly described. We aim to describe anti-diabetic (AD) agent utilization among diabetic pregnant women. We utilized IMS LifeLink, including administrative claims data of patients in US managed care plans, to establish a retrospective cohort of women, age 18-46 years (N = 96,740) with billed procedures for a live birth, and a 12 month eligibility period before and 3 month after delivery. Diabetes mellitus was identified from ≥2 in- or outpatient claims with diagnoses (ICD-9-CM 250.XX) before pregnancy. We estimated the prevalence of AD drugs before, during and after pregnancy, and secular trends across the study period (1999-2009), using linear regression. A sensitivity analysis was conducted to identify the extent of misclassification of trimesters. Almost six percent (n = 5,581) of the live birth cohort had diabetes mellitus. Throughout the study, 48% (1999) and 78% (2009) (p metformin, sulfonylureas, thiazolidinediones (TZD), and combination AD. The annual prevalence of insulin use increased by only 1% from 39% (1999) to 40% (2009) (p = 0.589) during pregnancy, while use of sulfonylureas and metformin increased from 2.5% and 4.2% (1999) to 17.3% and 15.3% (2009) (p use steadily increased in prevalence from the 1st to 3rd trimester (16.5% and 3.3% to 33.0% and 7.5%), while metformin and TZD use decreased (11.4% and 1.6% to 3.8% and 0.2%). AD use during pregnancy demonstrates the need for additional investigation regarding safety and efficacy of AD drugs on maternal outcomes.

  14. Plasmodium falciparum transfected with ultra bright NanoLuc luciferase offers high sensitivity detection for the screening of growth and cellular trafficking inhibitors.

    Directory of Open Access Journals (Sweden)

    Mauro F Azevedo

    Full Text Available Drug discovery is a key part of malaria control and eradication strategies, and could benefit from sensitive and affordable assays to quantify parasite growth and to help identify the targets of potential anti-malarial compounds. Bioluminescence, achieved through expression of exogenous luciferases, is a powerful tool that has been applied in studies of several aspects of parasite biology and high throughput growth assays. We have expressed the new reporter NanoLuc (Nluc luciferase in Plasmodium falciparum and showed it is at least 100 times brighter than the commonly used firefly luciferase. Nluc brightness was explored as a means to achieve a growth assay with higher sensitivity and lower cost. In addition we attempted to develop other screening assays that may help interrogate libraries of inhibitory compounds for their mechanism of action. To this end parasites were engineered to express Nluc in the cytoplasm, the parasitophorous vacuole that surrounds the intraerythrocytic parasite or exported to the red blood cell cytosol. As proof-of-concept, these parasites were used to develop functional screening assays for quantifying the effects of Brefeldin A, an inhibitor of protein secretion, and Furosemide, an inhibitor of new permeation pathways used by parasites to acquire plasma nutrients.

  15. A sensitive radioimmunoassay for the detection of monoclonal anti-idiotype antibodies

    International Nuclear Information System (INIS)

    Morahan, G.

    1983-01-01

    A radioimmunoassay was developed in order to detect anti-idiotypic antibodies in the supernatants of hybrid cells. This assay is both sensitive and specific for anti-idiotypic (but not anti-allotypic) antibodies. Monoclonal antibodies present in test supernatants are bound by an anti-immunoglobulin coated solid phase. Subsequent incubation with a source of mouse immunoglobulin 'blocks' unreacted anti-immunoglobulin antibodies on the solid phase. Anti-idiotypic antibodies are then detected by their ability to bind 125 I-labelled idiotype-bearing antibody. This paper describes the use of this assay to detect monoclonal anti-idiotypic antibodies in 2 systems; the cross-reactive idiotype of A/J anti-ABA antibodies, and the idiotype expressed by the myeloma protein HOPC 8. Similarly, 125 I-labelled anti-idiotype antibodies may be used in this assay to detect monoclonal idiotype-bearing antibodies. Further modifications are described which would allow the detection of monoclonal anti-allotype antibodies. (Auth.)

  16. Repurposing of Aspirin and Ibuprofen as Candidate Anti-Cryptococcus Drugs

    Science.gov (United States)

    Ogundeji, Adepemi O.; Pohl, Carolina H.

    2016-01-01

    The usage of fluconazole and amphotericin B in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. Thus, there is a constant need to find new drugs to better manage fungal infections. Toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. In vitro susceptibility tests, including a checkerboard assay, were performed to assess the response of Cryptococcus neoformans and Cryptococcus gattii to the above-mentioned anti-inflammatory drugs. Next, the capacity of these two drugs to induce stress as well as their mode of action in the killing of cryptococcal cells was determined. The studied fungal strains revealed a response to both aspirin and ibuprofen that was dose dependent, with ibuprofen exerting greater antimicrobial action. More importantly, the MICs of these drugs did not negatively (i) affect growth or (ii) impair the functioning of macrophages; rather, they enhanced the ability of these immune cells to phagocytose cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B. The treatment of cryptococcal cells with aspirin or ibuprofen led to stress induction via activation of the high-osmolarity glycerol (HOG) pathway, and cell death was eventually achieved through reactive oxygen species (ROS)-mediated membrane damage. The presented data highlight the potential clinical application of aspirin and ibuprofen as candidate anti-Cryptococcus drugs. PMID:27246782

  17. Treatment Failure for Malaria in Vietnam

    Centers for Disease Control (CDC) Podcasts

    2017-06-05

    WHO malaria expert, Dr. Charlotte Rasmussen, discusses anti-malarial drug resistance in Vietnam.  Created: 6/5/2017 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 6/5/2017.

  18. [Reversible infertility from nonsteroidal anti-inflammatory drugs].

    Science.gov (United States)

    Skomsvoll, Johan Fredrik; Rødevand, Erik; Koksvik, Hege Svean; Salvesen, Kjell Asmund; von Düring, Vidar; Rygnestad, Tarjei; Østensen, Monika

    2005-06-02

    Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors may interfere with ovulation and the rupture of the follicle, causing reversible infertility. Literature review. Reversible infertility is shown both in animal and human studies of these drugs. As determined by ultrasound, the drugs may delay or inhibit ovulation. These findings are also confirmed by a few randomized controlled studies showing an increase in time from the luteinizing hormone surge to rupture of the follicle and an increased size of the unruptured follicle. Most of the hormone analyses show values in accordance with the ovulation/menstrual cycle. Also, two epidemiological studies have shown an association between NSAID use and spontaneous abortion. These studies have methodological weaknesses and their findings have to be elucidated in future studies. Women with fertility problems should avoid not only the selective cyclooxygenase-2 inhibitors, but also the traditional NSAIDs. However, women with rheumatic disease responding well to therapy should consult their physicians before stopping treatment. Reduced dose of a NSAID and temporary stop of drug treatment early in the menstrual cycle, or alternative drug treatment, may be a solution. NSAIDs should not be used in the last eight weeks of pregnancy.

  19. Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis

    DEFF Research Database (Denmark)

    Ahlehoff, O; Skov, L; Gislason, G

    2014-01-01

    BACKGROUND: Psoriasis is a common disease and is associated with cardiovascular diseases. Systemic anti-inflammatory drugs may reduce risk of cardiovascular events. We therefore examined the rate of cardiovascular events, i.e. cardiovascular death, myocardial infarction and stroke, in patients...... with severe psoriasis treated with systemic anti-inflammatory drugs. METHODS: Individual-level linkage of administrative registries was used to perform a longitudinal nationwide cohort study. Time-dependent multivariable adjusted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence...... intervals (CIs) of cardiovascular events associated with use of biological drugs, methotrexate, cyclosporine, retinoids and other antipsoriatic therapies, including topical treatments, phototherapy and climate therapy. RESULTS: A total of 6902 patients (9662 treatment exposures) with a maximum follow...

  20. International comparison of the factors influencing reimbursement of targeted anti-cancer drugs.

    Science.gov (United States)

    Lim, Carol Sunghye; Lee, Yun-Gyoo; Koh, Youngil; Heo, Dae Seog

    2014-11-29

    Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost-effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (ρ = -0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs.

  1. 49 CFR 655.11 - Requirement to establish an anti-drug use and alcohol misuse program.

    Science.gov (United States)

    2010-10-01

    ... use and alcohol misuse program. Each employer shall establish an anti-drug use and alcohol misuse... 49 Transportation 7 2010-10-01 2010-10-01 false Requirement to establish an anti-drug use and alcohol misuse program. 655.11 Section 655.11 Transportation Other Regulations Relating to Transportation...

  2. Gastrointestinal Complications Depending on the Selectivity of Non-Steroidal Anti-Inflammatory Drug

    Directory of Open Access Journals (Sweden)

    G.V. Dzyak

    2013-02-01

    Full Text Available The article deals with the problem of gastrointestinal complications during administration of nonsteroidal anti-inflammatory drugs, commonly used to treat a range of conditions, particularly rheumatic diseases. The results of own researches, which served to define the characteristics of changes in the state of gastric secretory function in patients receiving non-selective and selective anti-inflammatory agent and their comparative analysis, are provided. The data obtained demonstrated a certain contribution to the understanding of the mechanism of development of complications from the gastrointestinal tract when taken drugs of above group.

  3. Hyper-reactive Malarial Splenomegaly: A Case Report and Review ...

    African Journals Online (AJOL)

    Hyper-reactive malarial splenomegaly is thought to represent a dysfunctional immune response to recurrent malaria infection. A 14 year old male child with hms, hypersplenism, ascites and peripheral lymphadenopathy is reported. There was initial poor response to proguanil aggravated by non compliance. He was started ...

  4. Adjuvant Anti-Angiogenesis Drugs Are No Benefit in Kidney Cancer

    Science.gov (United States)

    Results from a recent clinical trial show that post-surgical therapy with two anti-angiogenesis drugs does not improve progression-free survival for patients with kidney cancer and may cause serious side effects.

  5. Anti-malarial activity of ethanolic leaf extract of Piliostigma thonningii ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-06-07

    Jun 7, 2010 ... Key words: Piliostigma thonningii, anti plasmodial, Plasmodium berghei berghei NK65. ... predicted that a reliable malaria vaccine is several years away. The global ... nature and its petals are white to pinkish colour produced between ... randomized into three groups of three mice each and were given.

  6. Sonochemically synthesized biocompatible zirconium phosphate nanoparticles for pH sensitive drug delivery application

    Energy Technology Data Exchange (ETDEWEB)

    Kalita, Himani, E-mail: hkalita74@gmail.com [Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302 (India); Prashanth Kumar, B.N., E-mail: prasanthkumar999@gmail.com [School of Medical Science and Technology, Indian Institute of Technology Kharagpur, West Bengal 721302 (India); Konar, Suraj, E-mail: suraj.konar@gmail.com [Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302 (India); Tantubay, Sangeeta, E-mail: sang.chem2@gmail.com [Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302 (India); Mahto, Madhusudan Kr., E-mail: mahtomk0@gmail.com [Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302 (India); Mandal, Mahitosh, E-mail: mahitosh@smst.iitkgp.ernet.in [School of Medical Science and Technology, Indian Institute of Technology Kharagpur, West Bengal 721302 (India); Pathak, Amita, E-mail: ami@chem.iitkgp.ernet.in [Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302 (India)

    2016-03-01

    The present work reports the synthesis of biocompatible zirconium phosphate (ZP) nanoparticles as nanocarrier for drug delivery application. The ZP nanoparticles were synthesized via a simple sonochemical method in the presence of cetyltrimethylammonium bromide and their efficacy for the delivery of drugs has been tested through various in-vitro experiments. The particle size and BET surface area of the nanoparticles were found to be ~ 48 nm and 206.51 m{sup 2}/g respectively. The conventional MTT assay and cellular localization studies of the particles, performed on MDA-MB-231 cell lines, demonstrate their excellent biocompatibility and cellular internalization behavior. The loading of curcumin, an antitumor drug, onto the ZP nanoparticles shows the rapid drug uptake ability of the particles, while the drug release study, performed at two different pH values (at 7.4 and 5) depicts pH sensitive release-profile. The MTT assay and cellular localization studies revealed higher cellular inhibition and better bioavailability of the nanoformulated curcumin compared to free curcumin. - Highlights: • Biocompatible zirconium phosphate nanoparticles were synthesized by a simple sonochemical approach. • Curcumin was rapidly loaded onto the particles by the aid by hydrogen bond formation. • The curcumin loaded zirconium phosphate nanoparticles depict pH triggered drug release phenomenon. • The nanoformulated curcumin showed enhanced anti-tumor activity as compared to the native curcumin.

  7. Sonochemically synthesized biocompatible zirconium phosphate nanoparticles for pH sensitive drug delivery application

    International Nuclear Information System (INIS)

    Kalita, Himani; Prashanth Kumar, B.N.; Konar, Suraj; Tantubay, Sangeeta; Mahto, Madhusudan Kr.; Mandal, Mahitosh; Pathak, Amita

    2016-01-01

    The present work reports the synthesis of biocompatible zirconium phosphate (ZP) nanoparticles as nanocarrier for drug delivery application. The ZP nanoparticles were synthesized via a simple sonochemical method in the presence of cetyltrimethylammonium bromide and their efficacy for the delivery of drugs has been tested through various in-vitro experiments. The particle size and BET surface area of the nanoparticles were found to be ~ 48 nm and 206.51 m"2/g respectively. The conventional MTT assay and cellular localization studies of the particles, performed on MDA-MB-231 cell lines, demonstrate their excellent biocompatibility and cellular internalization behavior. The loading of curcumin, an antitumor drug, onto the ZP nanoparticles shows the rapid drug uptake ability of the particles, while the drug release study, performed at two different pH values (at 7.4 and 5) depicts pH sensitive release-profile. The MTT assay and cellular localization studies revealed higher cellular inhibition and better bioavailability of the nanoformulated curcumin compared to free curcumin. - Highlights: • Biocompatible zirconium phosphate nanoparticles were synthesized by a simple sonochemical approach. • Curcumin was rapidly loaded onto the particles by the aid by hydrogen bond formation. • The curcumin loaded zirconium phosphate nanoparticles depict pH triggered drug release phenomenon. • The nanoformulated curcumin showed enhanced anti-tumor activity as compared to the native curcumin.

  8. Tanzanie | Page 32 | CRDI - Centre de recherches pour le ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    insecticides et les médicaments antipaludiques abordables sont des leviers ... Alexander Soucy is correct to identify insecticide-treated bednets and inexpensive anti-malarial drugs as crucial to the global fight against malaria ('An easy way to ...

  9. Precarity and Preparedness: Non-Adherence as Institutional Work in Diagnosing and Treating Malaria in Uganda.

    Science.gov (United States)

    Umlauf, René

    2017-07-01

    Access to anti-malarial drugs is increasingly governed by novel regulation technologies like rapid diagnostic tests (RDTs). However, high rates of non-adherence particularly to negative RDT results have been reported, threatening the cost-effectiveness of the two interrelated goals of improving diagnosis and reducing the over-prescription of expensive anti-malarial drugs. Below I set out to reconstruct prior treatment forms like presumptive treatment of malaria by paying particular attention to their institutional groundings. I show how novel regulation technologies affect existing institutions of care and argue that the institutional work of presumptive treatment goes beyond the diagnosis and treatment of a currently observed fever episode. Instead, in contexts of precarity, through what I will call "practices of preparedness," presumptive treatment includes a variety of practices, performances, temporalities, and opportunities that allow individuals to prepare for future episodes of fever.

  10. Interactions of Rosiglitazone and Anti.Arrhythmic Drugs in Animal ...

    African Journals Online (AJOL)

    Interactions of Rosiglitazone and Anti.Arrhythmic Drugs in Animal Model. YM Mohammed, EI Mohammed, N Mohiuddin, SS Syeda. Abstract. Background: Diabetes increases the risk of vascular problems by two times compared with a healthy individual, with deposition of fats in blood vessel and this includes cardiovascular ...

  11. PhytoNanotechnology: Enhancing Delivery of Plant Based Anti-cancer Drugs

    Directory of Open Access Journals (Sweden)

    Tabassum Khan

    2018-02-01

    Full Text Available Natural resources continue to be an invaluable source of new, novel chemical entities of therapeutic utility due to the vast structural diversity observed in them. The quest for new and better drugs has witnessed an upsurge in exploring and harnessing nature especially for discovery of antimicrobial, antidiabetic, and anticancer agents. Nature has historically provide us with potent anticancer agents which include vinca alkaloids [vincristine (VCR, vinblastine, vindesine, vinorelbine], taxanes [paclitaxel (PTX, docetaxel], podophyllotoxin and its derivatives [etoposide (ETP, teniposide], camptothecin (CPT and its derivatives (topotecan, irinotecan, anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin, and others. In fact, half of all the anti-cancer drugs approved internationally are either natural products or their derivatives and were developed on the basis of knowledge gained from small molecules or macromolecules that exist in nature. Three new anti-cancer drugs introduced in 2007, viz. trabectedin, epothilone derivative ixabepilone, and temsirolimus were obtained from microbial sources. Selective drug targeting is the need of the current therapeutic regimens for increased activity on cancer cells and reduced toxicity to normal cells. Nanotechnology driven modified drugs and drug delivery systems are being developed and introduced in the market for better cancer treatment and management with good results. The use of nanoparticulate drug carriers can resolve many challenges in drug delivery to the cancer cells that includes: improving drug solubility and stability, extending drug half-lives in the blood, reducing adverse effects in non-target organs, and concentrating drugs at the disease site. This review discusses the scientific ventures and explorations involving application of nanotechnology to some selected plant derived molecules. It presents a comprehensive review of formulation strategies of phytoconstituents in

  12. A strategy to find novel candidate anti-Alzheimer's disease drugs by constructing interaction networks between drug targets and natural compounds in medical plants.

    Science.gov (United States)

    Chen, Bi-Wen; Li, Wen-Xing; Wang, Guang-Hui; Li, Gong-Hua; Liu, Jia-Qian; Zheng, Jun-Juan; Wang, Qian; Li, Hui-Juan; Dai, Shao-Xing; Huang, Jing-Fei

    2018-01-01

    Alzheimer' disease (AD) is an ultimately fatal degenerative brain disorder that has an increasingly large burden on health and social care systems. There are only five drugs for AD on the market, and no new effective medicines have been discovered for many years. Chinese medicinal plants have been used to treat diseases for thousands of years, and screening herbal remedies is a way to develop new drugs. We used molecular docking to screen 30,438 compounds from Traditional Chinese Medicine (TCM) against a comprehensive list of AD target proteins. TCM compounds in the top 0.5% of binding affinity scores for each target protein were selected as our research objects. Structural similarities between existing drugs from DrugBank database and selected TCM compounds as well as the druggability of our candidate compounds were studied. Finally, we searched the CNKI database to obtain studies on anti-AD Chinese plants from 2007 to 2017, and only clinical studies were included. A total of 1,476 compounds (top 0.5%) were selected as drug candidates. Most of these compounds are abundantly found in plants used for treating AD in China, especially the plants from two genera Panax and Morus. We classified the compounds by single target and multiple targets and analyzed the interactions between target proteins and compounds. Analysis of structural similarity revealed that 17 candidate anti-AD compounds were structurally identical to 14 existing approved drugs. Most of them have been reported to have a positive effect in AD. After filtering for compound druggability, we identified 11 anti-AD compounds with favorable properties, seven of which are found in anti-AD Chinese plants. Of 11 anti-AD compounds, four compounds 5,862, 5,863, 5,868, 5,869 have anti-inflammatory activity. The compound 28,814 mainly has immunoregulatory activity. The other six compounds have not yet been reported for any biology activity at present. Natural compounds from TCM provide a broad prospect for the

  13. Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

    Directory of Open Access Journals (Sweden)

    Ronald E. See

    2011-06-01

    Full Text Available Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches.

  14. Low-Dose Tramadol and Non-Steroidal Anti-Inflammatory Drug Combination Therapy Prevents the Transition to Chronic Low Back Pain.

    Science.gov (United States)

    Inage, Kazuhide; Orita, Sumihisa; Yamauchi, Kazuyo; Suzuki, Takane; Suzuki, Miyako; Sakuma, Yoshihiro; Kubota, Go; Oikawa, Yasuhiro; Sainoh, Takeshi; Sato, Jun; Fujimoto, Kazuki; Shiga, Yasuhiro; Abe, Koki; Kanamoto, Hirohito; Inoue, Masahiro; Kinoshita, Hideyuki; Takahashi, Kazuhisa; Ohtori, Seiji

    2016-08-01

    Retrospective study. To determine whether low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy could prevent the transition of acute low back pain to chronic low back pain. Inadequately treated early low back pain transitions to chronic low back pain occur in approximately 30% of affected individuals. The administration of non-steroidal anti-inflammatory drugs is effective for treatment of low back pain in the early stages. However, the treatment of low back pain that is resistant to non-steroidal anti-inflammatory drugs is challenging. Patients who presented with acute low back pain at our hospital were considered for inclusion in this study. After the diagnosis of acute low back pain, non-steroidal anti-inflammatory drug administration was started. Forty patients with a visual analog scale score of >5 for low back pain 1 month after treatment were finally enrolled. The first 20 patients were included in a non-steroidal anti-inflammatory drug group, and they continued non-steroidal anti-inflammatory drug therapy for 1 month. The next 20 patients were included in a combination group, and they received low-dose tramadol plus non-steroidal anti-inflammatory drug combination therapy for 1 month. The incidence of adverse events and the improvement in the visual analog scale score at 2 months after the start of treatment were analyzed. No adverse events were observed in the non-steroidal anti-inflammatory drug group. In the combination group, administration was discontinued in 2 patients (10%) due to adverse events immediately following the start of tramadol administration. At 2 months, the improvement in the visual analog scale score was greater in the combination group than in the non-steroidal anti-inflammatory drug group (ppain to chronic low back pain.

  15. Private sector role, readiness and performance for malaria case management in Uganda, 2015.

    Science.gov (United States)

    Kaula, Henry; Buyungo, Peter; Opigo, Jimmy

    2017-05-25

    survey illustrate that the majority of anti-malarials were distributed through the private sector (54.3%), with 31.4% of all anti-malarials distributed through drug stores and 14.4% through private for-profit health facilities. Availability of different anti-malarials and diagnostic testing in the private sector was: ACT (80.7%), quality-assured (QA) ACT (72.0%), sulfadoxine-pyrimethamine (SP) (47.1%), quinine (73.2%) and any malaria blood testing (32.9%). Adult QAACT ($1.62) was three times more expensive than SP ($0.48). The results from the fever case management study found 44.4% of respondents received a malaria test, and among those who tested positive for malaria, 60.0% received an ACT, 48.5% received QAACT; 14.4% a non-artemisinin therapy; 14.9% artemether injection, and 42.5% received an antibiotic. The private sector plays an important role in malaria case management in Uganda. While several private sector initiatives have improved availability of QAACT, there are gaps in malaria diagnosis and distribution of non-artemisinin monotherapies persists. Further private sector strategies, including those focusing on drug stores, are needed to increase coverage of parasitological testing and removal of non-artemisinin therapies from the marketplace.

  16. Use of non-steroidal anti-inflammatory drugs and nutritional ...

    African Journals Online (AJOL)

    Background. The use of medications by football players in many populations is known to be high. Data on African players are scarce. Objective. To determine the magnitude of use of non-steroidal anti-inflammatory drugs (NSAIDs) and nutritional supplements by Zimbabwean football players. Methods. We conducted a ...

  17. Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers.

    Science.gov (United States)

    Nair, Madhavan; Guduru, Rakesh; Liang, Ping; Hong, Jeongmin; Sagar, Vidya; Khizroev, Sakhrat

    2013-01-01

    Although highly active anti-retroviral therapy has resulted in remarkable decline in the morbidity and mortality in AIDS patients, inadequately low delivery of anti-retroviral drugs across the blood-brain barrier results in virus persistence. The capability of high-efficacy-targeted drug delivery and on-demand release remains a formidable task. Here we report an in vitro study to demonstrate the on-demand release of azidothymidine 5'-triphosphate, an anti-human immunodeficiency virus drug, from 30 nm CoFe2O4@BaTiO3 magneto-electric nanoparticles by applying a low alternating current magnetic field. Magneto-electric nanoparticles as field-controlled drug carriers offer a unique capability of field-triggered release after crossing the blood-brain barrier. Owing to the intrinsic magnetoelectricity, these nanoparticles can couple external magnetic fields with the electric forces in drug-carrier bonds to enable remotely controlled delivery without exploiting heat. Functional and structural integrity of the drug after the release was confirmed in in vitro experiments with human immunodeficiency virus-infected cells and through atomic force microscopy, spectrophotometry, Fourier transform infrared and mass spectrometry studies.

  18. Current trends in malarial chemotherapy | Ibezim | African Journal of ...

    African Journals Online (AJOL)

    Malaria is a tropical disease caused by the genus Plasmodium. The sexual stage of the plasmodium is carried by mosquito while the asexual stage is carried by man. Transmission from the mosquito to man is through mosquito bite. Commonly presented symptoms of malarial attack include fever, weakness, anorexia, and ...

  19. In vitro efficacy and release study with anti-inflammatory drugs incorporated in adhesive transdermal drug delivery systems.

    Science.gov (United States)

    Meyer, Stefanie; Peters, Nils; Mann, Tobias; Wolber, Rainer; Pörtner, Ralf; Nierle, Jens

    2014-04-01

    The topical application of two different anti-inflammatory extracts incorporated in adhesive transdermal drug delivery systems (TDDSs) was investigated. Therefore, anti-inflammatory properties and percutaneous absorption behavior of adhesive TDDSs were characterized in vitro conducting experiments with a dermatologically relevant human skin model. Anti-inflammatory efficacy against UV irradiation of both TDDSs was determined in vitro with EpiDerm™. The reduction of the release of proinflammatory cytokines by topically applied TDDSs was compared with the reduction during the presence of the specific cyclooxygenase inhibitor diclofenac in the culture medium. A similar anti-inflammatory efficacy of the topically applied TDDSs in comparison with the use of diclofenac in the culture medium should be achieved. Furthermore, percutaneous absorption in efficacy tests was compared with percutaneous absorption in diffusion studies with porcine cadaver skin. Both the topically applied TDDSs showed a significant anti-inflammatory activity. Permeation coefficients through the stratum corneum and the epidermis gained from the release studies on porcine cadaver skin (Magnolia: 2.23·10(-5) cm/h, licorice: 4.68·10(-6) cm/h) were approximately five times lower than the permeation coefficients obtained with the EpiDerm™ skin model (Magnolia: 9.48·10(-5) cm/h, licorice: 24.0·10(-6) cm/h). Therefore, an adjustment of drug doses during experiments with the EpiDerm™ skin model because of weaker skin barrier properties should be considered.

  20. Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities.

    Science.gov (United States)

    Huang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, Xinyong

    2015-12-01

    The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophysical detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallographic overlays, fragment growth exploiting dynamic combinatorial chemistry, and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.

  1. Viability, biofilm formation, and MazEF expression in drug-sensitive and drug-resistant Mycobacterium tuberculosis strains circulating in Xinjiang, China.

    Science.gov (United States)

    Zhao, Ji-Li; Liu, Wei; Xie, Wan-Ying; Cao, Xu-Dong; Yuan, Li

    2018-01-01

    Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is one of the most common chronic infectious amphixenotic diseases worldwide. Prevention and control of TB are greatly difficult, due to the increase in drug-resistant TB, particularly multidrug-resistant TB. We speculated that there were some differences between drug-sensitive and drug-resistant MTB strains and that mazEF 3,6,9 toxin-antitoxin systems (TASs) were involved in MTB viability. This study aimed to investigate differences in viability, biofilm formation, and MazEF expression between drug-sensitive and drug-resistant MTB strains circulating in Xinjiang, China, and whether mazEF 3,6,9 TASs contribute to MTB viability under stress conditions. Growth profiles and biofilm-formation abilities of drug-sensitive, drug-resistant MTB strains and the control strain H37Rv were monitored. Using molecular biology experiments, the mRNA expression of the mazF 3, 6, and 9 toxin genes, the mazE 3, 6, and 9 antitoxin genes, and expression of the MazF9 protein were detected in the different MTB strains, H37RvΔ mazEF 3,6,9 mutants from the H37Rv parent strain were generated, and mutant viability was tested. Ex vivo culture analyses demonstrated that drug-resistant MTB strains exhibit higher survival rates than drug-sensitive strains and the control strain H37Rv. However, there was no statistical difference in biofilm-formation ability in the drug-sensitive, drug-resistant, and H37Rv strains. mazE 3,6 mRNA-expression levels were relatively reduced in the drug-sensitive and drug-resistant strains compared to H37Rv. Conversely, mazE 3,9 expression was increased in drug-sensitive strains compared to drug-resistant strains. Furthermore, compared with the H37Rv strain, mazF 3,6 expression was increased in drug-resistant strains, mazF 9 expression was increased in drug-sensitive strains, and mazF 9 exhibited reduced expression in drug-resistant strains compared with drug-sensitive strains. Protein expression of mazF9

  2. Anti-thyroid drugs in pediatric Graves′ disease

    Directory of Open Access Journals (Sweden)

    Mathew John

    2015-01-01

    Full Text Available Graves′ disease is the most common cause of hyperthyroidism in children. Most children and adolescents are treated with anti-thyroid drugs as the initial modality. Studies have used Methimazole, Carbimazole and Propylthiouracil (PTU either as titration regimes or as block and replacement regimes. The various studies of anti-thyroid drug (ATD treatment of Graves′ disease in pediatric patients differ in terms of the regimes, remission rate, duration of therapy for adequate remission, follow up and adverse effects of ATD. Various studies show that lower thyroid hormone levels, prolonged duration of treatment, lower levels of TSH receptor antibodies, smaller goiter and increased age of child predicted higher chance of remission after ATD. A variable number of patients experience minor and major adverse effects limiting initial and long term treatment with ATD. The adverse effects of various ATD seem to more in children compared to that of adults. In view of liver injury including hepatocellular failure need of liver transplantation associated with PTU, the use has been restricted in children. The rate of persistent remission with ATD following discontinuation is about 30%. Radioactive iodine therapy is gaining more acceptance in older children with Graves′s disease in view of the limitations of ATD. For individual patients, risk-benefit ratio of ATD should be weighed against benefits of radioactive iodine therapy and patient preferences.

  3. Assessment Of Pattern Of Non-steroidal Anti-Inflammatory Drugs ...

    African Journals Online (AJOL)

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of pains. Self-medication is a common practice all over the world. Unwanted effects from use of this class of medication could pose health challenges. This study evaluated the prevalence and pattern of inappropriate use of NSAIDs among ...

  4. Prescription practice of anti-tuberculosis drugs in Yunnan, China: A clinical audit.

    Directory of Open Access Journals (Sweden)

    Lin Xu

    Full Text Available China has a high burden of drug-resistant tuberculosis (TB. As irrational use and inadequate dosing of anti-TB drugs may contribute to the epidemic of drug-resistant TB, we assessed the drug types and dosages prescribed in the treatment of TB cases in a representative sample of health care facilities in Yunnan.We applied multistage cluster sampling using probability proportion to size to select 28 counties in Yunnan. Consecutive pulmonary TB patients were enrolled from either the TB centers of Yunnan Center of Disease Control or designated TB hospitals. Outcomes of interest included the regimen used in the treatment of new and retreatment TB patients; and the proportion of patients treated with adequate dosing of anti-TB drugs. Furthermore, we assess whether there has been reduction in the use of fluoroquinolone and second line injectables in Tuberculosis Clinical Centre (TCC after the training activity in late 2012.Of 2390 TB patients enrolled, 582 (24.4% were prescribed second line anti-TB drugs (18.0% in new cases and 60.9% in retreatment cases; 363(15.2% prescribed a fluoroquinolone. General hospitals (adjusted odds ratio (adjOR 1.97, 95% confidence interval (CI 1.47-2.66, retreatment TB cases (adjOR 4.75, 95% CI 3.59-6.27, smear positive cases (adjOR 1.69, 95% CI 1.22-2.33, and extrapulmonary TB (adjOR 2.59, 95% CI 1.66-4.03 were significantly associated with the use of fluoroquinolones. The proportion of patients treated with fluoroquinolones decreased from 41.4% before 2013 to 13.5% after 2013 (adjOR 0.19, 95% CI 0.12-0.28 in TCC. The proportion of patients with correct, under and over dosages of isoniazid was 88.2%, 1.5%, and 10.4%, respectively; of rifampicin was 50.2%, 46.8%, and 2.9%; of pyrazinamide was 67.6%, 31.7% and 0.7%; and of ethambutol was 41.4%, 57.5%, and 1.0%.The prescribing practice of anti-TB drugs was not standardized, findings with significant programmatic implication.

  5. Malarial infection among HIV Patients on Antiretroviral Therapy (ART)

    African Journals Online (AJOL)

    Malarial infection among patients on antiretroviral therapy (ART) attending Federal Medical Centre, Makurdi, Benue State was investigated between April and August 2008 to determine the level of malaria infection in HIV/AIDS patients on ART and those not on ART with respect to CD4+ counts, age and gender. A total of ...

  6. Price Sensitivity of Demand for Prescription Drugs

    DEFF Research Database (Denmark)

    Simonsen, Marianne; Skipper, Lars; Skipper, Niels

    2016-01-01

    We investigate price sensitivity of demand for prescription drugs, using drug purchase records for the entire Danish population. We identify price responsiveness by exploiting variation in prices caused by kinked reimbursement schemes and implement a regression kink design. The results suggest some...... price responsiveness with corresponding price elasticities ranging from −0.2 to −0.7. Individuals with chronic disease and especially individuals above the age of 65 respond less to the price of drugs....

  7. Determination of Residual Nonsteroidal Anti-Inflammatory Drugs in Aqueous Sample Using Magnetic Nanoparticles Modified with Cetyltrimethylammonium Bromide by High Performance Liquid Chromatography

    OpenAIRE

    Khoeini Sharifabadi, Malihe; Saber-Tehrani, Mohammad; Waqif Husain, Syed; Mehdinia, Ali; Aberoomand-Azar, Parviz

    2014-01-01

    A simple and sensitive solid-phase extraction method for separation and preconcentration of trace amount of four nonsteroidal anti-inflammatory drugs (naproxen, indomethacin, diclofenac, and ibuprofen) using Fe3O4 magnetic nanoparticles modified with cetyltrimethylammonium bromide has been developed. For this purpose, the surface of MNPs was modified with cetyltrimethylammonium bromide (CTAB) as a cationic surfactant. Effects of different parameters influencing the extraction efficiency of dr...

  8. Effectiveness of various non-steroidal anti-inflammatory drugs in ...

    African Journals Online (AJOL)

    Purpose: To study the effectiveness of various nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with vertebral fractures. Methods: A total of 78 patients (17 males and 61 females) with a mean age of 69.5 years were included. The major inclusion criterion was an osteoporotic vertebral fracture between T7 and L3.

  9. A rodent malarial model of Plasmodium berghei for the development ...

    African Journals Online (AJOL)

    A rodent malarial model of Plasmodium berghei for the development of pyrimethamine and sulphadoxine-pyrimethamine resistant malaria in mice. ... course approach with 125/6.25mg/kg S/P. The stability of resistance phenotypes, parasite pathogenic disposition and host leukocyte response were also investigated.

  10. The history of the Greek Anti-Malaria League and the influence of the Italian School of Malariology.

    Science.gov (United States)

    Tsiamis, Costas; Piperaki, Evangelia Theophano; Tsakris, Athanassios

    2013-03-01

    In 1905, a group of eminent Greek physicians led by Professor of Hygiene and Microbiology Constantinos Savvas and the pediatrician Dr. Ioannis Kardamatis founded the Greek Anti-Malaria League. The League assumed a role that the State would not, and for the next 25 years organized the country's anti-malaria campaign. During its first steps, the Greek Anti-Malaria League adopted the principles of Professor Angelo Celli's Italian Anti-Malaria League. The League's accomplishments include a decrease in malarial prevalence, due to mass treatment with quinine, new legislation ensuring the provision of quinine, State monopoly and the collection of epidemiologic data. However, defeat in the Greek-Turkish War (1922) and the massive influx of one million Greek refugees that ensued, led to a change in malarial epidemiology. In 1928, following a visit to Italy, the Greek League adopted the organization and knowledge of the Italian Malaria Schools in Rome and in Nettuno, and this experience served as the basis of their proposal to the State for the development of the anti-malaria services infrastructure. The State adopted many of Professor Savvas' proposals and modified his plan according to Greek needs. The League's experience, accumulated during its 25 years of struggle against malaria, was its legacy to the campaigns that eventually accomplished the eradication of malaria from Greece after World War II.

  11. Drug-laden 3D biodegradable label using QR code for anti-counterfeiting of drugs.

    Science.gov (United States)

    Fei, Jie; Liu, Ran

    2016-06-01

    Wiping out counterfeit drugs is a great task for public health care around the world. The boost of these drugs makes treatment to become potentially harmful or even lethal. In this paper, biodegradable drug-laden QR code label for anti-counterfeiting of drugs is proposed that can provide the non-fluorescence recognition and high capacity. It is fabricated by the laser cutting to achieve the roughness over different surface which causes the difference in the gray levels on the translucent material the QR code pattern, and the micro mold process to obtain the drug-laden biodegradable label. We screened biomaterials presenting the relevant conditions and further requirements of the package. The drug-laden microlabel is on the surface of the troches or the bottom of the capsule and can be read by a simple smartphone QR code reader application. Labeling the pill directly and decoding the information successfully means more convenient and simple operation with non-fluorescence and high capacity in contrast to the traditional methods. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report.

    Science.gov (United States)

    Etxagibel, Aitziber; Julià, M Rosa; Brotons, Alvaro; Company, M Margarita; Dolz, Carlos

    2008-01-28

    Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis.

  13. Development of fluorescent Plasmodium falciparum for in vitro growth inhibition assays

    Directory of Open Access Journals (Sweden)

    Crabb Brendan S

    2010-06-01

    Full Text Available Abstract Background Plasmodium falciparum in vitro growth inhibition assays are widely used to evaluate and quantify the functional activity of acquired and vaccine-induced antibodies and the anti-malarial activity of known drugs and novel compounds. However, several constraints have limited the use of these assays in large-scale population studies, vaccine trials and compound screening for drug discovery and development. Methods The D10 P. falciparum line was transfected to express green fluorescent protein (GFP. In vitro growth inhibition assays were performed over one or two cycles of P. falciparum asexual replication using inhibitory polyclonal antibodies raised in rabbits, an inhibitory monoclonal antibody, human serum samples, and anti-malarials. Parasitaemia was evaluated by microscopy and flow cytometry. Results Transfected parasites expressed GFP throughout all asexual stages and were clearly detectable by flow cytometry and fluorescence microscopy. Measurement of parasite growth inhibition was the same when determined by detection of GFP fluorescence or staining with ethidium bromide. There was no difference in the inhibitory activity of samples when tested against the transfected parasites compared to the parental line. The level of fluorescence of GFP-expressing parasites increased throughout the course of asexual development. Among ring-stages, GFP-fluorescent parasites were readily separated from uninfected erythrocytes by flow cytometry, whereas this was less clear using ethidium bromide staining. Inhibition by serum and antibody samples was consistently higher when tested over two cycles of growth compared to one, and when using a 1 in 10 sample dilution compared to 1 in 20, but there was no difference detected when using a different starting parasitaemia to set-up growth assays. Flow cytometry based measurements of parasitaemia proved more reproducible than microscopy counts. Conclusions Flow cytometry based assays using GFP

  14. Sale of anti-tuberculosis drugs through private pharmacies: a cross sectional study in Kerala, India.

    Directory of Open Access Journals (Sweden)

    Binoo Divakaran

    2011-03-01

    Full Text Available

    Background: Private health care providers are largely the first point of contact for Tuberculosis (TB patients, who either undergo treatment from private practitioners or buy medicines on their own from private pharmacies. Aims: This study assessed the availability, sale and magnitude of anti-tuberculosis drugs dispensing through private pharmacies.

    Methodology: The present cross sectional study was conducted among private pharmacies located along the national highway from Thalassery to Payyannur in the Kannur district of Kerala, India. A total of 38 private pharmacies located along the national highway were included.

    Results: The duration that anti–TB drugs had been on sale showed that 74.3% of pharmacies had started to sell these drugs only less than ten years ago. The majority (82.9% of the private pharmacies received up to 5 prescriptions for anti-TB drugs weekly. Out of the total of 35 pharmacies selling these drugs, 22 (62.9% reported an increase in their sales. Nearly 82% of those pharmacies that reported an increase in the sale of anti-TB drugs were selling these drugs for less than the past ten years.

    Conclusions: The current study shows that a large number of tuberculosis patients are still approaching private pharmacies for anti-tuberculosis drugs. This tendency has to be completely stopped and needs properly planned strategies to encourage private pharmacies to participate actively in the DOTS (Direct Observation Treatment Short course program of the Government, by providing them attractive alternative incentives

  15. A gastroenterologist and arheumatologist answer the questions on the use ofnon-steroidal anti-inflammatory drugs raised by primary care physicians

    Directory of Open Access Journals (Sweden)

    Przemysław Dyrla

    2016-03-01

    Full Text Available Non-steroidal anti-inflammatory drugs are drugs of choice for chronic pain, which is most common in chronic conditions, rheumatism in particular. According to  current recommendations, these medications should be used continuously or intermittently, and their choice should be tailored to each patient. Unfortunately, non-steroidal anti-inflammatory drugs have multiple adverse effects ranging from the most insignificant dyspepsia to severe upper gastrointestinal bleeding. Therefore, gastroscopy and, in the case of confirmed Helicobacter pylori infection, eradication is advisable for planned long-term treatment with these agents. Long-term use of proton pump inhibitors is recommended in rheumatic patients chronically receiving non-selective non-steroidal anti-inflammatory drugs, while celecoxib (a selective COX-2 inhibitor combined with proton pump inhibitor should be administered in patients at high risk of gastrointestinal complications. In rheumatic patients, the type of non-steroidal anti-inflammatory drug and the route of its administration should be tailored to each patient in terms of strength and duration of drug action, the type of disease and comorbidities as well as contraindications. Adverse gastrointestinal effects are due to the mechanism of action of non-steroidal anti-inflammatory drugs, and therefore independent of the route of administration. The use of proton pump inhibitors with cardioprotective doses of aspirin should be limited to patients with risk factors for gastrointestinal complications. High non-steroidal anti-inflammatory drug doses are limited to gout attack, acute pain and axial spondyloarthropathy showing high clinical activity. In other cases, the lowest effective non-steroidal anti-inflammatory drug dose is recommended. Advancing age is characterised by impairment in the function of all organs, therefore elderly patients should receive lower non-steroidal anti-inflammatory drug

  16. Download this PDF file

    African Journals Online (AJOL)

    User

    INTRODUCTION. Chloroquine resistant malaria remains a major cause of morbidity and mortality in sub Saharan African children . Although the World Health Organisation. (WHO) has recommended Artemisin-based. Combination therapies (ACTs) as the best anti- malarial drugs currently available , the use of ACTs.

  17. Placental malaria and immunity to infant measles

    NARCIS (Netherlands)

    Owens, S.; Harper, G.; Amuasi, J.; Offei-Larbi, G.; Ordi, J.; Brabin, B. J.

    2006-01-01

    The efficiency of transplacental transfer of measles specific antibody was assessed in relation to placental malaria. Infection at delivery was associated with a 30% decrease in expected cord measles antibody titres. Uninfected women who received anti-malarial drugs during pregnancy transmitted 30%

  18. Fear Conditioning Effects on Sensitivity to Drug Reward

    Science.gov (United States)

    2010-06-01

    motivational responses and self-administration behaviors (Robbins et al., 2008). Pavlovian conditioning mechanisms link unconditioned drug responses...model. Induction of fear conditioning is followed by measurement of sensitivity to drug reward using a conditioned place preference (CPP) model to...morphine. Conditioned drug reward is a relevant model in addiction because environmental cues (e.g. a barroom) induce craving and persistent

  19. Novel delivery systems with nonsteroidal anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Cvijić Sandra

    2016-01-01

    Full Text Available Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs is associated with increased risk of serious gastrointestinal side effects. Therefore, recent trends in the development of NSAIDs aim to reduce the incidence of side effects, and improve patient compliance. One of the strategies to improve efficacy and safety of oral NSAIDs is the development of combination products that contain gastroprotective agents. Several products containing NSAID in combination with proton pump inhibitors (ketoprofen/omeprazole, naproxen/esomeprazole, H2-receptor antagonists (ibuprofen/famotidine, and prostaglandin analogues (diclofenac/misoprostol are currently available on the market. Another approach refer to the special formulation design to allow dose reduction while preserving drug therapeutic efficacy. An example is SoluMatrix® technology, a manufacturing process that produce submicron-sized drug particles with enhanced dissolution and absorption properties. Patented SoluMatrix® technology has been successfully employed to develop low-dose diclofenac, meloxicam, indomethacin and naproxen products. Topical NSAID formulations enable drug delivery to target tissues, while reducing systemic exposure and concomitant side effects associated with oral NSAIDs. Dermal/transdermal NSAID delivery systems are subject of intensive investigation. So far, several 'advanced' drug delivery systems with diclofenac, ibuprofen and ketoprofen have been designed.

  20. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

    2011-01-01

    Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

  1. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  2. Consumption and awareness of students about nonsteroidal anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Wawryk-Gawda Ewelina

    2014-09-01

    Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs are used by millions of people worldwide to neutralize pain that is of different origin, as well as to treat fever and inflammation. However, NSAIDs misuse/overuse can induce many adverse effects and some potentially serious complications. The aim of the our study was to ascertain young people’s knowledge about non-steroidal anti-inflammatory drugs. The research tool was a questionnaire. This study was carried out among students of the Medical University in Lublin, and it involved 236 persons of an average age of 20 years. The questions were intended to assess the frequency of NSAIDs use and the general knowledge that is held with respect to them. The results of this work show that more than 77% of the respondents confirmed that they use NSAIDs. Our results revealed no statistical correlation between the place of living or origin and the use of this drug. Hence, it can be said that while young adults quite often use NSAIDs, their knowledge about the dangers associated with the use of NSAIDs is low. Therefore, it is necessary to more intensively disseminate knowledge on the potential adverse effects of NSAID utilization.

  3. Solvents effects on crystallinity and dissolution of β-artemether.

    Science.gov (United States)

    Xu, Jianghui; Singh, Vikramjeet; Yin, Xianzhen; Singh, Parbeen; Wu, Li; Xu, Xiaonan; Guo, Tao; Sun, Lixin; Gui, Shuangying; Zhang, Jiwen

    2017-03-01

    β-artemether (ARM) is a widely used anti-malarial drug isolated from the Chinese antimalarial plant, Artemisia annua. The solvent effects on crystal habits and dissolution of ARM were thoroughly investigated and discussed herein. The ARM was recrystallized in nine different solvents of varied polarity, namely, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, trichloromethane, ethyl acetate, acetone and hexane by solvent evaporation method. The obtained crystals were morphologically characterized using scanning electron microscope (SEM). The average sizes of crystals were 1.80-2.64 μm calculated from microscopic images using Image-Pro software. No significant change in chemical structure was noticed after recrystallization and the specific band at 875 cm -1 wavenumber (C-O-O-C) confirmed the presence of most sensitive functional group in the ARM chemical structure. The existence and production of two polymorphic forms, polymorph A and polymorph B, was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The data suggested that the fabrication of polymorph B can be simply obtained from the recrystallization of ARM in a specific solvent. Significant effects of solvent polarity, crystals shapes and sizes on drug dissolution were noticed during in vitro dissolution test. The release kinetics were calculated and well fitted by the Higuchi and Hixon-Crowell models. The ARM-methanol and ARM-hexane showed highest and slowest dissolution, respectively, due to the effects of solvent polarity and crystal morphologies. Overall, proper selection of the solvents for the final crystallization of ARM helps to optimize dissolution and bioavailability for a better delivery of anti-malarial drug.

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

    Directory of Open Access Journals (Sweden)

    Ryohei Miyazaki

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

  5. PFCRT and DHFR-TS Sequences for Monitoring Drug Resistance in ...

    African Journals Online (AJOL)

    Erah

    from falciparum malaria isolates collected in Adzopé City, Côte d'Ivoire in 2007. Methods: Blood ... performed using specific primers of pfcrt and dhfr-ts. During the study .... The following mixture was prepared to a final volume of 50 ..... following the withdrawal of these anti- malarials as ... Malaria vaccines in Africa. Acta Trop.

  6. Sortase A: an ideal target for anti-virulence drug development.

    Science.gov (United States)

    Cascioferro, Stella; Totsika, Makrina; Schillaci, Domenico

    2014-12-01

    Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Drug sensitivity testing platforms for gastric cancer diagnostics.

    Science.gov (United States)

    Lau, Vianne; Wong, Andrea Li-Ann; Ng, Christopher; Mok, Yingting; Lakshmanan, Manikandan; Yan, Benedict

    2016-02-01

    Gastric cancer diagnostics has traditionally been histomorphological and primarily the domain of surgical pathologists. Although there is an increasing usage of molecular and genomic techniques for clinical diagnostics, there is an emerging field of personalised drug sensitivity testing. In this review, we describe the various personalised drug sensitivity testing platforms and discuss the challenges facing clinical adoption of these assays for gastric cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  8. Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites.

    Science.gov (United States)

    Ponsuwanna, Patrath; Kochakarn, Theerarat; Bunditvorapoom, Duangkamon; Kümpornsin, Krittikorn; Otto, Thomas D; Ridenour, Chase; Chotivanich, Kesinee; Wilairat, Prapon; White, Nicholas J; Miotto, Olivo; Chookajorn, Thanat

    2016-01-29

    Malaria parasites have evolved a series of intricate mechanisms to survive and propagate within host red blood cells. Intra-erythrocytic parasitism requires these organisms to digest haemoglobin and detoxify iron-bound haem. These tasks are executed by haemoglobin-specific proteases and haem biocrystallization factors that are components of a large multi-subunit complex. Since haemoglobin processing machineries are functionally and genetically linked to the modes of action and resistance mechanisms of several anti-malarial drugs, an understanding of their evolutionary history is important for drug development and drug resistance prevention. Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within Plasmodium species, and with the representatives of Apicomplexan species with various host tropisms, were created. Genetic variants were mapped onto existing three-dimensional structures. Genome-wide single nucleotide polymorphism data were used to analyse the selective pressure and the effect of these mutations at the structural level. Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites especially in the Plasmodium falciparum and P. reichenowi lineage. Expansion of haemoglobin-specific plasmepsins occurred after the separation event of Plasmodium species, but the other members of the plasmepsin family were evolutionarily conserved with one copy for each sub-group in every Apicomplexan species. Haemoglobin-specific falcipains are separated from invasion-related falcipain, and their expansions within one specific locus arose independently in both P. falciparum and P. vivax lineages. Gene conversion between P. falciparum falcipain 2A and 2B was observed in artemisinin-resistant strains. Comparison between the numbers of non-synonymous and synonymous mutations suggests a strong selective pressure at falcipain and plasmepsin genes. The locations of amino acid changes from non

  9. Negative effect of non-steroidal anti-inflammatory drugs on the ...

    African Journals Online (AJOL)

    Ciprofloxacin, a second generation fluoroquinolone is often co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) in life threatening situations in which Staphylococcus aureus infections are accompanied with pain and inflammation. This study was carried out to investigate possible in vitro interactions in co ...

  10. A systematic study of the effect of low pH acid treatment on anti-drug antibodies specific for a domain antibody therapeutic: Impact on drug tolerance, assay sensitivity and post-validation method assessment of ADA in clinical serum samples.

    Science.gov (United States)

    Kavita, Uma; Duo, Jia; Crawford, Sean M; Liu, Rong; Valcin, Joan; Gleason, Carol; Dong, Huijin; Gadkari, Snaehal; Dodge, Robert W; Pillutla, Renuka C; DeSilva, Binodh S

    2017-09-01

    We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and

  11. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.

    Science.gov (United States)

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

  12. Biodegradable polymers for targeted delivery of anti-cancer drugs.

    Science.gov (United States)

    Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

    2016-06-01

    Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

  13. Combined Transcriptomics and Metabolomics in a Rhesus Macaque Drug Administration Study

    Directory of Open Access Journals (Sweden)

    Kevin J. Lee

    2014-10-01

    Full Text Available We describe a multi-omic approach to understanding the effects that the anti-malarial drug pyrimethamine has on immune physiology in rhesus macaques (Macaca mulatta. Whole blood and bone marrow RNA-Seq and plasma metabolome profiles (each with over 15,000 features have been generated for five naïve individuals at up to seven time-points before, during and after three rounds of drug administration. Linear modelling and Bayesian network analyses are both considered, alongside investigations of the impact of statistical modeling strategies on biological inference. Individual macaques were found to be a major source of variance for both omic data types, and factoring individuals into subsequent modelling increases power to detect temporal effects. A major component of the whole blood transcriptome follows the bone marrow with a time-delay, while other components of variation are unique to each compartment. We demonstrate that pyrimethamine administration does impact both compartments throughout the experiment, but very limited perturbation of transcript or metabolite abundance following each round of drug exposure is observed. New insights into the mode of action of the drug are presented in the context of pyrimethamine’s predicted effect on suppression of cell division and metabolism in the immune system.

  14. Systematic review on traditional medicinal plants used for the treatment of malaria in Ethiopia: trends and perspectives.

    Science.gov (United States)

    Alebie, Getachew; Urga, Befikadu; Worku, Amha

    2017-08-01

    Ethiopia is endowed with abundant medicinal plant resources and traditional medicinal practices. However, available research evidence on indigenous anti-malarial plants is highly fragmented in the country. The present systematic review attempted to explore, synthesize and compile ethno-medicinal research evidence on anti-malarial medicinal plants in Ethiopia. A systematic web search analysis and review was conducted on research literature pertaining to medicinal plants used for traditional malaria treatment in Ethiopia. Data were collected from a total of 82 Ethiopian studies meeting specific inclusion criteria including published research articles and unpublished thesis reports. SPSS Version 16 was used to summarize relevant ethno-botanical/medicinal information using descriptive statistics, frequency, percentage, tables, and bar graphs. A total of 200 different plant species (from 71 families) used for traditional malaria treatment were identified in different parts of Ethiopia. Distribution and usage pattern of anti-malarial plants showed substantial variability across different geographic settings. A higher diversity of anti-malarial plants was reported from western and southwestern parts of the country. Analysis of ethno-medicinal recipes indicated that mainly fresh leaves were used for preparation of remedies. Decoction, concoction and eating/chewing were found to be the most frequently employed herbal remedy preparation methods. Notably, anti-malarial herbal remedies were administered by oral route. Information on potential side effects of anti-malarial herbal preparations was patchy. However, some anti-malarial plants were reported to have potentially serious side effects using different local antidotes and some specific contra-indications. The study highlighted a rich diversity of indigenous anti-malarial medicinal plants with equally divergent herbal remedy preparation and use pattern in Ethiopia. Baseline information gaps were observed in key geographic

  15. Peptide drug stability: The anti-inflammatory drugs Pep19-2.5 and Pep19-4LF in cream formulation.

    Science.gov (United States)

    Kuhlmann, Nicole; Heinbockel, Lena; Correa, Wilmar; Gutsmann, Thomas; Goldmann, Torsten; Englisch, Uwe; Brandenburg, Klaus

    2018-03-30

    In previous years, we developed anti-infective drugs based on antimicrobial peptides (AMPs), which have been shown to effectively block severe infections and inflammation in vitro as well as in vivo. Besides systemic application, the occurrence of severe local infections necessitates a topical application for example in the case of severe skin and soft tissue infections (SSTI). Recent investigations show that the synthetic anti-lipopolysaccharide peptide (SALP) Pep19-2.5 (Aspidasept® I) and a variant called Pep19-4LF (Aspidasept® II) are able to supress inflammation reactions also in keratinocytes, Langerhans cells, and dendritic cells from the skin. For topical application, a possible formulation represents the drug dispersed into a pharmaceutical cream (DAC base cream). Here, we present investigations on the stability of the peptides using this formulation in dependence on time, which includes the evaluation of the extraction procedure, the quantitative analysis of the peptides after extraction, its sensitivity to protease degradation and its ability to maintain activity against LPS-induced inflammation in vitro. We have developed an extraction procedure for the peptides with an optimum yield and showed that Pep19-2.5 is present as a dimer after extraction from the cream, whereas Pep19-4LF retains its monomeric form. Both peptides show no degradation by chymotrypsin after extraction for at least 1 h, which is indicative for an attachment of constituents of the base cream, inhibiting the cutting into peptidic part structures. The extracted peptides and in particular the dimeric Pep19-2.5 are still able to inhibit the LPS-induced inflammation reaction in human mononuclear cells. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Cell based assays for anti-Plasmodium activity evaluation.

    Science.gov (United States)

    Mokgethi-Morule, Thabang; N'Da, David D

    2016-03-10

    Malaria remains one of the most common and deadly infectious diseases worldwide. The severity of this global public health challenge is reflected by the approximately 198 million people, who were reportedly infected in 2013 and by the more than 584,000 related deaths in that same year. The rising emergence of drug resistance towards the once effective artemisinin combination therapies (ACTs) has become a serious concern and warrants more robust drug development strategies, with the objective of eradicating malaria infections. The intricate biology and life cycle of Plasmodium parasites complicate the understanding of the disease in such a way that would enhance the development of more effective chemotherapies that would achieve radical clinical cure and that would prevent disease relapse. Phenotypic cell based assays have for long been a valuable approach and involve the screening and analysis of diverse compounds with regards to their activities towards whole Plasmodium parasites in vitro. To achieve the Millennium Development Goal (MDG) of malaria eradication by 2020, new generation drugs that are active against all parasite stages (erythrocytic (blood), exo-erythrocytic (liver stages and gametocytes)) are needed. Significant advances are being made in assay development to overcome some of the practical challenges of assessing drug efficacy, particularly in the liver and transmission stage Plasmodium models. This review discusses primary screening models and the fundamental progress being made in whole cell based efficacy screens of anti-malarial activity. Ongoing challenges and some opportunities for improvements in assay development that would assist in the discovery of effective, safe and affordable drugs for malaria treatments are also discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Anti-inflammatory, anti-cholinergic and cytotoxic effects of Sida rhombifolia.

    Science.gov (United States)

    Mah, Siau Hui; Teh, Soek Sin; Ee, Gwendoline Cheng Lian

    2017-12-01

    Sida (Malvaceae) has been used as a traditional remedy for the treatment of diarrhoea, malarial, gastrointestinal dysentery, fevers, asthma and inflammation. This study evaluates the anti-inflammatory, cytotoxic and anti-cholinergic activities of Sida rhombifolia Linn. whole plant for the first time. S. rhombifolia whole plant was extracted by n-hexane, ethyl acetate and methanol using Soxhlet apparatus. The plant extracts were evaluated for their antioxidant (DPPH, FIC and FRAP), anti-inflammatory (NO and protein denaturation inhibitions), cytotoxic (MTT) and anti-cholinesterase (AChE) properties in a range of concentrations to obtain IC 50 values. GC-MS analysis was carried out on the n-hexane extract. The ethyl acetate extract exhibited the most significant antioxidant activities by scavenging DPPH radicals and ferrous ions with EC 50 of 380.5 and 263.4 μg/mL, respectively. In contrast, the n-hexane extract showed the strongest anti-inflammatory activity with IC 50 of 52.16 and 146.03 μg/mL for NO and protein denaturation inhibition assays, respectively. The same extract also revealed the strongest effects in anti-cholinesterase and cytotoxic tests at the concentration of 100 μg/mL, AChE enzyme inhibition was 58.55% and human cancer cells, SNU-1 and Hep G2 inhibition was 68.52% and 47.82%, respectively. The phytochemicals present in the n-hexane extract are palmitic acid, linoleic acid and γ-sitosterol. The present study revealed that the n-hexane extract possessed relatively high pharmacological activities in anti-inflammation, cytotoxicity and anti-cholinesterase assays. Thus, further work on the detail mechanism of the bioactive phytochemicals which contribute to the biological properties are strongly recommended.

  18. First evidence that drugs of abuse produce behavioral sensitization and cross-sensitization in planarians

    Science.gov (United States)

    Rawls, Scott M.; Patil, Tavni; Yuvasheva, Ekaternia; Raffa, Robert B.

    2010-01-01

    Behavioral sensitization in mammals, including humans, is sensitive to factors such as administration route, testing environment, and pharmacokinetic confounds, unrelated to the drugs themselves, that are difficult to eliminate. Simpler animals less susceptible to these confounding influences may be advantageous substitutes for studying sensitization. We tested this hypothesis by determining if planarians display sensitization and cross-sensitization to cocaine and glutamate. Planarian hyperactivity was quantified as the number of C-like hyperkinesias during a 1-min drug exposure. Planarians exposed initially to cocaine (or glutamate) on day 1 were challenged with cocaine (or glutamate) after 2 or 6 days of abstinence. Acute cocaine or glutamate produced concentration-related hyperactivity. Cocaine or glutamate challenge after 2 and 6 days of abstinence enhanced the hyperactivity, indicating the substances produced planarian behavioral sensitization (pBS). Cross-sensitization experiments showed that cocaine produced greater hyperactivity in planarians previously exposed to glutamate than in glutamate-naïve planarians, and vice versa. Behavioral responses were pharmacologically selective because neither scopolamine nor caffeine produced pBS despite causing hyperactivity after initial administration, and acute GABA did not cause hyperactivity. Demonstration of pharmacologically-selective behavioral sensitization in planarians suggests these flatworms represent a sensitive in vivo model to study cocaine behavioral sensitization and to screen potential abuse-deterrent therapeutics. PMID:20512030

  19. Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

    Directory of Open Access Journals (Sweden)

    Kathleen Ingenhoven

    2017-07-01

    Full Text Available ObjectiveTo develop and validate a method for the detection of binding anti-drug antibodies (ADAs against interferon beta (IFN-β in human serum as part of a European initiative (ABIRISK aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk.MethodA two-tiered bridging enzyme-linked immunosorbent assay (ELISA format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled Streptavidin and TMB substrate. Confirmation assay: Screen “putative positive” samples are tested in the presence of excess drug (preincubation of sera with 0.3 µg/mL of soluble IFN-β and percentage of inhibition is calculated.ResultsThe assay is precise, and the sensitivity of the assay was confirmed to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-β in human sera as the positive control.ConclusionAn ultrasensitive ELISA for IFN-β-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-β with regards to its clinical relevance and may allow for the development of predictive tools, key aims within the ABIRISK consortium.

  20. Non-steroidal Anti-inflammatory Drugs Ranking by Nondeterministic Assessments of Probabilistic Type

    Directory of Open Access Journals (Sweden)

    Madalina luiza MOLDOVEANU

    2012-09-01

    Full Text Available With a number of common therapeutic prescriptions, common mechanisms, common pharmacological effects - analgesic, antipyretic and anti-inflammatory (acetaminophen excepted, common side effects (SE (platelet dysfunction, gastritis and peptic ulcers, renal insufficiency in susceptible patients, water and sodium retention, edemas, nephropathies, and only a few different characteristics – different chemical structures, pharmacokinetics and different therapeutic possibility, different selectivities according to cyclooxygenase pathway 1 and 2, non-steroidal anti-inflammatory drugs (NSAIDs similarities are more apparent than differences. Being known that in a correct treatment benefits would exceed risks, the question “Which anti-inflammatory drug presents the lowest risks for a patient?” is just natural. By the Global Risk Method (GRM and the Maximum Risk Method (MRM we have determined the ranking of fourteen NSAIDs considering the risks presented by each particular NSAID. Nimesulide, Etoricoxib and Celecoxib safety level came superior to the other NSAIDs, whereas Etodolac and Indomethacin present an increased side effects risk.

  1. Three-dimensional quick response code based on inkjet printing of upconversion fluorescent nanoparticles for drug anti-counterfeiting

    Science.gov (United States)

    You, Minli; Lin, Min; Wang, Shurui; Wang, Xuemin; Zhang, Ge; Hong, Yuan; Dong, Yuqing; Jin, Guorui; Xu, Feng

    2016-05-01

    Medicine counterfeiting is a serious issue worldwide, involving potentially devastating health repercussions. Advanced anti-counterfeit technology for drugs has therefore aroused intensive interest. However, existing anti-counterfeit technologies are associated with drawbacks such as the high cost, complex fabrication process, sophisticated operation and incapability in authenticating drug ingredients. In this contribution, we developed a smart phone recognition based upconversion fluorescent three-dimensional (3D) quick response (QR) code for tracking and anti-counterfeiting of drugs. We firstly formulated three colored inks incorporating upconversion nanoparticles with RGB (i.e., red, green and blue) emission colors. Using a modified inkjet printer, we printed a series of colors by precisely regulating the overlap of these three inks. Meanwhile, we developed a multilayer printing and splitting technology, which significantly increases the information storage capacity per unit area. As an example, we directly printed the upconversion fluorescent 3D QR code on the surface of drug capsules. The 3D QR code consisted of three different color layers with each layer encoded by information of different aspects of the drug. A smart phone APP was designed to decode the multicolor 3D QR code, providing the authenticity and related information of drugs. The developed technology possesses merits in terms of low cost, ease of operation, high throughput and high information capacity, thus holds great potential for drug anti-counterfeiting.Medicine counterfeiting is a serious issue worldwide, involving potentially devastating health repercussions. Advanced anti-counterfeit technology for drugs has therefore aroused intensive interest. However, existing anti-counterfeit technologies are associated with drawbacks such as the high cost, complex fabrication process, sophisticated operation and incapability in authenticating drug ingredients. In this contribution, we developed a

  2. Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs

    DEFF Research Database (Denmark)

    Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V

    2016-01-01

    of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along...

  3. TOPICALITY OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS IN TREATMENT OF FEVER IN CHILDREN

    Directory of Open Access Journals (Sweden)

    O.A. Mubarakshina

    2010-01-01

    Full Text Available Nonsteroidal anti-inflammatory drugs are widely used in pediatric practice for the treatment of fever. The choice of the drug from this group must be based on high effectiveness of medication and the lowest risk of adverse events. Only paracetamol and ibuprofen completely fulfill these requirements at the present times. They are officially recommended by WHO for the use as an anti-fever pediatric medication. The article examines advantages of ibuprofen compared to paracetamol on the basis of results of randomized studies. Author describes a safety of ibuprofen and opportunities of combined treatment with ibuprofen and paracetamol.Key words: children, fever, ibuprofen, paracetamol, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2010;9(2:156-160

  4. Non-steroidal anti-inflammatory drugs and risk of pulmonary embolism

    NARCIS (Netherlands)

    Biere-Rafi, Sara; Di Nisio, Marcello; Gerdes, Victor; Porreca, Ettore; Souverein, Patrick; de Boer, Anthonius; Büller, Harry; Kamphuisen, Pieter

    2011-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with an increased risk of arterial thrombosis, but their effect on venous thrombotic events is less well established. The study aimed to assess the risk of symptomatic pulmonary embolism (PE) in patients using NSAIDs and to evaluate

  5. Non-steroidal anti-inflammatory drugs for chronic low back pain

    NARCIS (Netherlands)

    W.T.M. Enthoven (Wendy); P.D.D.M. Roelofs (Pepijn); R.A. Deyo (Richard); M.W. van Tulder (Maurits); B.W. Koes (Bart)

    2016-01-01

    textabstractBackground: Chronic back pain is an important health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat people with low back pain, especially people with acute back pain. Short term NSAID use is also recommended for pain relief in people with chronic back

  6. Anti-plasmodial activity of Dicoma tomentosa (Asteraceae) and identification of urospermal A-15-O-acetate as the main active compound

    Science.gov (United States)

    2012-01-01

    Background Natural products could play an important role in the challenge to discover new anti-malarial drugs. In a previous study, Dicoma tomentosa (Asteraceae) was selected for its promising anti-plasmodial activity after a preliminary screening of several plants traditionally used in Burkina Faso to treat malaria. The aim of the present study was to further investigate the anti-plasmodial properties of this plant and to isolate the active anti-plasmodial compounds. Methods Eight crude extracts obtained from D. tomentosa whole plant were tested in vitro against two Plasmodium falciparum strains (3D7 and W2) using the p-LDH assay (colorimetric method). The Peters’ four-days suppressive test model (Plasmodium berghei-infected mice) was used to evaluate the in vivo anti-plasmodial activity. An in vitro bioguided fractionation was undertaken on a dichloromethane extract, using preparative HPLC and TLC techniques. The identity of the pure compound was assessed using UV, MS and NMR spectroscopic analysis. In vitro cytotoxicity against WI38 human fibroblasts (WST-1 assay) and haemolytic activity were also evaluated for extracts and pure compounds in order to check selectivity. Results The best in vitro anti-plasmodial results were obtained with the dichloromethane, diethylether, ethylacetate and methanol extracts, which exhibited a high activity (IC50 ≤ 5 μg/ml). Hot water and hydroethanolic extracts also showed a good activity (IC50 ≤ 15 μg/ml), which confirmed the traditional use and the promising anti-malarial potential of the plant. The activity was also confirmed in vivo for all tested extracts. However, most of the active extracts also exhibited cytotoxic activity, but no extract was found to display any haemolytic activity. The bioguided fractionation process allowed to isolate and identify a sesquiterpene lactone (urospermal A-15-O-acetate) as the major anti-plasmodial compound of the plant (IC50 < 1 μg/ml against both 3D7 and W2 strains). This was also

  7. Renal Side Effects of Non-Steroidal Anti-Inflammatory Drugs in Neonates

    Directory of Open Access Journals (Sweden)

    Marc Gewillig

    2010-02-01

    Full Text Available Non-steroidal anti-inflammatory drugs like ibuprofen or indomethacin are commonly prescribed drugs to induce pharmacologic closure of a patent ductus arteriosus in preterm neonates. Based on a recently published Cochrane meta-analysis, both drugs are equally effective to induce closure. Drug choice can therefore be based on differences in side effects or pharmaco-economic arguments. The current review quantifies the negative impact of either ibuprofen or indomethacin on renal function, including diuresis, glomerular filtration rate and renal tubular function. Both ibuprofen and indomethacin have a quantifiable impact on renal function. However, compared to ibuprofen, the negative impact of indomethacin is more pronounced.

  8. CHAPTER 1

    African Journals Online (AJOL)

    Dr Olaleye

    Changes in Plasmodium Falciparum Population Dynamics in ... vaccine. The most polymorphic genetic loci is msp-2 gene and it has been suggested that ... Thick blood smears stained with Giemsa were prepared ... specific Polymerase Chain Reaction (PCR). ..... anti-malarial drug treatment in Tanzanian children with acute.

  9. 78 FR 3440 - Government-Owned Inventions; Availability for Licensing

    Science.gov (United States)

    2013-01-16

    ... no vaccine for malaria, and there is growing resistance to existing anti-malarial drugs. Sexual stage... Applications: Malaria vaccine, diagnostic and therapeutic. Competitive Advantages: Single protein malaria... candidate oral anthrax vaccine exists and would result in an easy-to-administer oral delivery system to...

  10. Fiscal 2000 pioneering research report on the basic technology for novel DNA drug creation using anti-gene engineering; 2000 nendo anti gene kogaku ni yoru shinki DNA drug soshutsu kiban gijutsu chosa kenkyu hokokusho

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-03-01

    Research is conducted concerning the possibility of anti-gene engineering basic to the application of DNA (deoxyribonucleic acid) drugs capable of serving as functional DNAs to the control of the expression of industrially useful substance producing genes or of anomalous genes and concerning the possibility of novel industry creation on the strength of the said engineering. The specific research items are described below. Technical seeds are investigated relating to the tissue- and cell-specific drug delivery system for the expression of the molecular device function of the DNA drug. Concerning molecular target technologies such as the anti-sense method, possibilities are studied of utilizing the currently available technical seeds for the eventual creation of novel industries. Concerning novel designing methods utilizing genome information such as SNPs (single nucleotide polymorphisms), investigations are conducted to determine if they would help novel technology development and novel material development. The domestic state is surveyed in relation to DNA drugs, and possibilities are investigated of novel substance production and novel medicine creation with the aid of anti-gene engineering. (NEDO)

  11. Anxiety sensitivity and self-reported reasons for drug use.

    Science.gov (United States)

    Stewart, S H; Karp, J; Pihl, R O; Peterson, R A

    1997-01-01

    Two studies examined the relationships between anxiety sensitivity (AS), drug use, and reasons for drug use. In Study 1, 229 university students (57% F) completed the Anxiety Sensitivity Index (ASI) and a drug use survey, assessing use of a variety of drugs within the last month, and coping reasons for drug use. Consistent with a modified tension-reduction hypothesis, ASI scores were positively correlated with the number of both anxiety- and depression-related reasons for drug use endorsed. In Study 2, 219 university students (74% F) completed the ASI and a drug use survey, assessing use of several drugs (e.g., alcohol, cigarettes, caffeine, and marijuana/hashish) within the last year, and primary reasons (coping, affiliative, or enhancement) for the use of each drug. Marijuana/hashish users reported lower ASI scores than non-users supporting a negative relation between AS and the use of cannabis. ASI scores were positively correlated with the use of alcohol primarily to cope, and negatively correlated with the use of alcohol primarily to affiliate, among both gender groups, and ASI scores were positively correlated with the use of nicotine primarily to cope among the females. Implications of these findings for understanding risk for abuse of stress-response-dampening drugs by high AS individuals are discussed.

  12. Anti-Obesity Agents and the US Food and Drug Administration.

    Science.gov (United States)

    Casey, Martin F; Mechanick, Jeffrey I

    2014-09-01

    Despite the growing market for obesity care, the US Food and Drug Administration (FDA) has approved only two new pharmaceutical agents-lorcaserin and combination phentermine/topiramate-for weight reduction since 2000, while removing three agents from the market in the same time period. This article explores the FDA's history and role in the approval of anti-obesity medications within the context of a public health model of obesity. Through the review of obesity literature and FDA approval documents, we identified two major barriers preventing fair evaluation of anti-obesity agents including: (1) methodological pitfalls in clinical trials and (2) misaligned values in the assessment of anti-obesity agents. Specific recommendations include the use of adaptive (Bayesian) design protocols, value-based analyses of risks and benefits, and regulatory guidance based on a comprehensive, multi-platform obesity disease model. Positively addressing barriers in the FDA approval process of anti-obesity agents may have many beneficial effects within an obesity disease model.

  13. Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report

    Directory of Open Access Journals (Sweden)

    Etxagibel Aitziber

    2008-01-01

    Full Text Available Abstract Introduction Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. Case presentation We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Conclusion Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis.

  14. The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR) modulating poly(p-dioxanone-co-l-phenylalanine) prodrug.

    Science.gov (United States)

    Wang, Bing; Wen, Aiping; Feng, Chengmin; Niu, Lijing; Xiao, Xin; Luo, Le; Shen, Chengyi; Zhu, Jiang; Lei, Jun; Zhang, Xiaoming

    2018-04-13

    In present study, the apoptosis induction and proliferation suppression effects of l-phenylalanine (l-Phe) on fibroblasts were confirmed. The action sites of l-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca 2+ stores; disruption of intracellular Ca 2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l-Phe, and the results those l-Phe triggered the increasing of intracellular Ca 2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-l-phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l-Phe for the sustained release of l-Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-β1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. We have previously demonstrated that poly(p-dioxanone-co-l-phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l-phenylalanine. In present study, the inhibition mechanism of l-phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l-phenylalanine, and then the ER Ca 2+ stores were released

  15. pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

    Science.gov (United States)

    Wang, Xue-Qing; Zhang, Qiang

    2012-10-01

    pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. A short history of anti-rheumatic therapy - VI. Rheumatoid arthritis drugs

    Directory of Open Access Journals (Sweden)

    G. Pasero

    2011-09-01

    Full Text Available The treatment of rheumatoid arthritis traditionally includes symptomatic drugs, showing a prompt action on pain and infl ammation, but without any infl uence on disease progression, and other drugs that could modify the disease course and occasionally induce clinical remission (DMARDs or disease modifying anti-rheumatic drugs. This review describes the historical steps that led to the use of the main DMARDs in rheumatoid arthritis, such as gold salts, sulphasalazine, chloroquine and hydroxychloroquine, D-penicillamine, and other immunoactive drugs, including methotrexate, azathioprine, cyclosporin and lefl unomide. The historical evolution of use of these drugs is then discussed, including the strategy of progressive (“therapeutic pyramid” or of more aggressive treatment, through the simultaneous use of two or more DMARDs (“combination therapy”.

  17. Pricing appraisal of anti-cancer drugs in the South East Asian, Western Pacific and East Mediterranean Region.

    Science.gov (United States)

    Salmasi, Shahrzad; Lee, Kah Seng; Ming, Long Chiau; Neoh, Chin Fen; Elrggal, Mahmoud E; Babar, Zaheer-Ud- Din; Khan, Tahir Mehmood; Hadi, Muhammad Abdul

    2017-12-28

    Globally, cancer is one of the leading causes of mortality. High treatment cost, partly owing to higher prices of anti-cancer drugs, presents a significant burden on patients and healthcare systems. The aim of the present study was to survey and compare retail prices of anti-cancer drugs between high, middle and low income countries in the South-East Asia, Western Pacific and Eastern Mediterranean regions. Cross-sectional survey design was used for the present study. Pricing data from ten counties including one from South-East Asia, two from Western Pacific and seven from Eastern Mediterranean regions were used in this study. Purchasing power parity (PPP)-adjusted mean unit prices for 26 anti-cancer drug presentations (similar pharmaceutical form, strength, and pack size) were used to compare prices of anti-cancer drugs across three regions. A structured form was used to extract relevant data. Data were entered and analysed using Microsoft Excel®. Overall, Taiwan had the lowest mean unit prices while Oman had the highest prices. Six (23.1%) and nine (34.6%) drug presentations had a mean unit price below US$100 and between US$100 and US$500 respectively. Eight drug presentations (30.7%) had a mean unit price of more than US$1000 including cabazitaxel with a mean unit price of $17,304.9/vial. There was a direct relationship between income category of the countries and their mean unit price; low-income countries had lower mean unit prices. The average PPP-adjusted unit prices for countries based on their income level were as follows: low middle-income countries (LMICs): US$814.07; high middle income countries (HMICs): US$1150.63; and high income countries (HICs): US$1148.19. There is a great variation in pricing of anticancer drugs in selected countires and within their respective regions. These findings will allow policy makers to compare prices of anti-cancer agents with neighbouring countries and develop policies to ensure accessibility and affordability of

  18. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

    Science.gov (United States)

    Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

    2017-06-01

    The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

  19. Non-Steroidal Anti-inflammatory Drugs As Host-Directed Therapy for Tuberculosis : A Systematic Review

    NARCIS (Netherlands)

    Kroesen, Vera M.; Gröschel, Matthias I.; Martinson, Neil; Zumla, Alimuddin; Maeurer, Markus; van der Werf, Tjip S.; Vilaplana, Cristina

    2017-01-01

    Lengthy, antimicrobial therapy targeting the pathogen is the mainstay of conventional tuberculosis treatment, complicated by emerging drug resistances. Host-directed therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), in contrast, target host factors to mitigate disease severity. In

  20. Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease

    DEFF Research Database (Denmark)

    Chaparro, M; Verreth, A; Lobaton, T

    2018-01-01

    OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs...... in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non......-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox...

  1. N-Acetylcysteine enhances the action of anti-inflammatory drugs as suppressors of prostaglandin production in monocytes

    Directory of Open Access Journals (Sweden)

    Erica Hoffer

    2002-01-01

    Full Text Available The anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs is associated with inhibition of cyclooxygenase (COX, the rate-limiting enzyme responsible for the synthesis of prostaglandins. Since oxygen free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract, it seems plausible that antioxidants might affect the production of prostaglandin by activated cells. This research is focused on the effect of the antioxidant N-acetylcysteine (NAC on the inhibition of prostaglandin E2 formation in activated monocytes by specific and non-specific COX inhibitors. We found that lipopolysaccharide-induced prostaglandin E2 formation was significantly reduced by rofecoxib and by diclofenac, two NSAIDs. Addition of NAC to each of these drugs enhanced the effect of the NSAIDs. These results suggest that one might expect either a potentiation of the anti-inflammatory effect of COX inhibitors by their simultaneous administration with NAC, or obtaining the same anti-inflammatory at lower drug levels.

  2. Ankle sprain: the effects of non-steroidal anti-inflammatory drugs

    NARCIS (Netherlands)

    Struijs, Peter A. A.; Kerkhoffs, Gino M. M. J.

    2015-01-01

    Injury of the lateral ligament complex of the ankle joint occurs in about one in 10,000 people per day, accounting for a quarter of all sports injuries. We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of non-steroidal anti-inflammatory drugs

  3. Current trend of drug sensitivity in bovine mastitis

    Directory of Open Access Journals (Sweden)

    Rajeev Ranjan

    2010-02-01

    Full Text Available The study was conducted on 190 milk samples of bovine mastitis and 138 samples were confirmed positives for microorganisms. All the 138 samples were subjected to drug sensitivity test. The most effective antibiotic was enrofloxacin (91.67% followed by ciprofloxacin (90.15%, amikacin (87.12%, ceftriaxone (84.10%, chloramphenicol (80.31%, cefotaxime (79.55% and gentamicin (77.27%. Microorganisms were mostly resistant to drugs like streptomycin, penicillinG, ampicillin, cloxacillin, amoxycillin and neomycin in increasing order of resistance. Hence, it is suggested that the line of treatment should be based on antibiogram study of various isolates from bovine mastitis. Further, the selection of drugs after culture and sensitivity test should be based on their ability to cross blood tissue barrier or mammary parenchyma, lipophilicity and ability to work in alkaline pH. [Vet. World 2010; 3(1.000: 17-20

  4. Increased fluidity and oxidation of malarial lipoproteins: relation with severity and induction of endothelial expression of adhesion molecules

    Directory of Open Access Journals (Sweden)

    Looareesuwan Sornchai

    2004-06-01

    Full Text Available Abstract Introduction Oxidative stress has been demonstrated in malaria. The potential oxidative modification of lipoproteins derived from malaria patients was studied. These oxidized lipids may have role in pathogenesis of malaria. Method The plasma lipid profile and existence of oxidized forms of very low density lipoprotein (VLDL, low density lipoprotein (LDL and high density lipoprotein (HDL were investigated in malaria (17 mild and 24 severe patients and 37 control subjects. Thiobarbituric acid reactive substances (TBARs, conjugated dienes, tryptophan fluorescence and fluidity of lipoproteins were determined as markers of oxidation. The biological effect of malarial lipoproteins was assessed by the expression of adhesion molecules on endothelial cells. Results Malarial lipoproteins had decreased cholesterol (except in VLDL and phospholipid. The triglyceride levels were unchanged. The cholesterol/phospholipid ratio of LDL was decreased in malaria, but increased in VLDL and HDL. TBARs and conjugate dienes were increased in malarial lipoproteins, while the tryptophan fluorescence was decreased. The fluidity of lipoproteins was increased in malaria. These indicated the presence of oxidized lipoproteins in malaria by which the degree of oxidation was correlated with severity. Of three lipoproteins from malarial patients, LDL displayed the most pronounced oxidative modification. In addition, oxidized LDL from malaria patients increased endothelial expression of adhesion molecules. Conclusion In malaria, the lipoproteins are oxidatively modified, and the degree of oxidation is related with severity. Oxidized LDL from malarial patients increases the endothelial expression of adhesion molecules. These suggest the role of oxidized lipoproteins, especially LDL, on the pathogenesis of disease.

  5. Antiplasmodial activity of some phenolic compounds from ...

    African Journals Online (AJOL)

    Background: Plasmodium falciparum, one of the causative agents of malaria, has high adaptability through mutation and is resistant to many types of anti-malarial drugs. This study presents an in vitro assessment of the antiplasmodial activity of some phenolic compounds isolated from plants of the genus Allanblackia.

  6. Postoperative use of non-steroidal anti-inflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection

    DEFF Research Database (Denmark)

    Klein, Mads; Gögenur, Ismail; Rosenberg, Jacob

    2012-01-01

    To evaluate the effect of postoperative use of non-steroidal anti-inflammatory drugs (NSAIDs) on anastomotic leakage requiring reoperation after colorectal resection.......To evaluate the effect of postoperative use of non-steroidal anti-inflammatory drugs (NSAIDs) on anastomotic leakage requiring reoperation after colorectal resection....

  7. Inhibition of amyloidogenesis by non-steroidal anti-inflammatory drugs and their hybrid nitrates

    Science.gov (United States)

    Schiefer, Isaac T.; Abdul-Hay, Samer; Wang, Huali; Vanni, Michael; Qin, Zhihui; Thatcher, Gregory R. J.

    2011-01-01

    Poor blood-brain barrier penetration of non-steroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer’s disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogs were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogs were obtained with enhanced anti-inflammatory and anti-amyloidogenic properties compared to 1, however, esterification led to elevated Aβ1–42 levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate, CHF5074. Although hybrid nitrates elevated Aβ1–42 at higher concentration, SALA activity was observed at low concentrations (≤ 1 µM): both Aβ1–42 and the ratio of Aβ1–42/Aβ1–40 were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach towards a clinically useful SALA. PMID:21405086

  8. In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

    Science.gov (United States)

    Agarwal, Drishti; Sharma, Manish; Dixit, Sandeep K; Dutta, Roshan K; Singh, Ashok K; Gupta, Rinkoo D; Awasthi, Satish K

    2015-02-05

    Emergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT). Fluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters' four-day suppressive test. Promising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW). In vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.

  9. Sensitivity test of tumor cell to anticancer drug using diffusion chamber

    Energy Technology Data Exchange (ETDEWEB)

    Soejima, S [Hirosaki Univ., Aomori (Japan). School of Medicine

    1978-11-01

    The diffusion chamber method and xenogeneic transplantation of human cancer cells in rats were studied clinically to test the sensitivity of these cells to anticancer drugs. The growth of Hirosaki sarcoma in a diffusion chamber inserted in to Wistar rats was influenced by the difference in tumor cell counts in the chamber. The growth rate in the chamber inserted in to the subcutaneous tissue was more constant than in the abdominal cavity, but the degree of proliferation of tumor cells in the abdominal cavity was more than in the subcutaneous tissue. Sarcoma and solid type sarcoma were affected by mitomycin C (MMC). The effect was greater in dd-mice than in Donryu rats. Solid type Yoshida sarcoma inserted in to the subcutaneous tissue of Donryu rat was not affected by MMC. The degree of sensitivity of methylcholanthrene induced tumor cells, inserted in to the subcutaneous tissue of Donryu rats, to MMC differed according to various conditions of the hosts. Clinically, the influences of anticancer drugs on human cancer cells inserted in to the subcutaneous tissue of /sup 60/Co-irradiated Donryu rats were observed. There were various grades of sensitivity of gastric cancer cells to anticancer drugs. MMC was effective in 53% of the cases, Cyclophosphamide in 40%, 5-FU in 54%, cytosine arabinoside in 32%, and FT-207 in 57%. Twenty-seven percent were not affected by anticancer drugs. On histological examination, tubular adenocarcinoma cells had a high sensitivity to anticancer drugs, while poorly differentiated adenocarcinoma cells had a low sensitive. Anticancer drugs selected according to the sensitivity of human cancer cells had a marked effective on advanced cancer cells. The diffusion chamber method was useful in determining the degree of bone marrow toxicity of anticancer drugs.

  10. Development of a Nafion/MWCNT-SPCE-Based Portable Sensor for the Voltammetric Analysis of the Anti-Tuberculosis Drug Ethambutol

    Directory of Open Access Journals (Sweden)

    Rosa A. S. Couto

    2016-06-01

    Full Text Available Herein we describe the development, characterization and application of an electrochemical sensor based on the use of Nafion/MWCNT-modified screen-printed carbon electrodes (SPCEs for the voltammetric detection of the anti-tuberculosis (anti-TB drug ethambutol (ETB. The electrochemical behaviour of the drug at the surface of the developed Nafion/MWCNT-SPCEs was studied through cyclic voltammetry (CV and square wave voltammetry (SWV techniques. Electrochemical impedance spectroscopy (EIS and scanning electron microscopy (SEM were employed to characterize the modified surface of the electrodes. Results showed that, compared to both unmodified and MWCNTs-modified SPCEs, negatively charged Nafion/MWCNT-SPCEs remarkably enhanced the electrochemical sensitivity and selectivity for ETB due to the synergistic effect of the electrostatic interaction between cationic ETB molecules and negatively charged Nafion polymer and the inherent electrocatalytic properties of both MWCNTs and Nafion. Nafion/MWCNT-SPCEs provided excellent biocompatibility, good electrical conductivity, low electrochemical interferences and a high signal-to-noise ratio, providing excellent performance towards ETB quantification in microvolumes of human urine and human blood serum samples. The outcomes of this paper confirm that the Nafion/MWCNT-SPCE-based device could be a potential candidate for the development of a low-cost, yet reliable and efficient electrochemical portable sensor for the low-level detection of this antimycobacterial drug in biological samples.

  11. The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity.

    Science.gov (United States)

    Nyfeler, B; Pichler, W J

    1997-02-01

    The diagnosis of a drug allergy is mainly based upon a very detailed history and the clinical findings. In addition, several in vitro or in vivo tests can be performed to demonstrate a sensitization to a certain drug. One of the in vitro tests is the lymphocyte transformation test (LTT), which can reveal a sensitization of T-cells by an enhanced proliferative response of peripheral blood mononuclear cells to a certain drug. To evaluate the sensitivity and specificity of the LTT, 923 case histories of patients with suspected drug allergy in whom a LTT was performed were retrospectively analysed. Based on the history and provocation tests, the probability (P) of a drug allergy was estimated to be > 0.9, 0.5-0.9, 0.1-0.5 or 0.9) had a positive LTT, which indicates a sensitivity of 78%. If allergies to betalactam-antibiotics were analysed separately, the sensitivity was 74.4%. Fifteen of 102 patients where a classical drug allergy could be excluded (P sensitization could be demonstrated as well (i.e. hen's egg lysozyme, 7/7). In 632 of the 923 cases, skin tests were also performed (scratch and/or epicutaneous), for which we found a lower sensitivity than for the LTT (64%), while the specificity was the same (85%). Although our data are somewhat biased by the high number of penicillin allergies and cannot be generalized to drug allergies caused by other compounds, we conclude that the LTT is a useful diagnostic test in drug allergies, able to support the diagnosis of a drug allergy and to pinpoint the relevant drug.

  12. Use of biomarkers in the discovery of novel anti-schizophrenia drugs

    DEFF Research Database (Denmark)

    Mikkelsen, Jens D.; Thomsen, Morten S.; Hansen, Henrik

    2010-01-01

    Schizophrenia is characterized by a diverse symptomatology that often includes positive, cognitive and negative symptoms. Current anti-schizophrenic drugs act at multiple receptors, but little is known about how each of these receptors contributes to their mechanisms of action. Screening of novel...

  13. Detecting drug-drug interactions using a database for spontaneous adverse drug reactions: an example with diuretics and non-steroidal anti-inflammatory drugs.

    Science.gov (United States)

    van Puijenbroek, E P; Egberts, A C; Heerdink, E R; Leufkens, H G

    2000-12-01

    Drug-drug interactions are relatively rarely reported to spontaneous reporting systems (SRSs) for adverse drug reactions. For this reason, the traditional approach for analysing SRS has major limitations for the detection of drug-drug interactions. We developed a method that may enable signalling of these possible interactions, which are often not explicitly reported, utilising reports of adverse drug reactions in data sets of SRS. As an example, the influence of concomitant use of diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) on symptoms indicating a decreased efficacy of diuretics was examined using reports received by the Netherlands Pharmacovigilance Foundation Lareb. Reports received between 1 January 1990 and 1 January 1999 of patients older than 50 years were included in the study. Cases were defined as reports with symptoms indicating a decreased efficacy of diuretics, non-cases as all other reports. Exposure categories were the use of NSAIDs or diuretics versus the use of neither of these drugs. The influence of the combined use of both drugs was examined using logistic regression analysis. The odds ratio of the statistical interaction term of the combined use of both drugs was increased [adjusted odds ratio 2.0, 95% confidence interval (CI) 1.1-3.7], which may indicate an enhanced effect of concomitant drug use. The findings illustrate that spontaneous reporting systems have a potential for signal detection and the analysis of possible drug-drug interactions. The method described may enable a more active approach in the detection of drug-drug interactions after marketing.

  14. Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

    Directory of Open Access Journals (Sweden)

    January Weiner 3rd

    2016-08-01

    Full Text Available In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

  15. C_1_8-attached membrane funnel-based spray ionization mass spectrometry for quantification of anti-diabetic drug from human plasma

    International Nuclear Information System (INIS)

    Li, Wan; Chen, Xiangfeng; Wong, Y.-L. Elaine; Hung, Y.-L. Winnie; Wang, Ze; Deng, Liulin; Dominic Chan, T.-W.

    2016-01-01

    In this work, sorbent-attached membrane funnel-based spray ionization mass spectrometry was explored for quantitative analysis of anti-diabetic drugs spiked in human plasma. C_1_8-attached membrane funnel was fabricated for in situ extraction and clean-up to alleviate matrix suppression effect in the ionization process. Repaglinide was used as a target analyte of anti-diabetic drugs. Under optimal working conditions, good linearity (R"2 > 0.99) was obtained in the concentration range of 1–100 ng mL"−"1. The method detection limit of target drugs spiked in the human plasma was around 0.30 ng mL"−"1. Through the application of an isotope-labeled internal standard, the signal fluctuation caused by residual background matrices was largely alleviated and the precision of measurement (RSD) was below 15%. The recovery of repaglinide for 5, 25, and 100 ng mL"−"1 of spiked human plasma matrixes ranged from 87% to 112%. The developed method was successfully applied to determine repaglinide in plasma volunteers who orally received a dose of drug association. Our results demonstrated that membrane funnel-based spray is a simple and sensitive method for rapid screening analysis of complex biological samples. - Highlights: • Sorbent attached membrane funnel based spray platform was used for drug determination in human plasma. • The matrix suppression effect of human plasma was largely eliminated. • The method was applied to determine repaglinide in plasma volunteers. • Membrane funnel-based spray is promising for analysis of biological samples.

  16. Modulation of the formation and release of bovine SRS-A in vitro by several anti-anaphylactic drugs.

    Science.gov (United States)

    Burka, J F; Eyre, P

    1975-01-01

    Slow-reacting substance of anaphylaxis (SRS-A) is released immunologically from bovine lung in vitro. Various drugs known to protect calves and other animals during anaphylaxis were tested to investigate their modulation of the formation and release of SRS-A. The anti-inflammatory drugs, meclofenamate and aspirin, potentiated SRS-A release. Chlorphenesin and diethylcarbamazine citrate at high concentrations both inhibited SRS-A release. Two new anti-anaphylactic drugs, PR-D-92-EA and M&B 22,948, were particularly effective in inhibiting SRS-A release at low concentrations. The possible modes of actions of these drugs are discussed.

  17. Anti-chemokine small molecule drugs: a promising future?

    Science.gov (United States)

    Proudfoot, Amanda E I; Power, Christine A; Schwarz, Matthias K

    2010-03-01

    Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry. Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review. In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future. In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.

  18. Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

    International Nuclear Information System (INIS)

    Khanim, F L; Merrick, B A M E; Giles, H V; Jankute, M; Jackson, J B; Giles, L J; Birtwistle, J; Bunce, C M; Drayson, M T

    2011-01-01

    Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity

  19. 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

    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...

  20. Tanzania | Page 41 | IDRC - International Development Research ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Alexander Soucy is correct to identify insecticide-treated bednets and inexpensive anti-malarial drugs as crucial to the global fight against malaria ('An easy way to save three million lives,' April 26). Read more about Tanzania ... Legislation on competition brings productivity and business investment to Tanzania. Increasing ...

  1. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting.

    Directory of Open Access Journals (Sweden)

    Alyaa M Abdel-Haleem

    2018-01-01

    Full Text Available Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale metabolic models (GeMMs of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1, choline, and pantothenate (vitamin B5 metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  2. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting

    KAUST Repository

    Abdel-Haleem, Alyaa M.

    2018-01-04

    Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale models (GEMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1), choline, and pantothenate (vitamin B5) metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  3. [Digestive and extra-digestive complications of nonsteroidal anti-inflammatory drugs. Preventive and curative strategies].

    Science.gov (United States)

    Sternon, J; Adler, M

    1997-04-01

    The authors review the digestive ulceration risk factors and the criteria for selecting a non steroidal antiinflammatory (NSAI), included the most recent drugs, such as selective anti-cyclo-oxygenases 2. They actualize the preventive strategies and insist on the values of misoprostol and of slow acting anti-rheumatic drugs. In the case of digestive ulcerations, they plead for the immediate stop of the NSAI and its replacement if necessary by corticosteroids, for the prescription of a proton pump inhibitor (PPI) or mesalazine according to the localisation of the lesion, finally for the eradication within 8 days of Helicobacter pylori.

  4. Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety

    OpenAIRE

    Roth, Sandford

    2011-01-01

    Sanford H RothArizona Research and Education, Arthritis Laboratory, Arizona State University, Phoenix, AZ, USAAbstract: Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less...

  5. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences

    KAUST Repository

    Coll, Francesc

    2015-05-27

    Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

  6. [Tuberculosis and drug-resistance tuberculosis in prisoners. Colombia, 2010-2012].

    Science.gov (United States)

    Gómez, Ingrid T; Llerena, Claudia R; Zabaleta, Angie P

    2015-01-01

    To characterize tuberculosis drug-resistance using anti-tuberculosis drug-sensitivity tests in Colombian prisoners. Descriptive-retrospective analyses were performed on cases of tuberculosis in prisoners. Samples were evaluated by the National Reference Laboratory. Conditions like gender, TB/VIH co-infection and drug-resistance were evaluated. Anti-tuberculosis drug-sensitivity tests were carried out on 72 prisoners. Results showed a distribution of 90.7 % of cases in males and 9.3 % of cases in females. 12 % of cases were TB/VIH co-infections, 94 % of the cases had not received any anti-tuberculosis treatment before, six isolates were drug-resistant corresponding to 8.8 % of total cases, and two cases were multi drug-resistant representing 1.3 % of the cases. Of the drug-resistant cases, 83.3 % were TB/VIH co-infected. Previously treated cases corresponded to 5.6 % of the total cases analyzed. One case with TB/VIH co-infection and rifampicin resistance was observed, representing 1.3 % of the total cases. The government must create a clear policy for prisoners in Colombia, because a high rate of disease in prisoners was observed. In addition, the results showed an association between drug-resistance and TB/VIH co-infection. Overcrowding and low quality of life in penitentiaries could become an important public health problem.

  7. Synthesis of a novel thermo/pH sensitive nanogel based on salep modified graphene oxide for drug release

    Energy Technology Data Exchange (ETDEWEB)

    Bardajee, Ghasem Rezanejade, E-mail: rezanejad@pnu.ac.ir; Hooshyar, Zari; Farsi, Maryam; Mobini, Akram; Sang, Golnaz

    2017-03-01

    Nanogels (NGs) are three-dimensional water soluble cross-linked hydrogel materials in the nanoscale size range with a high loading capacity for guest molecules and act as drug carrier systems. In the present work, a new type of thermo/pH sensitive NG comprising salep modified graphene oxide (SMGO) with branched N-isopropylacrylamide (NIPAM) and acrylic acid (AA) was prepared. The SMGO/P(NIPAM-co-AA) NGs exhibited nanoporous structure and spherical particles with diameters about 82 nm as characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The samples were also characterized by Fourier transform infrared spectroscopy (FT-IR) and thermo gravimetric analysis (TGA) to further confirm about the formation of NGs. Doxorubicin (DOX) loaded SMGO/P(NIPAM-co-AA) NGs showed thermo/pH dependent releasing behavior: slow drug release at neutral pH and lower temperature but increased significantly in acidic pH and higher temperature, without any burst release. In addition, the NGs exhibited no effect on the cell viability in the tested concentration range up to 410 μg/mL and drug release systems enhanced toxicity to HeLa cells when compared to the equivalent dose of the free drug. Overall, our results put forth NGs as potential candidates in the development of a new nanocarrier for anti-cancer drug delivery. - Highlights: • A novel thermo/pH sensitive nanogels (NGs) was successfully synthesized. • NGs showed high loading capacity for DOX drug and slow drug release at neutral pH. • NGs exhibited no effect on the cell viability in the tested concentration range.

  8. Synthesis of a novel thermo/pH sensitive nanogel based on salep modified graphene oxide for drug release

    International Nuclear Information System (INIS)

    Bardajee, Ghasem Rezanejade; Hooshyar, Zari; Farsi, Maryam; Mobini, Akram; Sang, Golnaz

    2017-01-01

    Nanogels (NGs) are three-dimensional water soluble cross-linked hydrogel materials in the nanoscale size range with a high loading capacity for guest molecules and act as drug carrier systems. In the present work, a new type of thermo/pH sensitive NG comprising salep modified graphene oxide (SMGO) with branched N-isopropylacrylamide (NIPAM) and acrylic acid (AA) was prepared. The SMGO/P(NIPAM-co-AA) NGs exhibited nanoporous structure and spherical particles with diameters about 82 nm as characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The samples were also characterized by Fourier transform infrared spectroscopy (FT-IR) and thermo gravimetric analysis (TGA) to further confirm about the formation of NGs. Doxorubicin (DOX) loaded SMGO/P(NIPAM-co-AA) NGs showed thermo/pH dependent releasing behavior: slow drug release at neutral pH and lower temperature but increased significantly in acidic pH and higher temperature, without any burst release. In addition, the NGs exhibited no effect on the cell viability in the tested concentration range up to 410 μg/mL and drug release systems enhanced toxicity to HeLa cells when compared to the equivalent dose of the free drug. Overall, our results put forth NGs as potential candidates in the development of a new nanocarrier for anti-cancer drug delivery. - Highlights: • A novel thermo/pH sensitive nanogels (NGs) was successfully synthesized. • NGs showed high loading capacity for DOX drug and slow drug release at neutral pH. • NGs exhibited no effect on the cell viability in the tested concentration range.

  9. EFFECT OF TWO COMMERCIAL ANTI-STRESS DRUGS ON THE GROWTH OF ARTIFICIALLY INDUCED STRESSED BROILERS

    Directory of Open Access Journals (Sweden)

    A. Memon, N. A. Qureshi, Mol. Rind, A.A. Solangi and G. Memono1

    2001-01-01

    Full Text Available The Study was carried out to evaluate the efficacy of anti-stress commercial drugs (Vitasol Super and Vitamionic-33 on growth of stressed broilers, at the Poultry Experimental Station, Sindh Agriculture University Tandojam during August-September, 1998. A-day old 150 chicks were equally housed in three groups that were A, Band C. In group “A” five grams Vitasol Super was added in 40 litres of drinking water, while in group “B” one gram of Vitaminic-33 was added in three litres of drinking water. Group “C” was kept as control, where no anti-stress drug was supplemented in water. Results revealed highly significant difference among weight gain of broilers fed on ration supplemented with different anti-stress drugs. Average weight gain of all groups A, Band C were 1796.50, 1899.80 and 1760.52 gms, respectively. Average feed consumption of different groups were 3830, 3859 and 3818 gms, respectively. Average feed conversion ratio of different groups A, Band C was 2.14, 2.03 and 2.17, respectively. The average dressing percentage of difference groups were 62.10, 64.52 and 61.60. Highly significant difference was observed in weight of internal organs of different groups. The average per kilogram of broilers profit of different groups were Rs. 10.49, 13.81 and 10.95, respectively. The birds of group B, which was, earned maximum profit given Vitaminic-33 (anti-stress drug. It was concluded that anti-stress vitamin (Vitaminic-33 at the rate of 5grams/40 litres of water ad libitum can be successfully used for better growth of broilers

  10. Non-steroidal anti-inflammatory drugs and ulcer complications: a risk factor analysis for clinical decision-making

    DEFF Research Database (Denmark)

    Hansen, J M; Hallas, J; Lauritsen, Jens

    1996-01-01

    Use of non-steroidal anti-inflammatory drugs (NSAIDs) is recognized as an important cause of peptic ulcer complications. The aim of this nested case-control study was to identify risk factors for NSAID-related ulcer complications.......Use of non-steroidal anti-inflammatory drugs (NSAIDs) is recognized as an important cause of peptic ulcer complications. The aim of this nested case-control study was to identify risk factors for NSAID-related ulcer complications....

  11. Anti-metastatic Action of Non-steroidal Anti-inflammatory Drugs

    Directory of Open Access Journals (Sweden)

    Wen-Chun Hung

    2008-08-01

    Full Text Available Epidemiological studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs reduce the incidence and mortality of several types of human cancer. However, the molecular mechanisms by which NSAIDs exert their chemopreventive and anticancer effects are not fully understood. Cyclooxygenase 1 (COX-1 and COX-2 are the main targets for NSAIDs. Recent studies demonstrate that COX-2 is overexpressed in many human cancers and may promote tumorigenesis via: (1 stimulation of cancer cell proliferation; (2 increase of tumor angiogenesis; (3 prevention of cancer cell apoptosis; (4 modulation of immunoregulatory reactions; and (5 enhancement of tumor metastasis. NSAIDs may target the signaling molecules (from upstream activators to downstream effectors involved in these mechanisms to attenuate the development and progression of cancer. In this review, we discuss the recent findings with regard to the mechanisms by which NSAIDs inhibit tumorigenesis and will specifically focus on the elucidation of NSAID-induced inhibition of tumor metastasis.

  12. Drug selection principles in intra-arterial infusion chemotherapy

    International Nuclear Information System (INIS)

    Wang Gefang; Cheng Yongde

    2009-01-01

    The intra-arterial infusion chemotherapy is an effective treatment for malignant tumors. The following ten principles should be taken into account when the choice of infusion medication is to be made. (1) The tumor-sensitive drugs should be selected. (2) Pay attention to the compatibility of medicines. (3) Select the type of drug compatibility and drug interactions. (4) Concentration-dependent drugs are the drugs of first choice. (5) Pay attention to side effects when anti-cancer drug compatibility is considered.(6) The perfusion anti-cancer drugs exert their killing effect on the tumor cells in their prototype. (7) Pay attention to the administration order of the drugs and the intervals of treatment. (8) The medication should be individualized as the physical condition and tumor's heterogeneity are different from patient to patient. It is one of the fundamental principles to formulate a specific scheme for every given patient. (9) Make full use of the pharmacokinetics features of the anti-cancer drugs in clinical practice. (10) To be familiar with commonly used drugs and common tumor chemotherapeutic formulae is a matter of cardinal significance. (authors)

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

    Science.gov (United States)

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

    2011-08-01

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

  14. A Smart pH-responsive Nano-Carrier as a Drug Delivery System: A hybrid system comprised of mesoporous nanosilica MCM-41 (as a nano-container) & a pH-sensitive polymer (as smart reversible gatekeepers): Preparation, characterization and in vitro release studies of an anti-cancer drug.

    Science.gov (United States)

    Abbaszad Rafi, Abdolrahim; Mahkam, Mehrdad; Davaran, Soodabeh; Hamishehkar, Hamed

    2016-10-10

    A smart pH-responsive drug nano-carrier for controlled release of anti-cancer therapeutics was developed through a facile route. The nano-carrier consisted of two main parts: first, the nano-container part (that mesoporous silica nanoparticles (MCM-41) were selected for this aim); and second, pH-sensitive gatekeepers (that a pH-sensitive polymer, Poly4-vinylpyridine, played this role). In the first step, MCM-41 was synthesized via template assisted sol-gel process. In the second step, polymerizable functional groups were attached onto pore entrances rather than inside walls. In the third step, polymeric gatekeepers were introduced onto pore entrances via precipitation polymerization of functionalized MCM-41 with monomers. Different methods and analysis, such as Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Powder Diffraction (XRD), Thermo-Gravimetric Analysis (TGA), Energy-Dispersive X-ray Spectroscopy (EDX), Zeta Potentials, Dynamic Light Scattering (DLS), Field Emission Scanning Electron Microscope (FE-SEM) and Transmission Electron Microscopy (TEM) were employed to approve the successful attachment of gatekeepers. Furthermore, the release studies of methotroxate (MTX), an anti-cancer drug, were performed in different media (pH4, 5.8 and 7.4) at 37±1°C. The release profiles and curves show that the release rates are completely pH-dependent and it proceeds with a decrease in pH. It is concluded that in the higher pH the gatekeepers are in their close state, but they switch to the open state as a consequence of repulsive forces between positively charged polymer chains appear in acidic media. The results suggest that this smart nano-carrier can be considered as an appropriate candidate to deliver therapeutics to cancerous tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Primary and secondary anti-tuberculosis drug resistance in Hitossa District of Arsi Zone, Oromia Regional State, Central Ethiopia

    Directory of Open Access Journals (Sweden)

    Shallo Daba Hamusse

    2016-07-01

    Full Text Available Abstract Background Multidrug-resistant tuberculosis (MDR-TB drugs which is resistant to the major first-line anti-TB drugs, Isoniazid and Rifampicin, has become a major global challenge in tuberculosis (TB control programme. However, its burden at community level is not well known. Thus, the aim of study was to assess the prevalence of primary and secondary resistance to any first line anti-TB drugs and MDR TB in Hitossa District of Oromia Regional State, Central Ethiopia. Methods Population based cross- sectional study was conducted on individuals aged ≥15 years. Those with symptoms suggestive of TB were interviewed and two sputum specimens were collected from each and examined using Lowenstein-Jensen (LJ culture medium. Further, the isolates were confirmed by the Ziehl-Neelsen microscopic examination method. Drug susceptibility test (DST was also conducted on LJ medium using a simplified indirect proportion method. The resistance strains were then determined by percentage of colonies that grew on the critical concentration of Isoniazid, Streptomycin, Rifampicin and Ethambutol. Results The overall resistance of all forms of TB to any first-line anti-TB drug was 21.7 %. Of the total new and previously treated culture positive TB cases, 15.3 and 48.8 % respectively were found to be a resistant to any of the first-line anti-TB drugs. Further, of all forms of TB, the overall resistance of MDR-TB was 4.7 %. However, of the total new TB cases, 2.4 % had primary while 14.3 % had secondary MDR-TB. Resistance to any of the first-line anti-TB drugs (adjusted odd ratio (AOR, 8.1; 95 % CI: 2.26–29.30 and MDR-TB (AOR, 7.1; 95 % CI: 2.6–43.8 was found to be linked with previous history of anti-TB treatment. Conclusions The study has identified a high rate of primary and secondary resistance to any of the first-line anti-TB drugs and MDR-TB in the study area. The resistance may have resulted from sub-optimal performance of directly observed

  16. Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork

    Energy Technology Data Exchange (ETDEWEB)

    Izzotti, Alberto, E-mail: izzotti@unige.it [Mutagenesis Unit, IRCCS AOU San Martino – IST, Genova (Italy); Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa (Italy); La Maestra, Sebastiano; Micale, Rosanna Tindara; Longobardi, Maria Grazia [Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa (Italy); Saccà, Sergio Claudio [Ophthalmology Unit, IRCCS AOU San Martino-IST, Genova (Italy)

    2015-02-15

    Highlights: • Glaucoma drug preservatives induce DNA damage in trabecular meshwork cells. • Cellular alteration is related with the occurrence of activation of apoptosis through the intrinsic pathway. • Drug preservatives unable to induce cell damage are ineffective in killing bacteria. • Anti glaucoma drugs should be formulated as single-dose usage devoid of genotoxic preservatives. - Abstract: Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3

  17. pattern of anti diabetic drug prescription at a health facility in jos

    African Journals Online (AJOL)

    Administrator

    Jos Journal of Medicine, Volume 9 No. 1. PATTERN OF ANTI ... diabetic drug prescription at a private health facility in North Central Nigeria. Methodology: this was a ... Figure gender distribution of subjects ( 0 = males 1. = females ). Regimen.

  18. Validation of an LC-MS/MS method for analysis of anti-diabetic drugs in botanical dietary supplements labeled for blood sugar management.

    Science.gov (United States)

    Ma, Jun; Pawar, Rahul S; Grundel, Erich

    2018-03-01

    We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to detect and quantitate 14 anti-diabetic, 2 anti-obesity, and 3 cholesterol-lowering drugs in botanical dietary supplements marketed for blood sugar management. Many botanical dietary supplements which carry label statements related to blood sugar management are available over the Internet. Potential adulteration of such dietary supplements with anti-diabetic and other prescription drugs, some of which have been removed from the market due to adverse events, is of concern. No significant matrix effects were observed and mean recoveries of all 19 analytes from a single product matrix were 88 to 113% at spiking concentrations from 500 to 2000 μg/g. Mean recoveries of metformin, phenformin, and sibutramine from matrices prepared from multiple product composites ranged from 93 to 115% at a spiking concentration of 100 μg/g. The relative standard deviations (RSD) (%) of intra-day analyses ranged from 0.2 to 13 for all recovery studies. Eighty dietary supplements obtained in the USA and carrying label statements related to blood sugar management were analyzed using this method and none were found to be adulterated with the above 19 drugs. Two products obtained outside of the USA and known to be adulterated were also analyzed by this method and found to contain phenformin, glibenclamide, and sibutramine. This method provided satisfactory selectivity, linearity, accuracy, precision, and sensitivity for rapid determination of 19 drugs and has broad applicability for the analysis of dietary supplements for possible adulteration with these compounds. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  19. Acute nonsteroidal anti-inflammatory drug-induced colitis

    Directory of Open Access Journals (Sweden)

    Massimo Tonolini

    2013-01-01

    Full Text Available Resulting from direct toxicity on the bowel mucosa, nonsteroidal anti-inflammatory drug (NSAID-induced colitis is an underestimated although potentially serious condition. Plain abdominal radiographs and multidetector computed tomography allow to identify a right-sided acute colitis with associated pericolonic inflammation, progressively diminished changes along the descending and sigmoid colon, and rectal sparing, consistent with the hypothesized pathogenesis of NSAID colitis. Increased awareness of this condition should reduce morbidity through both prevention and early recognition. High clinical suspicion and appropriate patient questioning, together with consistent instrumental findings, negative biochemistry, and stool investigations should help physicians not to miss this important diagnosis.

  20. Central and peripheral haemodynamic effects of non-steroidal anti-inflammatory drugs in man.

    Science.gov (United States)

    Wennmalm, A; Carlsson, I; Edlund, A; Eriksson, S; Kaijser, L; Nowak, J

    1984-01-01

    The haemodynamic effects of non-steroidal anti-inflammatory (NSAI) drugs can be attributed either to their common property of inhibiting the formation of prostaglandins (PG) in the cardiovascular system, or to direct actions on the tone and sensitivity of the resistance vessels in various regions. Indomethacin (IND) is the most frequently studied NSAI drug, in animals and in man. Its cardiovascular effects differ somewhat from those of other NSAI, due to the fact that, besides inhibiting PG formation, IND acts as a direct vasoconstrictor. The stimulatory effect of IND in vascular smooth muscle results in an increased systemic vascular resistance which, although partially compensated by a decreased cardiac output, gives rise to a moderate increase in systemic blood pressure. The vasoconstrictor effect of IND is of particular interest in patients with ischemic heart disease, since it lowers their already decreased coronary flow, and may thereby accentuate the risk of myocardial infarction. Administration of IND also leads to a decreased blood flow in the splanchnic region, the kidneys, and the brain. The cerebral blood flow is lowered by 25-35%; in addition, IND almost entirely erases the hyperemic flow response to hypercapnia. Of other NSAI drugs, at least aspirin and naproxen are completely devoid of such actions on the cerebral circulation. A common vascular effect of all NSAI drugs is a diminution of reactive hyperemia, the local hyperemia that develops in a tissue subjected to a short period of arterial occlusion. Part of this hyperemic response is dependent on an intact vascular PG formation and consequently it is inhibited when PG formation is blocked. In contrast, NSAI drugs do not affect the functional increase in the blood flow in working skeletal muscle.

  1. ANN multiscale model of anti-HIV drugs activity vs AIDS prevalence in the US at county level based on information indices of molecular graphs and social networks.

    Science.gov (United States)

    González-Díaz, Humberto; Herrera-Ibatá, Diana María; Duardo-Sánchez, Aliuska; Munteanu, Cristian R; Orbegozo-Medina, Ricardo Alfredo; Pazos, Alejandro

    2014-03-24

    This work is aimed at describing the workflow for a methodology that combines chemoinformatics and pharmacoepidemiology methods and at reporting the first predictive model developed with this methodology. The new model is able to predict complex networks of AIDS prevalence in the US counties, taking into consideration the social determinants and activity/structure of anti-HIV drugs in preclinical assays. We trained different Artificial Neural Networks (ANNs) using as input information indices of social networks and molecular graphs. We used a Shannon information index based on the Gini coefficient to quantify the effect of income inequality in the social network. We obtained the data on AIDS prevalence and the Gini coefficient from the AIDSVu database of Emory University. We also used the Balaban information indices to quantify changes in the chemical structure of anti-HIV drugs. We obtained the data on anti-HIV drug activity and structure (SMILE codes) from the ChEMBL database. Last, we used Box-Jenkins moving average operators to quantify information about the deviations of drugs with respect to data subsets of reference (targets, organisms, experimental parameters, protocols). The best model found was a Linear Neural Network (LNN) with values of Accuracy, Specificity, and Sensitivity above 0.76 and AUROC > 0.80 in training and external validation series. This model generates a complex network of AIDS prevalence in the US at county level with respect to the preclinical activity of anti-HIV drugs in preclinical assays. To train/validate the model and predict the complex network we needed to analyze 43,249 data points including values of AIDS prevalence in 2,310 counties in the US vs ChEMBL results for 21,582 unique drugs, 9 viral or human protein targets, 4,856 protocols, and 10 possible experimental measures.

  2. Price Sensitivity of Demand for Prescription Drugs: Exploiting a Regression Kink Design

    DEFF Research Database (Denmark)

    Simonsen, Marianne; Skipper, Lars; Skipper, Niels

    This paper investigates price sensitivity of demand for prescription drugs using drug purchase records for at 20% random sample of the Danish population. We identify price responsiveness by exploiting exogenous variation in prices caused by kinked reimbursement schemes and implement a regression ...... education and income are, however, more responsive to the price. Also, essential drugs that prevent deterioration in health and prolong life have lower associated average price sensitivity....... kink design. Thus, within a unifying framework we uncover price sensitivity for different subpopulations and types of drugs. The results suggest low average price responsiveness with corresponding price elasticities ranging from -0.08 to -0.25, implying that demand is inelastic. Individuals with lower...

  3. The use of paediatric artemisinin combinations in sub-Saharan Africa: a snapshot questionnaire survey of health care personnel

    Directory of Open Access Journals (Sweden)

    Agnandji Selidji T

    2011-12-01

    Full Text Available Abstract Background Paediatric drug formulations for artemisinin combination therapy (P-ACT have been developed over the past few years and have been shown to improve the therapeutic management of young children with uncomplicated falciparum malaria. This process was however not equally paralleled by a timely adoption of P-ACT in national and international treatment recommendations. National malaria programmes in sub-Saharan Africa have not yet widely embraced this new therapeutic tool. To which extent P-ACT is used in the field in sub-Saharan Africa is not known to date. Methods This snapshot questionnaire survey aimed to provide an overview on the current routine practices for the availability and use of P-ACT as anti-malarial treatment for young children in sub-Saharan Africa. Health care personnel in seven countries in West-, Central, and East-Africa were invited to answer a structured questionnaire assessing use and availability of P-ACT. Results A total of 71 respondents including doctors, nurses and pharmacy personnel responsible for the anti-malarial treatment of young children were interviewed. P-ACT was used by 83% (95% confidence interval: 73-90%; n = 59 as first-line treatment for young children. Use of 15 different P-ACT products was reported among which only two have received WHO prequalification status and approval by a stringent registration authority. Use of a specific P-ACT product was not linked to consumer prices or availability of supporting clinical trial data, but may depend more on the marketing capacity of the manufacturer. Major differences in frequency and dosing of anti-malarial regimens with identical anti-malarial compounds and the marketing of loose combinations were recorded. Conclusion Paediatric ACT is widely used for the treatment of uncomplicated malaria in young children. However, the majority of P-ACT formulations in use do not meet highest international quality standards evoking concerns for patients

  4. When ubiquitin meets NF-κB: a trove for anti-cancer drug development.

    Science.gov (United States)

    Wu, Zhao-Hui; Shi, Yuling

    2013-01-01

    During the last two decades, the studies on ubiquitination in regulating transcription factor NF-κB activation have elucidated the expanding role of ubiquitination in modulating cellular events by non-proteolytic mechanisms, as well as by proteasomal degradation. The significance of ubiquitination has also been recognized in regulating gene transcription, epigenetic modifications, kinase activation, DNA repair and subcellular translocation. This progress has been translated into novel strategies for developing anti-cancer therapeutics, exemplified by the success of the first FDA-approved proteasome inhibitor drug Bortezomib. Here we discuss the current understanding of the ubiquitin-proteasome system and how it is involved in regulating NF-κB signaling pathways in response to a variety of stimuli. We also focus on the recent progress of anti-cancer drug development targeting various steps of ubiquitination process, and the potential of these drugs in cancer treatment as related to their impact on NF-κB activation.

  5. Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?

    DEFF Research Database (Denmark)

    Andersen, K; Launer, L J; Ott, A

    1995-01-01

    Based on reports that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer's disease (AD), we studied the cross-sectional relation between NSAID use and the risk for AD in a population-based study of disease and disability in older people. After controlling...

  6. Identification of anti-HBV activities in Paeonia suffruticosa Andr. using GRP78 as a drug target on Herbochip®.

    Science.gov (United States)

    Lam, Iao-Fai; Huang, Min; Chang, Margaret Dah-Tysr; Yao, Pei-Wun; Chou, Yu-Ting; Ng, Sim-Kun; Tsai, Ying-Lin; Lin, Yu-Chang; Zhang, Yun-Feng; Yang, Xiao-Yuan; Lai, Yiu-Kay

    2017-01-01

    Herbochip ® technology is a high throughput drug screening platform in a reverse screening manner, in which potential chemical leads in herbal extracts are immobilized and drug target proteins can be used as probes for screening process [BMC Complementary and Alternative Medicine (2015) 15:146]. While herbal medicines represent an ideal reservoir for drug screenings, here a molecular chaperone GRP78 is demonstrated to serve as a potential target for antiviral drug discovery. We cloned and expressed a truncated but fully functional form of human GRP78 (hGRP78 1-508 ) and used it as a probe for anti-HBV drug screening on herbochips. In vitro cytotoxicity and in vitro anti-HBV activity of the herbal extracts were evaluated by MTT and ELISA assays, respectively. Finally, anti-HBV activity was confirmed by in vivo assay using DHBV DNA levels in DHBV-infected ducklings as a model. Primary screenings using GRP78 on 40 herbochips revealed 11 positives. Four of the positives, namely Dioscorea bulbifera , Lasiosphaera fenzlii , Paeonia suffruticosa and Polygonum cuspidatum were subjected to subsequent assays. None of the above extracts was cytotoxic to AML12 cells, but P. cuspidatum extract (PCE) was found to be cytotoxic to HepG2 2.2.15 cells. Both PCE and P. suffruticosa extract (PSE) suppressed secretion of HBsAg and HBeAg in HepG2 2.2.15 cells. The anti-HBV activity of PSE was further confirmed in vivo. We have demonstrated that GRP78 is a valid probe for anti-HBV drug screening on herbochips. We have also shown that PSE, while being non-cytotoxic, possesses in vitro and in vivo anti-HBV activities. Taken together, our data suggest that PSE may be a potential anti-HBV agent for therapeutic use.

  7. Cytochrome P450 2E1 gene polymorphisms/haplotypes and anti-tuberculosis drug-induced hepatitis in a Chinese cohort.

    Directory of Open Access Journals (Sweden)

    Shaowen Tang

    Full Text Available The pathogenic mechanism of anti-tuberculosis (anti-TB drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs of cytochrome P450 2E1(CYP2E1 in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort.A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology.Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644 were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis.Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.

  8. Synthesis and anti-angiogenic effect of conjugates between serum albumin and non-steroidal anti-inflammatory drugs

    DEFF Research Database (Denmark)

    Kjær, Birgitte; Struve, Casper; Friis, Tina

    2010-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit tumor growth and angiogenesis. Covalent linkage of naproxen to human serum albumin (HSA) has been shown to target it efficiently to the liver and this may potentially be exploited for liver-selective inhibition of angiogenesis. With the aim...... effect on endothelial cells at or above the level of the non-conjugated NSAIDs in an in vitro angiogenesis assay....

  9. Pregnant women and non-steroidal anti-inflammatory drugs: Knowledge, perception and drug consumption pattern during pregnancy in Ethiopia

    OpenAIRE

    Chalelgn Kassaw; Nasir Tajure Wabe

    2012-01-01

    Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the widely used drugs and are often used by pregnant women. However, they can have significant teratogenic effects. The aim of the study was to investigate pregnant women′s knowledge about NSAIDs use during pregnancy and their perception and consumption pattern. Materials and Methods: The study was a cross sectional study on women waiting for a consultation in the selected maternity hospitals in Addis Ababa, Ethiopia. The pr...

  10. A population-based case-control study of the safety of oral anti-tuberculosis drug treatment during pregnancy

    DEFF Research Database (Denmark)

    Czeizel, A.E.; Rockenbauer, M.; Olsen, J.

    2001-01-01

    OUTCOME MEASURES: Congenital abnormalities in newborn infants and fetuses diagnosed prenatally during the second and third trimesters, and postnatally from birth to the age of one year. RESULTS: Of 38,151 controls, 29 (0.08%) were exposed to anti-tuberculosis drug treatment during pregnancy......OBJECTIVE: To study the human teratogenic potential of isoniazid and other anti-tuberculosis drug treatment during pregnancy. DESIGN AND SETTING: Cases from a large population-based dataset at the Hungarian Case-Control Surveillance of Congenital Abnormalities, and controls from the National Birth...... Registry, between 1980 and 1996. Information on all oral anti-tuberculosis drug treatments during pregnancy was medically recorded. STUDY PARTICIPANTS: Women who had newborns or fetuses with congenital abnormalities (case group), and women who had babies with no congenital abnormality (control group). MAIN...

  11. Characterization of a sensitive mouse Aβ40 PD biomarker assay for Alzheimer's disease drug development in wild-type mice.

    Science.gov (United States)

    Lu, Yanmei; Hoyte, Kwame; Montgomery, William H; Luk, Wilman; He, Dongping; Meilandt, William J; Zuchero, Y Joy Yu; Atwal, Jasvinder K; Scearce-Levie, Kimberly; Watts, Ryan J; DeForge, Laura E

    2016-05-01

    Transgenic mice that overexpress human amyloid precursor protein with Swedish or London (APPswe or APPlon) mutations have been widely used for preclinical Alzheimer's disease (AD) drug development. AD patients, however, rarely possess these mutations or overexpress APP. We developed a sensitive ELISA that specifically and accurately measures low levels of endogenous Aβ40 in mouse plasma, brain and CSF. In wild-type mice treated with a bispecific anti-TfR/BACE1 antibody, significant Aβ reductions were observed in the periphery and the brain. APPlon transgenic mice showed a slightly less reduction, whereas APPswe mice did not have any decrease. This sensitive and well-characterized mouse Aβ40 assay enables the use of wild-type mice for preclinical PK/PD and efficacy studies of potential AD therapeutics.

  12. Evaluation of dry blood spot technique for quantification of an Anti-CD20 monoclonal antibody drug in human blood samples.

    Science.gov (United States)

    Lin, Yong-Qing; Zhang, Yilu; Li, Connie; Li, Louis; Zhang, Kelley; Li, Shawn

    2012-01-01

    To evaluate the dried blood spot (DBS) technique in ELISA quantification of larger biomolecular drugs, an anti-CD20 monoclonal antibody drug was used as an example. A method for the quantification of the anti-CD20 drug in human DBS was developed and validated. The drug standard and quality control samples prepared in fresh human blood were spotted on DBS cards and then extracted. A luminescent ELISA was used for quantification of the drug from DBS samples. The assay range of the anti-CD20 drug standards in DBS was 100-2500ng/mL. The intra-assay precision (%CV) ranged from 0.4% to 10.1%, and the accuracy (%Recovery) ranged from 77.9% to 113.9%. The inter assay precision (%CV) ranged from 5.9% to 17.4%, and the accuracy ranged from 81.5% to 110.5%. The DBS samples diluted 500 and 50-fold yielded recovery of 88.7% and 90.7%, respectively. The preparation of DBS in higher and lower hematocrit (53% and 35%) conditions did not affect the recovery of the drug. Furthermore, the storage stability of the anti-CD20 drug on DBS cards was tested at various conditions. It was found that the anti-CD20 drug was stable for one week in DBS stored at room temperature. However, it was determined that the stability was compro]mised in DBS stored at high humidity, high temperature (55°C), and exposed to direct daylight for a week, as well as for samples stored at room temperature and high humidity conditions for a month. Stability did not change significantly in samples that underwent 3 freeze/thaw cycles. Our results demonstrated a successful use of DBS technique in ELISA quantification of an anti-CD20 monoclonal antibody drug in human blood. The stability data provides information regarding sample storage and shipping for future clinical studies. It is, therefore, concluded that the DBS technique is applicable in the quantification of other large biomolecule drugs or biomarkers. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Hydroxypropyl-β-cyclodextrin–graphene oxide conjugates: Carriers for anti-cancer drugs

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Jingting; Meng, Na; Fan, Yunting; Su, Yutian; Zhang, Ming [Jiangsu Collaborative Innovation Center for Biological Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); National and Local Joint Engineering Research Center of Biomedical Functional Materials, Nanjing 210023 (China); Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing 210023 (China); Xiao, Yinghong, E-mail: yhxiao@njnu.edu.cn [Jiangsu Collaborative Innovation Center for Biological Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); National and Local Joint Engineering Research Center of Biomedical Functional Materials, Nanjing 210023 (China); Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing 210023 (China); Zhou, Ninglin, E-mail: zhouninglin@njnu.edu.cn [Jiangsu Collaborative Innovation Center for Biological Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); National and Local Joint Engineering Research Center of Biomedical Functional Materials, Nanjing 210023 (China); Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing 210023 (China); Nanjing Zhou Ninglin Advanced Materials Technology Company Limited, Nanjing 211505 (China)

    2016-04-01

    A novel drug carrier based on hydroxypropyl-β-cyclodextrin (HP-β-CD) modified carboxylated graphene oxide (GO-COOH) was designed to incorporate anti-cancer drug paclitaxel (PTX). The formulated nanomedicines were characterized by Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Results showed that PTX can be incorporated into GO-COO-HP-β-CD nanospheres successfully, with an average diameter of about 100 nm. The solubility and stability of PTX-loaded GO-COO-HP-β-CD nanospheres in aqueous media were greatly enhanced compared with the untreated PTX. The results of hemolysis test demonstrated that the drug-loaded nanospheres were qualified with good blood compatibility for intravenous use. In vitro anti-tumor activity was measured and results demonstrated that the incorporation of PTX into the newly developed GO-COO-HP-β-CD carrier could confer significantly improved cytotoxicity to the nanosystem against tumor cells than single application of PTX. GO-COO-HP-β-CD nanospheres may represent a promising formulation platform for a broad range of therapeutic agent, especially those with poor solubility. - Highlights: • Hydroxypropyl-β-cyclodextrin (HP-β-CD) modified carboxylated graphene oxide (GO-COOH) was designed as a drug carrier. • The prepared PTX-loaded nanospheres can be dispersed in aqueous medium stably. • The GO-COO-HP-β-CD nanospheres are safe for blood-contact applications. • This newly developed PTX-delivery system could confer significantly improved cytotoxicity against tumor cells.

  14. Non-adherence to anti-TB drugs among TB/HIV co-infected patients ...

    African Journals Online (AJOL)

    Non-adherence to anti-TB drugs among TB/HIV co-infected patients in Mbarara Hospital ... and its associated factors have not been studied in these patients in Uganda. ... Methods: A cross-sectional study with qualitative and quantitative data ...

  15. Evaluation of anti-GERD activity of gastro retentive drug delivery system of itopride hydrochloride.

    Science.gov (United States)

    Satapathy, Trilochan; Panda, Prasana K; Goyal, Amit K; Rath, Goutam

    2010-08-01

    The present work describes the formulation and evaluation of the gastroretentive system of Itopride hydrochloride. In this research, we have formulated floating hydrogel-based microspheres employing calcium carbonate (CaCO(3)) as a gas forming agent dispersed in alginate matrix. In vitro characterizations such as drug content, particle size, and drug release were carried out. GI motility was determined by administration of charcoal meal to rats. Results demonstrated that prepared microspheres were spherical in shape with smooth surface, good loading efficiency, and excellent buoyancy. The gastro retentive dosage form of itiopride demonstrated significant antacid, anti-ulcer, and anti-GERD activity after 12 hours in comparison with the conventional dosage form.

  16. Amoxicillin rash in patients with infectious mononucleosis: evidence of true drug sensitization.

    Science.gov (United States)

    Ónodi-Nagy, Katinka; Kinyó, Ágnes; Meszes, Angéla; Garaczi, Edina; Kemény, Lajos; Bata-Csörgő, Zsuzsanna

    2015-01-01

    It hasn't been clearly understood yet whether sensitization to antibiotics, the virus itself or transient loss of drug tolerance due to the virus, is responsible for the development of maculopapular exanthems following amoxicillin intake in patients with infectious mononucleosis. We aimed to examine whether sensitization to penicillin developed among patients with skin rash following amoxicillin treatment within infectious mononucleosis. Ten patients were investigated for drug sensitization by lymphocyte transformation test and six patients were further tested by prick-, intradermal and patch tests employing the penicillin's main antigens. Lymphocyte transformation test showed negative results with amoxicillin, while one patient had positive reaction to cefixime. Six patients with suspected sensitization to amoxicillin were then investigated by in vivo tests. Prick tests were negative in all six patients, but the intradermal tests showed positive reactions in four patients. Our data demonstrate that in vitro testing is not sensitive enough in determining drug sensitization to penicillin. In vivo tests should be performed to detect sensitization and indeed with skin tests our results confirmed that sensitization to aminopenicillin may develop within infectious mononucleosis.

  17. C{sub 18}-attached membrane funnel-based spray ionization mass spectrometry for quantification of anti-diabetic drug from human plasma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Wan [Department of Chemistry, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Hong Kong); Chen, Xiangfeng, E-mail: xiangfchensdas@163.com [Department of Chemistry, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Hong Kong); Shandong Analysis and Test Centre, Shandong Academy of Sciences, Jinan, Shandong (China); Wong, Y.-L. Elaine; Hung, Y.-L. Winnie; Wang, Ze; Deng, Liulin [Department of Chemistry, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Hong Kong); Dominic Chan, T.-W., E-mail: twdchan@cuhk.edu.hk [Department of Chemistry, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Hong Kong)

    2016-08-24

    In this work, sorbent-attached membrane funnel-based spray ionization mass spectrometry was explored for quantitative analysis of anti-diabetic drugs spiked in human plasma. C{sub 18}-attached membrane funnel was fabricated for in situ extraction and clean-up to alleviate matrix suppression effect in the ionization process. Repaglinide was used as a target analyte of anti-diabetic drugs. Under optimal working conditions, good linearity (R{sup 2} > 0.99) was obtained in the concentration range of 1–100 ng mL{sup −1}. The method detection limit of target drugs spiked in the human plasma was around 0.30 ng mL{sup −1}. Through the application of an isotope-labeled internal standard, the signal fluctuation caused by residual background matrices was largely alleviated and the precision of measurement (RSD) was below 15%. The recovery of repaglinide for 5, 25, and 100 ng mL{sup −1} of spiked human plasma matrixes ranged from 87% to 112%. The developed method was successfully applied to determine repaglinide in plasma volunteers who orally received a dose of drug association. Our results demonstrated that membrane funnel-based spray is a simple and sensitive method for rapid screening analysis of complex biological samples. - Highlights: • Sorbent attached membrane funnel based spray platform was used for drug determination in human plasma. • The matrix suppression effect of human plasma was largely eliminated. • The method was applied to determine repaglinide in plasma volunteers. • Membrane funnel-based spray is promising for analysis of biological samples.

  18. SEXUAL DYSFUNCTION INDUCED BY ANTI-PSYCHOTICS AND ANTI-DEPRESSANTS IN DRUG NAIVE PATIENTS – A COMPARATIVE STUDY

    Directory of Open Access Journals (Sweden)

    M. Mohanalakshmi

    2017-03-01

    Full Text Available BACKGROUND The aim of this study was to determine and compare sexual dysfunction caused by anti-psychotics and anti-depressants in drug naïve patients. MATERIALS AND METHODS Patients diagnosed as drug naïve schizophrenic and depression as per DSM-5 criteria & age between 18-45 years were recruited and allocated into group A (n=30–receiving anti-psychotics & group B (n=30 receiving anti-depressants after informed consent by the patients. Sexual dysfunction was assessed by Arizona Sexual Experiences Scale (ASEX during the initial 2 months of therapy. RESULTS ASEX mean for patients receiving antipsychotics increased from the baseline of 7.97 to 17.23 and the ASEX mean for patients receiving antidepressants increased from baseline of 7.80 to 18.67 with p value of 0.249 which is not statistically significant. Among the antipsychotics haloperidol ASEX mean increased from 7.87 to 18.00 and risperidone mean increased from 8.07 to 16.47 with the p value of 0.335 which is not significant. More patients on haloperidol showed evidence of sexual dysfunction as assessed by ASEX scoring than risperidone though p value was not significant. Among the two antidepressants ASEX score mean for amitriptyline patients increased from 8.07 to 16.47, and that of fluoxetine from 7.53 to 16.47 with the p value of 0.018* statistically significant at α of 0.05 level. CONCLUSION This study shows presence of sexual dysfunction in patients receiving antipsychotics & antidepressants by 2 nd month of therapy though statistically not significant. Fluoxetine group patients developed statistically significant sexual dysfunction. Implications for future research about sexual dysfunction in all new treatments should be strongly taken into account because this side effect adds to the emotional stress and worsening of mental dysfunction.

  19. Potential Exposure to Anti-Drug Advertising and Drug-Related Attitudes, Beliefs, and Behaviors among United States Youth, 1995-2006

    Science.gov (United States)

    Terry-McElrath, Yvonne M.; Emery, Sherry; Szczypka, Glen; Johnston, Lloyd D.

    2010-01-01

    Using nationally representative data from the Monitoring the Future Study on United States middle and high school students, we related exposure to anti-drug television advertising as measured by Nielsen Media Research ratings points to student self-reported drug-related outcomes from 1995-2006. Multivariate analyses controlling for key socio-demographics and accounting for the complex survey design included 337,918 cases. Results indicated that attitudes, beliefs, and behaviors regarding substance use were significantly related to such advertising exposure over the six months prior to the date youth were surveyed. However, the observed relationships varied by grade level, over time and by advertising tagline and marijuana focus. Findings differed markedly between middle and high school students across the study interval. One factor that may partially explain observed differences may be variation in the degree to which the ads focused on marijuana. Putting a concerted effort into increasing anti-drug advertising will likely increase the exposure to and recall of such ads among youth. However, the likelihood that such advertising will result in youth being less likely to use drugs seems to depend heavily on the type of advertising utilized and how it relates to different ages and characteristics of targeted youth. PMID:20961691

  20. Methodologies Related to Computational models in View of Developing Anti-Alzheimer Drugs: An Overview.

    Science.gov (United States)

    Baheti, Kirtee; Kale, Mayura Ajay

    2018-04-17

    Since last two decades, there has been more focus on the development strategies related to Anti-Alzheimer's drug research. This may be attributed to the fact that most of the Alzheimer's cases are still mostly unknown except for a few cases, where genetic differences have been identified. With the progress of the disease, the symptoms involve intellectual deterioration, memory impairment, abnormal personality and behavioural patterns, confusion, aggression, mood swings, irritability Current therapies available for this disease give only symptomatic relief and do not focus on manipulations of biololecular processes. Nearly all the therapies to treat Alzheimer's disease, target to change the amyloid cascade which is considered to be an important in AD pathogenesis. New drug regimens are not able to keep pace with the ever-increasing understanding about dementia at molecular level. Looking into these aggravated problems, we though to put forth molecular modeling as a drug discovery approach for developing novel drugs to treat Alzheimer disease. The disease is incurable and it gets worst as it advances and finally causes death. Due to this, the design of drugs to treat this disease has become an utmost priority for research. One of the most important emerging technologies applied for this has been Computer-assisted drug design (CADD). It is a research tool that employs large scale computing strategies in an attempt to develop a model receptor site which can be used for designing of an anti-Alzheimer drug. The various models of amyloid-based calcium channels have been computationally optimized. Docking and De novo evolution are used to design the compounds. These are further subjected to absorption, distribution, metabolism, excretion and toxicity (ADMET) studies to finally bring about active compounds that are able to cross BBB. Many novel compounds have been designed which might be promising ones for the treatment of AD. The present review describes the research

  1. Evaluation of contact sensitivity to topical drugs in patients with contact dermatitis

    Directory of Open Access Journals (Sweden)

    Bilge Bülbül Şen

    2013-03-01

    Full Text Available Background and Design: Topical drugs are an important group of contact allergens. The present study aimed to evaluate contact sensitivity to topical drugs in patients with contact dermatitis. Materials and Methods: Between 2003 and 2008, 129 patients were followed up at the Department of Dermatology at Ankara University School of Medicine with clinically suspected contact sensitivity to topical drugs. In this study, the patch test reactions to the European Standard Battery and topical drugs used by the patients and medicament patch test results were evaluated. Results: Positive patch test reaction to one or more allergens was found in 80 (62.0% of 129 patients included in the study. Sixty-one of the 80 patients (61/129, 47.3% had positive patch test reaction to medicaments. Medicament sensitivity was detected in 37.9% (49/129 of subjects. Nitrofurazone was found to be the most common allergen (18.6%. Discussion: The present study showed that topical drugs are a frequent cause of allergic contact dermatitis. Therefore, the probability of contact sensitivity to topical drugs should also be considered in patients with the clinical diagnosis of allergic contact dermatitis and, suspected cases should be evaluated further with patch testing in order to find the responsible allergens.

  2. Claims in advertisements for anti hypertensive drugs in a Dutch medical journal

    NARCIS (Netherlands)

    Greving, Jacoba P.; Denig, Petra; de Zeeuw, Dick; Haaijer-Ruskamp, Flora M.

    Background Advertising claims must not conflict with the official summary of product characteristics. After a drug has been approved, new clinical evidence may become available. Aims To determine how the pharmaceutical industry deals with evolving clinical evidence in advertising claims for anti

  3. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

    Science.gov (United States)

    Fryauff, D J; Leksana, B; Masbar, S; Wiady, I; Sismadi, P; Susanti, A I; Nagesha, H S; Syafruddin; Atmosoedjono, S; Bangs, M J; Baird, J K

    2002-07-01

    Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene

  4. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs

    DEFF Research Database (Denmark)

    Aalykke, C; Lauritsen, Jens; Hallas, J

    1999-01-01

    Peptic ulcer complications related to use of nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common serious adverse drug reactions. Whether Helicobacter pylori infection potentiates this gastrointestinal toxicity of NSAIDs is still unresolved. In this study, we investigated...... the role of H. pylori as a cause of bleeding peptic ulcer among NSAID users....

  5. Complex compounds of terbium(III) with some nonsteroidal anti-inflammatory drugs and their analytical applications

    International Nuclear Information System (INIS)

    Teslyuk, O.I.; Egorova, A.V.; Yagodkin, B.N.; Bel'tyukova, S.V.

    2007-01-01

    Luminescence properties of the complexes of terbium(III) with nonsteroidal anti-inflammatory drugs (ibuprofen and orthofen) were studied. It was demonstrated that in the presence of organic bases (2,2'-dipyridyl and 1,10-phenanthroline) mixed-ligand complexes are formed and the luminescence intensity of terbium(III) increases by a factor of up to 250. The optimum complexation conditions were determined. It was proposed to use these complexes as analytical forms for the luminescence determination of nonsteroidal anti-inflammatory drugs (ibuprofen and orthofen) in pharmaceutical dosage forms. The detection limits are 2 and 0.05 μg/ml, respectively [ru

  6. Mitochondrial DNA is a direct target of anti-cancer anthracycline drugs

    International Nuclear Information System (INIS)

    Ashley, Neil; Poulton, Joanna

    2009-01-01

    The anthracyclines, such as doxorubicin (DXR), are potent anti-cancer drugs but they are limited by their clinical toxicity. The mechanisms involved remain poorly understood partly because of the difficulty in determining sub-cellular drug localisation. Using a novel method utilising the fluorescent DNA dye PicoGreen, we found that anthracyclines intercalated not only into nuclear DNA but also mitochondrial DNA (mtDNA). Intercalation of mtDNA by anthracyclines may thus contribute to the marked mitochondrial toxicity associated with these drugs. By contrast, ethidium bromide intercalated exclusively into mtDNA, without interacting with nuclear DNA, thereby explaining why mtDNA is the main target for ethidium. By exploiting PicoGreen quenching we also developed a novel assay for quantification of mtDNA levels by flow-cytometry, an approach which should be useful for studies of mitochondrial dysfunction. In summary our PicoGreen assay should be useful to study drug/DNA interactions within live cells, and facilitate therapeutic drug monitoring and kinetic studies in cancer patients.

  7. The prevalence, bacteriology and drug sensitivity of asymptomatic ...

    African Journals Online (AJOL)

    Objectives: To determine the prevalence of Asymptomatic Bacteriuria (AsB) and the ... education sessions on AsB and urinary tract infection during pregnancy. ... by the researcher for appropriate treatment according to their drug sensitivities.

  8. Analysis of the data on pregnancy and lactation provided by patient information leaflets of anti-rheumatic drugs in Argentina.

    Science.gov (United States)

    Sabando, Miguel Ormaza; Saavedra, Maira Arias; Sequeira, Gabriel; Kerzberg, Eduardo

    2018-04-01

    To analyse the level of consistency and updating of the information on pregnancy and lactation provided by patient information leaflets (PILs) of the antirheumatic drugs approved in Argentina. Inconsistencies between the 2016 EULAR Task Force recommendations on the use of anti-rheumatic drugs during pregnancy and lactation and the information provided by PILs of the same drugs approved in Argentina were analysed along with inconsistencies within the PILs of different registered trademarks of these drugs. Eighty-eight PILs of 32 drugs were analysed. Out of the 88 PILs, 50% presented information inconsistencies as to pregnancy. Medications comprised in this group were: hydroxychloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs (during the first two trimesters), celecoxib, some glucocorticoids, colchicine, and some anti-TNF drugs (etanercept, adalimumab and infliximab) during part of the pregnancy. As for lactation, 56% had information inconsistencies. Medications encompassed in this group were: hydroxychloroquine, chloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs, celecoxib, meprednisone, prednisone, colchicine, and anti-TNF drugs. Out of 17 drugs that had more than one registered trademark, information inconsistencies on pregnancy were found in the PILs of sulfasalazine, diclofenac, ibuprofen and methylprednisolone. Concerning lactation, inconsistencies were present in the PILs of hydroxychloroquine, sulfasalazine, diclofenac, ibuprofen, meprednisone, and colchicine. At least half of the PILs of anti-rheumatic drugs analysed in this study had information inconsistencies on pregnancy and lactation. This is a serious state of affairs because the consensual decision-making process between patient and professional may be compromised, which, in turn, may give rise to medical-legal issues.

  9. In-vitro evaluation of anti-trichomonal activities of Eugenia uniflora leaf.

    Science.gov (United States)

    Ibikunle, Gabriel Femi; Adebajo, Adeleke Clement; Famuyiwa, Funmilayo Gladys; Aladesanmi, Adetunji Joseph; Adewunmi, Clement Oladapo

    2011-01-01

    Eugenia uniflora, used ethnomedically in some tropical countries as an anti-infective, has shown anti-malarial and anti-trypanocidal activities. Therefore using bioactivity guided fractionation, anti-trichomonal activity of E. uniflora leaf was investigated. Anti-trichomonal activities of leaf methanol extract and its fractions against Trichomonas gallinae as well as their cytotoxicities using an in vitro haemaglutination assay were determined. Anti-trichomonacidal activities of the extract improved on purification up to a stage. Subfractions E(2-5) had LC(50) and LC(90) values of 4.77 - 5.28, 18.49 - 25.00 and 4.53 - 5.18, 18.32 - 19.07 µg/ml at 24 and 48 hrs, respectively that were better than those of metronidazole. Further purification of E(2-5) led to loss of activity suggesting that the active components were probably working synergistically and additively. Demonstration of low haemaglutination titre values of 0.00 - 5.33 by methanolic extract and its partition fractions suggested their low toxicity profile. The established safety of the leaf indicated that its anti-trichomonal activity was not due to non-specific cytotoxicity, hence could be used in ethnomedicine as an anti-trichomonal agent.

  10. The antiplasmodium effects of a traditional South American remedy: Zanthoxylum chiloperone var. angustifolium against chloroquine resistant and chloroquine sensitive strains of Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Gerardo Cebrian-Torrejon

    2011-06-01

    Full Text Available Zanthoxylum chiloperone var. angustifolium Engl., Rutaceae, is used in traditional medicine to treat fungal and protozoal infections in the central area of South America. Considering the increasing resistance of Plasmodium falciparum in malarial ridden areas, we explored the anti-plasmodial effects of three compounds isolated from Z. chiloperone. The pyranocoumarin transavicennol and the canthinone alkaloids, canthin-6-one and 5-methoxycanthin-6-one, were found to have IC50 on chloroquine/mefloquine resistant and sensitive strains of P. falciparum of 0.5-2.7, 2.0-5.3 and 5.1-10.4 ƒÊg/mL, respectively. Moreover, the formation of heme adducts by these compounds is described by a novel alternative method based on MS-CID methods. The alkylamide sanshool was also identified, for first time in this plant, in the dichloromethanic and ethanolic extracts and the extracts were found to be notably non-toxic and displayed good anti-plasmodial effects.

  11. Challenges in Modern Anti-Doping Analytical Science.

    Science.gov (United States)

    Ayotte, Christiane; Miller, John; Thevis, Mario

    2017-01-01

    The challenges facing modern anti-doping analytical science are increasingly complex given the expansion of target drug substances, as the pharmaceutical industry introduces more novel therapeutic compounds and the internet offers designer drugs to improve performance. The technical challenges are manifold, including, for example, the need for advanced instrumentation for greater speed of analyses and increased sensitivity, specific techniques capable of distinguishing between endogenous and exogenous metabolites, or biological assays for the detection of peptide hormones or their markers, all of which require an important investment from the laboratories and recruitment of highly specialized scientific personnel. The consequences of introducing sophisticated and complex analytical procedures may result in the future in a change in the strategy applied by the Word Anti-Doping Agency in relation to the introduction and performance of new techniques by the network of accredited anti-doping laboratories. © 2017 S. Karger AG, Basel.

  12. Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Kirsi Ketola

    Full Text Available Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram

  13. Autoradiographic and biochemical observations on the distribution of non-steroid anti-inflammatory drugs.

    Science.gov (United States)

    Rainsford, K D; Schweitzer, A; Brune, K

    1981-04-01

    A comparison has been made of the distribution of some new radioactively-labelled non-steroid anti-inflammatory (NSAI) drugs or pro-drugs with their respective progenitors and/or standard acidic NSAI drugs (i.e. aspirin, indomethacin and phenylbutazone), using whole body autoradiography and scintillation counting. The object of this study was to establish if the distribution of these new NSAI drugs may contribute to changes in their side-, or therapeutic effects compared with the older drugs. All the NSAI drugs accumulated in those tissues wherein the principle therapeutic and side-effects are manifest. The accumulation in inflamed tissues occurs regardless of the structural type of NSAI drugs, i.e. with specific accumulation occurring in this tissue of the acidic drugs or their acidic metabolites. New aspects of the distribution of the acetyl moiety of aspirin are reported which may be significant in relation to the side-effects induced by this drug.

  14. Molecular chess? Hallmarks of anti-cancer drug resistance.

    Science.gov (United States)

    Cree, Ian A; Charlton, Peter

    2017-01-05

    The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to 'molecular chess'. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

  15. Provider knowledge of treatment policy and dosing regimen with artemether-lumefantrine and quinine in malaria-endemic areas of western Kenya

    Directory of Open Access Journals (Sweden)

    Watsierah Carren A

    2012-12-01

    Full Text Available Abstract Background Due to widespread anti-malarial drug resistance in many countries, Kenya included, artemisinin-based Combination Therapy (ACT has been adopted as the most effective treatment option against malaria. Artemether-lumefantrine (AL is the first-line ACT for treatment of uncomplicated malaria in Kenya, while quinine is preferred for complicated and severe malaria. Information on the providers’ knowledge and practices prior to or during AL and quinine implementation is scanty. The current study evaluated providers’ knowledge and practices of treatment policy and dosing regimens with AL and quinine in the public, private and not-for-profit drug outlets. Methods A cross-sectional survey using three-stage sampling of 288 (126 public, 96 private and 66 not-for-profits providers in drug outlets was conducted in western Kenya in two Plasmodium falciparum-endemic regions with varying malarial risk. Information on provider in-service training, knowledge (qualification, treatment policy, dosing regimen, recently banned anti-malarials and on practices (request for written prescription, prescription of AL, selling partial packs and advice given to patients after prescription, was collected. Results Only 15.6% of providers in private outlets had received any in-service training on AL use. All (100% in public and majority (98.4% in not-for-profit outlets mentioned AL as first line-treatment drug. Quinine was mentioned as second-line drug by 47.9% in private outlets. A total of 92.0% in public, 57.3% in private and 78.8% in not-for-profit outlets stated correct AL dose for adults. A total of 85.7% of providers in public, 30.2% in private and 41.0% in not-for-profit outlets were aware that SP recommendations changed from treatment for mild malaria to IPTp in high risk areas. In-service training influenced treatment regimen for uncomplicated malaria (P = 0.039 and P = 0.039 and severe malaria (P P = 0.002 in children and adults

  16. Molecular Evidence of Increased Resistance to Anti-Folate Drugs in Plasmodium falciparum in North-East India: A Signal for Potential Failure of Artemisinin Plus Sulphadoxine-Pyrimethamine Combination Therapy

    Science.gov (United States)

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

    2014-01-01

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

  17. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

    Directory of Open Access Journals (Sweden)

    Qi-Liang Mao-Ying

    Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

  18. Impact of child malnutrition on the specific anti-Plasmodium falciparum antibody response

    Directory of Open Access Journals (Sweden)

    Fillol Florie

    2009-06-01

    Full Text Available Abstract Background In sub-Saharan Africa, preschool children represent the population most vulnerable to malaria and malnutrition. It is widely recognized that malnutrition compromises the immune function, resulting in higher risk of infection. However, very few studies have investigated the relationship between malaria, malnutrition and specific immunity. In the present study, the anti-Plasmodium falciparum IgG antibody (Ab response was evaluated in children according to the type of malnutrition. Methods Anthropometric assessment and blood sample collection were carried out during a cross-sectional survey including rural Senegalese preschool children. This cross-sectional survey was conducted in July 2003 at the onset of the rainy season. Malnutrition was defined as stunting (height-for-age P. falciparum whole extracts (schizont antigens was assessed by ELISA in sera of the included children. Results Both the prevalence of anti-malarial immune responders and specific IgG Ab levels were significantly lower in malnourished children than in controls. Depending on the type of malnutrition, wasted children and stunted children presented a lower specific IgG Ab response than their respective controls, but this difference was significant only in stunted children (P = 0.026. This down-regulation of the specific Ab response seemed to be explained by severely stunted children (HAZ ≤ -2.5 compared to their controls (P = 0.03, while no significant difference was observed in mildly stunted children (-2.5 P. falciparum Ab response appeared to be independent of the intensity of infection. Conclusion Child malnutrition, and particularly stunting, may down-regulate the anti-P. falciparum Ab response, both in terms of prevalence of immune responders and specific IgG Ab levels. This study provides further evidence for the influence of malnutrition on the specific anti-malarial immune response and points to the importance of taking into account child

  19. The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs.

    Science.gov (United States)

    Bax, Hannelore I; Bakker-Woudenberg, Irma A J M; de Vogel, Corné P; van der Meijden, Aart; Verbon, Annelies; de Steenwinkel, Jurriaan E M

    2017-07-01

    Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

    Directory of Open Access Journals (Sweden)

    Miyatake S

    2016-08-01

    Full Text Available Shouta Miyatake,1 Yuko Shimizu-Motohashi,2 Shin’ichi Takeda,1 Yoshitsugu Aoki1 1Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 2Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Abstract: Duchenne muscular dystrophy (DMD, an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD. Keywords: calcium channels, ryanodine receptor 1, exon skipping, NF-κB, myokine, ROS

  1. Beneficiary price sensitivity in the Medicare prescription drug plan market.

    Science.gov (United States)

    Frakt, Austin B; Pizer, Steven D

    2010-01-01

    The Medicare stand-alone prescription drug plan (PDP) came into existence in 2006 as part of the Medicare prescription drug benefit. It is the most popular plan type among Medicare drug plans and large numbers of plans are available to all beneficiaries. In this article we present the first analysis of beneficiary price sensitivity in the PDP market. Our estimate of elasticity of enrollment with respect to premium, -1.45, is larger in magnitude than has been found in the Medicare HMO market. This high degree of beneficiary price sensitivity for PDPs is consistent with relatively low product differentiation, low fixed costs of entry in the PDP market, and the fact that, in contrast to changing HMOs, beneficiaries can select a PDP without disrupting doctor-patient relationships.

  2. PEGylation of α-momorcharin retained its anti-tumor activity with ...

    African Journals Online (AJOL)

    user

    the anti-tumor activity of α-MMC-PEG decreased by about 30% in vitro. This sensitivity increase of 50 ... experiments and were acclimatized in the animal room. They were housed on aspen ..... PEGylation, successful approach to drug delivery.

  3. Anti-deuteron sensitivity studies at LHCb

    CERN Multimedia

    Baker, Sophie Katherine

    2018-01-01

    Measurements of anti-deuterons in collider experiments can help to reduce systematic uncertainties in indirect searches for dark matter. Two predominant unknowns in these searches are the production of secondary anti-deuterons in the cosmos from spallation processes, and anti-deuteron production from annihilating dark matter. LHCb is a forward spectrometer on the LHC ring, designed to measure b-hadron decays from high energy proton-proton collisions. With the detector's excellent particle identification capabilities, deuteron and anti-deuteron measurements at LHCb could help to parametrise the two cosmological processes. Recent studies of (anti-)deuteron identification at LHCb and the prospects for measuring prompt (anti-)deuterons from pp-collisions will be presented, as well as a working analysis of b-baryrons decaying to deuterons.

  4. Anti-Obesity Drugs: A Review about Their Effects and Safety

    Directory of Open Access Journals (Sweden)

    Jun Goo Kang

    2012-02-01

    Full Text Available The current recommendations for the treatment of obese people include increased physical activity and reduced calories intake. When the behavioral approach is not sufficient, a pharmacologic treatment is recommended. In past years, numerous drugs have been approved for the treatment of obesity; however, most of them have been withdrawn from the market because of their adverse effects. In fact, amphetamine, rimonabant and sibutramine licenses have been withdrawn due to an increased risk of psychiatric disorders and non-fatal myocardial infarction or stroke. Even if orlistat is not as effective as other drugs in reducing body weight, orlistat is presently the only available choice for the treatment of obesity because of its safety for cardiovascular events and positive effects on diabetic control. Hopefully, more effective and better tolerated anti-obesity drugs will be developed through an improved understanding of the multiple mechanisms and complex physiological systems targeting appetite.

  5. Herbs with anti-lipid effects and their interactions with statins as a chemical anti- hyperlipidemia group drugs: A systematic review

    Directory of Open Access Journals (Sweden)

    Hojjat Rouhi-Boroujeni

    2015-08-01

    Full Text Available BACKGROUND: The present systematic review aimed to express the clinical anti-lipid effects of different types of herbs, as well as described studied interactions between herbal remedies and prescribed drugs for hyperlipidemic patients which were based on in vitro experiments, animal studies, and empirical clinical experiences. METHODS: For this systematic review, we explored 2183 published papers about herbal drugs interactions from November 1967 to August 2014, fulfilling eligibility criteria by searching in some databases such as Web of Science, Medline, Scopus, Embase, Cinahl, and the Cochrane database. The main keywords used for searching included: herbal medicine, herbs, statin, lipid, and herb-drug interaction. RESULTS: Among published articles about herb-drug interactions, 185 papers met the initial search criteria and among them, 92 papers were potentially retrievable including a description of 17 herbs and medicinal plants. In first step and by reviewing all published manuscripts on beneficial effects of herbs on serum lipids level, 17 herbs were described to be effective on lipid profile as lowering serum triglyceride, total cholesterol, low-density lipoprotein cholesterol as well as increasing serum high-density lipoprotein level. Some herbs such as celery could even affect the hepatic triglyceride concentrations. The herbal reaction toward different types of statins is varied so that grapefruit or pomegranate was interacted with only some types of statins, but not with all statin types. In this context, administration of herbal materials can lead to decreased absorption of statins or decreased the plasma concentration of these drugs. CONCLUSION: Various types of herbs can potentially reduce serum lipid profile with the different pathways; however, the herb-drug interactions may decrease pharmacological therapeutic effects of anti-hyperlipidemic drugs that should be considered when approved herbs are prescribed. 

  6. Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder

    International Nuclear Information System (INIS)

    Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun; Shan, Kun; Yang, Hong; Yan, Biao; Jiang, Qin

    2015-01-01

    Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative and anti-inflammatory property. - Highlights: • Lenalidomide inhibits retinal endothelial cell viability in vitro. • Lenalidomide inhibits retinal endothelial cell migration and tube formation. • Lenalidomide inhibits pathological ocular angiogenesis in vivo. • Lenalidomide inhibits angiogenesis- and inflammation-related protein expression.

  7. Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun; Shan, Kun; Yang, Hong [Eye Hospital, Nanjing Medical University, Nanjing (China); The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing (China); Yan, Biao, E-mail: yanbiao1982@hotmail.com [Eye Hospital, Nanjing Medical University, Nanjing (China); The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing (China); Jiang, Qin, E-mail: jiangqin710@126.com [Eye Hospital, Nanjing Medical University, Nanjing (China); The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing (China)

    2015-10-02

    Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative and anti-inflammatory property. - Highlights: • Lenalidomide inhibits retinal endothelial cell viability in vitro. • Lenalidomide inhibits retinal endothelial cell migration and tube formation. • Lenalidomide inhibits pathological ocular angiogenesis in vivo. • Lenalidomide inhibits angiogenesis- and inflammation-related protein expression.

  8. The In vitro anti-acne activity of two unani drugs

    Directory of Open Access Journals (Sweden)

    Shahid Shah Chaudhary

    2013-01-01

    Full Text Available Background: Acne is the most common disorder treated by dermatologists. As many as 80-90% of all adolescents have some type of acne and 30% of them require medical treatment. It is an inflammatory disease of the pilosebaceous unit characterized by the formation of open and closed comedones, papules, pustules, nodules, and cysts. Aims: The present study was conducted to investigate the in vitro anti-acne activity of two Unani single drugs Darchini (Cinnamomum zeylanicum Bl. and Tukhm Khashkhash (Papaver somniferum L. seeds. Materials and Methods: The antibacterial activity of aqueous, ethanolic and hydroalcoholic extracts of both drugs were investigated against two acne causing bacteria, i.e., Propionibacterium acne and Staphylococcus epidermidis using well diffusion method. Results: The result showed that both drugs were active against the two bacteria. Against P. acne aqueous and ethanolic extract of Darchini and Tukhm Khashkhash showed the zone of inhibition of 18 ± 1.02 mm and 18 ± 1.6 mm and 13 ± 1.04 mm and 14 ± 1.8 mm, respectively. Against S. epidermidis aqueous, hydroalcoholic and ethanolic extracts of Darchini showed 22 ± 1.7 mm, 22 ± 1.2 mm and 15 ± 1.8 mm zone of inhibition respectively. Hydroalcoholic and ethanolic extracts of Tukhm Khashkhash showed 15 ± 1.09 mm and 13 ± 1.6 mm zone of inhibition respectively. Conclusion: This suggests that C. zeylanicum and P. somniferum have potential against acne causing bacteria and hence they can be used in topical anti-acne preparations and may address the antibiotic resistance of the bacteria.

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

    International Nuclear Information System (INIS)

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

    2007-01-01

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

  10. The origin of malarial parasites in orangutans.

    Directory of Open Access Journals (Sweden)

    M Andreína Pacheco

    Full Text Available BACKGROUND: Recent findings of Plasmodium in African apes have changed our perspectives on the evolution of malarial parasites in hominids. However, phylogenetic analyses of primate malarias are still missing information from Southeast Asian apes. In this study, we report molecular data for a malaria parasite lineage found in orangutans. METHODOLOGY/PRINCIPAL FINDINGS: We screened twenty-four blood samples from Pongo pygmaeus (Kalimantan, Indonesia for Plasmodium parasites by PCR. For all the malaria positive orangutan samples, parasite mitochondrial genomes (mtDNA and two antigens: merozoite surface protein 1 42 kDa (MSP-1(42 and circumsporozoite protein gene (CSP were amplified, cloned, and sequenced. Fifteen orangutans tested positive and yielded 5 distinct mitochondrial haplotypes not previously found. The haplotypes detected exhibited low genetic divergence among them, indicating that they belong to one species. We report phylogenetic analyses using mitochondrial genomes, MSP-1(42 and CSP. We found that the orangutan malaria parasite lineage was part of a monophyletic group that includes all the known non-human primate malaria parasites found in Southeast Asia; specifically, it shares a recent common ancestor with P. inui (a macaque parasite and P. hylobati (a gibbon parasite suggesting that this lineage originated as a result of a host switch. The genetic diversity of MSP-1(42 in orangutans seems to be under negative selection. This result is similar to previous findings in non-human primate malarias closely related to P. vivax. As has been previously observed in the other Plasmodium species found in non-human primates, the CSP shows high polymorphism in the number of repeats. However, it has clearly distinctive motifs from those previously found in other malarial parasites. CONCLUSION: The evidence available from Asian apes indicates that these parasites originated independently from those found in Africa, likely as the result of host

  11. An Aptamer Bio-barCode (ABC) assay using SPR, RNase H, and probes with RNA and gold-nanorods for anti-cancer drug screening.

    Science.gov (United States)

    Loo, Jacky Fong-Chuen; Yang, Chengbin; Tsang, Hing Lun; Lau, Pui Man; Yong, Ken-Tye; Ho, Ho Pui; Kong, Siu Kai

    2017-10-07

    With modifications to an ultra-sensitive bio-barcode (BBC) assay, we have developed a next generation aptamer-based bio-barcode (ABC) assay to detect cytochrome-c (Cyto-c), a cell death marker released from cancer cells, for anti-cancer drug screening. An aptamer is a short single-stranded DNA selected from a synthetic DNA library that is capable of binding to its target with high affinity and specificity based on its unique DNA sequence and 3D structure after folding. Similar to the BBC assay, Cyto-c is captured by a micro-magnetic particle (MMP) coated with capturing antibodies (Ab) and an aptamer specifically against Cyto-c to form sandwich structures ([MMP-Ab]-[Cyto-c]-[Aptamer]). After washing and melting, our aptamers, acting as a DNA bio-barcode, are released from the sandwiches and hybridized with the probes specially designed for RNase H for surface plasmon resonance (SPR) sensing. In an aptamer-probe duplex, RNase H digests the RNA in the probe and releases the intact aptamer for another round of hybridization and digestion. With signal enhancement effects from gold-nanorods (Au-NRs) on probes for SPR sensing, the detection limit was found to be 1 nM for the aptamer and 80 pM for Cyto-c. Without the time-consuming DNA amplification steps by PCR, the detection process of this new ABC assay can be completed within three hours. As a proof-of-concept, phenylarsine oxide was found to be a potent agent to kill liver cancer cells with multi-drug resistance at the nano-molar level. This approach thus provides a fast, sensitive and robust tool for anti-cancer drug screening.

  12. Injections, cocktails and diviners: therapeutic flexibility in the context of malaria elimination and drug resistance in Northeast Cambodia.

    Directory of Open Access Journals (Sweden)

    Charlotte Gryseels

    Full Text Available BACKGROUND: Adherence to effective malaria medication is extremely important in the context of Cambodia's elimination targets and drug resistance containment. Although the public sector health facilities are accessible to the local ethnic minorities of Ratanakiri province (Northeast Cambodia, their illness itineraries often lead them to private pharmacies selling "cocktails" and artemether injections, or to local diviners prescribing animal sacrifices to appease the spirits. METHODS: The research design consisted of a mixed methods study, combining qualitative (in-depth interviews and participant observation and quantitative methods (household and cross-sectional survey. RESULTS: Three broad options for malaria treatment were identified: i the public sector; ii the private sector; iii traditional treatment based on divination and ceremonial sacrifice. Treatment choice was influenced by the availability of treatment and provider, perceived side effects and efficacy of treatments, perceived etiology of symptoms, and patient-health provider encounters. Moreover, treatment paths proved to be highly flexible, changing mostly in relation to the perceived efficacy of a chosen treatment. CONCLUSIONS: Despite good availability of anti-malarial treatment in the public health sector, attendance remained low due to both structural and human behavioral factors. The common use and under-dosage of anti-malaria monotherapy in the private sector (single-dose injections, single-day drug cocktails represents a threat not only for individual case management, but also for the regional plan of drug resistance containment and malaria elimination.

  13. Cardiovascular effects of current and future anti-obesity drugs

    DEFF Research Database (Denmark)

    Comerma Steffensen, Simon Gabriel; Grann, Martin; Andersen, Charlotte U

    2014-01-01

    cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular...... side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol...

  14. A meta-analysis of drug resistant tuberculosis in Sub-Saharan Africa: how strongly associated with previous treatment and HIV co-infection?

    Science.gov (United States)

    Berhan, Asres; Berhan, Yifru; Yizengaw, Desalegn

    2013-11-01

    In Sub-Saharan Africa, the fight against tuberculosis (TB) has encountered a great challenge because of the emergence of drug resistant TB strains and the high prevalence of HIV infection. The aim of this meta-analysis was to determine the association of drug-resistant TB with anti-TB drug treatment history and HIV co-infection. After electronic based literature search in the databases of Medline, HINARI, EMBASE and the Cochrane library, article selection and data extraction were carried out. HIV co-infection and previous history of TB treatment were used as predictors for the occurrence of any anti-TB drug resistant or multiple drug resistant TB (MDR-TB). The risk ratios for each included study and for the pooled sample were computed using the random-effects model. Heterogeneity test, sensitivity analyses and funnel plots were also done. The pooled analysis showed that the risk of developing drug-resistant TB to at least one anti-TB drug was about 3 times higher in individuals who had a previous history of anti-TB treatment than new TB cases. The risk of having MDR-TB in previously anti-TB treated TB cases was more than 5-fold higher than that of new TB cases. Resistance to Ethambutol and Rifampicin was more than fivefold higher among the previously treated with anti-TB drugs. However, HIV infection was not associated with drug-resistant TB. There was a strong association of previous anti-TB treatment with MDR-TB. Primary treatment warrants special emphasis, and screening for anti-TB drugs sensitivity has to be strengthened.

  15. Cytotoxicity Enhancement in Breast Cancer Cells with Carbonate Apatite-Facilitated Intracellular Delivery of Anti-Cancer Drugs

    Science.gov (United States)

    Fatemian, Tahereh; Chowdhury, Ezharul Hoque

    2018-01-01

    Pharmacotherapy as the mainstay in the management of breast cancer has demonstrated various drawbacks, including non-targeted bio distribution and narrow therapeutic and safety windows. Thus, enhancements in pharmacodynamic and pharmacokinetic profiles of the classical anti-cancer drugs could lead to improved efficacy against cancer cells. Therefore, inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized to efficiently deliver various drugs into cancer cells. Following characterization and various modifications in the structure of CA complexes with different drugs, lifted outcomes were achieved. Markedly, complexing paclitaxel with CA resulted in 20.71 ± 4.34% loading efficiency together with 24.14 ± 2.21% enhancement in cytotoxicity on MCF-7 cells plus superior in vivo anti-tumour efficacy compared to free paclitaxel. PMID:29401738

  16. Cytotoxicity Enhancement in Breast Cancer Cells with Carbonate Apatite-Facilitated Intracellular Delivery of Anti-Cancer Drugs

    Directory of Open Access Journals (Sweden)

    Tahereh Fatemian

    2018-02-01

    Full Text Available Pharmacotherapy as the mainstay in the management of breast cancer has demonstrated various drawbacks, including non-targeted bio distribution and narrow therapeutic and safety windows. Thus, enhancements in pharmacodynamic and pharmacokinetic profiles of the classical anti-cancer drugs could lead to improved efficacy against cancer cells. Therefore, inorganic pH-dependent carbonate apatite (CA nanoparticles were utilized to efficiently deliver various drugs into cancer cells. Following characterization and various modifications in the structure of CA complexes with different drugs, lifted outcomes were achieved. Markedly, complexing paclitaxel with CA resulted in 20.71 ± 4.34% loading efficiency together with 24.14 ± 2.21% enhancement in cytotoxicity on MCF-7 cells plus superior in vivo anti-tumour efficacy compared to free paclitaxel.

  17. [Cost-effectiveness analysis of celecoxib versus non-selective non-steroidal anti-inflammatory drug therapy for the treatment of osteoarthritis in Spain: A current perspective].

    Science.gov (United States)

    De Lossada, A; Oteo-Álvaro, Á; Giménez, S; Oyagüez, I; Rejas, J

    2016-01-01

    To assess the cost-effectiveness of celecoxib and non-selective non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed «GI-Reasons» trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost-effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. Compared with non-selective non-steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs €201 and €157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (pcost-effectiveness ratio of €13,286 per QALY gained and €4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids

    DEFF Research Database (Denmark)

    Cox, Sharon E; Staalsoe, Trine; Arthur, Paul

    2005-01-01

    BACKGROUND: Vitamin A supplementation is believed to enhance immune responses to infection but few studies have assessed its effects on anti-malarial immunity, especially during pregnancy when women are at increased risk from both vitamin A deficiency and pregnancy-associated malaria. The patholo......BACKGROUND: Vitamin A supplementation is believed to enhance immune responses to infection but few studies have assessed its effects on anti-malarial immunity, especially during pregnancy when women are at increased risk from both vitamin A deficiency and pregnancy-associated malaria...... in vitro (anti-VSACSA IgG or anti-VSA IgG). Placental malarial infection was determined by placental blood smear and histology. RESULTS: Vitamin A supplementation was non-significantly associated with a decreased risk of active or chronic-active placental malarial infection compared to past, resolved...

  19. Anti-tumor necrosis factor (TNF drugs for the treatment of psoriatic arthritis: an indirect comparison meta-analysis

    Directory of Open Access Journals (Sweden)

    Thorlund K

    2012-12-01

    . For PsARC nonresponders, etanercept, infliximab, and golimumab yielded similar MDs, and adalimumab a notably lower MD. For PASI improvement, infliximab yielded the largest MD and golimumab the second largest, while etanercept yielded the smallest MD. In some instances, the estimated magnitudes of effect were notably different from the estimates of previous HTA indirect comparisons.Conclusion: There is insufficient statistical evidence to demonstrate differences in effectiveness between available anti-TNFs for PsA. Effect estimates seem sensitive to the analytic approach, and this uncertainty should be taken into account in future economic evaluations.Keywords: anti-tumour necrosis factor drugs, biologic DMARDs, indirect comparison meta-analysis, psoriatic arthritis, health assessment questionnaire, psoriatic arthritis response criteria, psoriasis area and severity index

  20. High sensitivity and specificity in proposed clinical diagnostic criteria for anti-N-methyl-D-aspartate receptor encephalitis.

    Science.gov (United States)

    Ho, Alvin C C; Mohammad, Shekeeb S; Pillai, Sekhar C; Tantsis, Esther; Jones, Hannah; Ho, Reena; Lim, Ming; Hacohen, Yael; Vincent, Angela; Dale, Russell C

    2017-12-01

    To determine the validity of the proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in paediatric patients. The diagnostic criteria for anti-NMDAR encephalitis proposed by Graus et al. (2016) use clinical features and conventional investigations to facilitate early immunotherapy before antibody status is available. The criteria are satisfied if patients develop four out of six symptom groups within 3 months, together with at least one abnormal investigation (electroencephalography/cerebrospinal fluid) and reasonable exclusion of other disorders. We evaluated the validity of the criteria using a retrospective cohort of paediatric patients with encephalitis. Twenty-nine patients with anti-NMDAR encephalitis and 74 comparison children with encephalitis were included. As expected, the percentage of patients with anti-NMDAR encephalitis who fulfilled the clinical criteria increased over time. During the hospital inpatient admission, most patients (26/29, 90%) with anti-NMDAR encephalitis fulfilled the criteria, significantly more than the comparison group (3/74, 4%) (panti-NMDAR encephalitis was 2 weeks from first symptom onset (range 1-6). The sensitivity of the criteria was 90% (95% confidence interval 73-98) and the specificity was 96% (95% confidence interval 89-99). The proposed diagnostic criteria for anti-NMDAR encephalitis have good sensitivity and specificity. Incomplete criteria do not exclude the diagnosis. The proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients. The median time of fulfilling the criteria in patients with anti-NMDAR was 2 weeks from first symptom onset. © 2017 Mac Keith Press.

  1. Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest

    International Nuclear Information System (INIS)

    Kim, Ju-Hwa; Yoo, Hye-In; Kang, Han Sung; Ro, Jungsil; Yoon, Sungpil

    2012-01-01

    Highlights: ► Sal sensitizes antimitotic drugs-treated cancer cells. ► Sal sensitizes them by prevention of G2 arrest and reduced cyclin D1 levels. ► Sal also sensitizes them by increasing DNA damage and reducing p21 level. ► A low concentration of Sal effectively sensitized the cancer cells to antimitotic drugs. -- Abstract: Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal-sensitization mechanisms. These results may contribute to the development of Sal-based chemotherapy for cancer patients treated with antimitotic drugs.

  2. Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ju-Hwa; Yoo, Hye-In; Kang, Han Sung; Ro, Jungsil [Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do (Korea, Republic of); Yoon, Sungpil, E-mail: yoons@ncc.re.kr [Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do (Korea, Republic of)

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Sal sensitizes antimitotic drugs-treated cancer cells. Black-Right-Pointing-Pointer Sal sensitizes them by prevention of G2 arrest and reduced cyclin D1 levels. Black-Right-Pointing-Pointer Sal also sensitizes them by increasing DNA damage and reducing p21 level. Black-Right-Pointing-Pointer A low concentration of Sal effectively sensitized the cancer cells to antimitotic drugs. -- Abstract: Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal-sensitization mechanisms. These results may contribute to the development of Sal-based chemotherapy for cancer patients treated with antimitotic drugs.

  3. High frequency of Plasmodium falciparum CICNI/SGEAA and CVIET haplotypes without association with resistance to sulfadoxine/pyrimethamine and chloroquine combination in the Daraweesh area, in Sudan

    DEFF Research Database (Denmark)

    A-Elbasit, I E; Khalil, I F; Elbashir, M I

    2008-01-01

    Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti-malarial d......Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti......-malarial drug resistance. In this study, malaria patients treated with SP alone (60) and SP with CQ (194) had a total treatment failure (TF) of 35.4%, with no difference between the two arms. The polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) method was used to identify polymorphisms...

  4. The role of polyamine catabolism in anti-tumour drug response.

    Science.gov (United States)

    Casero, R A; Wang, Y; Stewart, T M; Devereux, W; Hacker, A; Wang, Y; Smith, R; Woster, P M

    2003-04-01

    Interest in polyamine catabolism has increased since it has been directly associated with the cytotoxic response of multiple tumour types to exposure to specific anti-tumour polyamine analogues. Human polyamine catabolism was considered to be a two-step pathway regulated by the rate-limiting enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (APAO). Further, the super-induction of SSAT by several anti-tumour polyamine analogues has been implicated in the cytotoxic response of specific solid-tumour phenotypes to these agents. This high induction of SSAT has been correlated with cellular response to the anti-tumour polyamine analogues in several systems and considerable progress has been made in understanding the molecular mechanisms that regulate the analogue-induced expression of SSAT. A polyamine response element has been identified and the transacting transcription factors that bind and stimulate transcription of SSAT have been cloned and characterized. The link between SSAT activity and cellular toxicity is thought to be based on the production of H(2)O(2) by the activity of the constitutive APAO that uses the SSAT-produced acetylated polyamines. The high induction of SSAT and the subsequent activity of APAO are linked to the cytotoxic response of some tumour cell types to specific polyamine analogues. However, we have recently cloned a variably spliced human polyamine oxidase (PAOh1) that is inducible by specific polyamine analogues, efficiently uses unacetylated spermine as a substrate, and also produces toxic H(2)O(2) as a product. The results of studies with PAOh1 suggest that it is an additional enzyme in polyamine catabolism that has the potential to significantly contribute to polyamine homoeostasis and drug response. Most importantly, PAOh1 is induced by specific polyamine analogues in a tumour-phenotype-specific manner in cell lines representative of the major forms of solid tumours, including

  5. Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

    OpenAIRE

    Shotaro Michinaga; Yutaka Koyama

    2015-01-01

    Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available. Thus, the development of novel anti-edema drugs is required. The pathogenesis of brain edema is classified as vas...

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

    Directory of Open Access Journals (Sweden)

    Rogers William O

    2010-04-01

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

  7. MARKETING PREDICTIONS IN ANTI-DRUG SOCIAL PROGRAMS: USE OF CAUSAL METHODS IN THE STUDY AND PREVENTION OF DRUG ABUSE

    Directory of Open Access Journals (Sweden)

    Serban Corina

    2010-12-01

    Full Text Available Drug use is one of the major challenges that todays society faces; its effects are felt at the level of various social, professional and age categories. Over 50 non-profit organizations are involved in the development of anti-drug social programs in Romania. Their role is to improve the degree of awareness of the target population concerning the risks associated with drug use, but also to steer consumers towards healthy areas, beneficial to their future. This paper aims to detail the issue of drug use in Romania, by making predictions based on the evolution of this phenomenon during the next five years. The obtained results have revealed the necessity to increase the number of programs preventing drug use, aswell as the need to continue social programs that have proved effective in previous years.

  8. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions.

    Science.gov (United States)

    Adiwidjaja, Jeffry; McLachlan, Andrew J; Boddy, Alan V

    2017-09-01

    Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

  9. Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis

    DEFF Research Database (Denmark)

    Bachelet, Delphine; Hässler, Signe; Mbogning, Cyprien

    2016-01-01

    Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in S...

  10. Adverse drug reaction monitoring of newer oral anti diabetic drugs – a pharmacovigilance perspective

    Directory of Open Access Journals (Sweden)

    Ankita Bhattacharjee

    2016-04-01

    Full Text Available Objective: To monitor and evaluate adverse drug reactions (ADRs of newer oral anti-diabetic drugs in type II diabetics by spontaneous/solicited ADR monitoring.Material and methods: Two hundred and thirty two diabetic patients on newer oral antidiabetic drugs were evaluated prospectively in a cross-sectional study over a period of eighteen months. All patients were followed up for ADRs which were evaluated for incidence, frequency, severity and causality. ADR severity was graded according to University of Virginia Health System Adverse Drug Reaction Reporting program criteria and causality assessment was done using WHO-UMC scale.Results: 190 out of 232 patients (42 patients lost to follow up were evaluated. ADRs were observed in 34 cases (17.9%. Most common ADRs were gastrointestinal (44.2% followed by musculoskeletal (17.6%, metabolic (14.7%, infections (5.9% and others (17.6%. The maximal frequency of ADRs was seen with sitagliptin (6.4% followed by vildagliptin(3.8%, saxagliptin(2.7%, saroglitazar(2.1%, linagliptin(1.6%, canagliflozin(1.6%. 25(73.5%, 8(23.5% and 1(3% ADRs were mild, moderate and severe respectively. 24(70% ADRs were classified as possible, 9(27% probable and 1(3% unlikely on causality assessment. Conclusion: Newer oral antidiabetic drugs like gliptins and SGLT-2 inhibitors have potential to cause ADRs. Gastro-intestinal, musculoskeletal, metabolic were most common ADRs. Active pharmacovigilance should be carried out for risk identification and management. 

  11. Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis)

    NARCIS (Netherlands)

    Kroon, Feline P. B.; van der Burg, Lennart R. A.; Ramiro, Sofia; Landewé, Robert B. M.; Buchbinder, Rachelle; Falzon, Louise; van der Heijde, Désirée

    2015-01-01

    Axial spondyloarthritis (axSpA) comprises ankylosing spondylitis (radiographic axSpA) and non-radiographic (nr-)axSpA and is associated with psoriasis, uveitis and inflammatory bowel disease. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line drug treatment. To determine

  12. Evaluation of the Anti-plasmodial Activity of the Methanolic Root Extracts of Anthocleista nobilis G. Don, Nauclea latifolia Smith and Napoleona imperialis P. Beauv

    OpenAIRE

    Ijeoma H. Ogbuehi; Omotayo O. Ebong; Eme O. Asuquo; Chijioke A. Nwauche

    2014-01-01

    The emergence of resistant strains of the malaria parasite has necessitated the continued search for other effective, safe and cheap plant-based anti-malarial agents. This study was carried out to evaluate in vivo the anti-plasmodial effect of the extract of a combination of three plants as used in traditional medicine in South-east, Nigeria. Dried and ground roots of the three plants: Anthocleista nobilis, Nauclea latifolia and Napoleona imperialis were extracted in 70% methanol as a combina...

  13. Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration

    Energy Technology Data Exchange (ETDEWEB)

    Ishii, Isao [Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo (Japan); Harada, Yasuo [Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Shiga (Japan); Kasahara, Tadashi, E-mail: isao-ishii@umin.ac.jp [Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo (Japan)

    2012-10-02

    Pyrvinium pamoate (PP) is an FDA-approved classical anthelmintic, but is now attracting particular attention as an anti-cancer drug after recent findings of its potent cytotoxicity against various cancer cell lines only during glucose starvation, as well as its anti-tumor activity against hypovascular pancreatic cancer cells transplanted in mice. The molecular mechanisms by which PP promotes such preferential toxicity against cancer cells are currently under extensive investigation. PP suppressed the NADH-fumarate reductase system that mediates a reverse reaction of the mitochondrial electron-transport chain complex II in anaerobic organisms such as parasitic helminthes or mammalian cells under tumor microenvironment-mimicking hypoglycemic/hypoxic conditions, thereby inhibiting efficient ATP production. PP also inhibited the unfolded protein response induced by glucose starvation, thereby inhibiting the proliferation of pancreatic cancer cells. Even under normoglycemic/normoxic conditions, PP suppressed the mitochondrial electron-transport chain complex I and thereby STAT3, inhibiting the proliferation of myeloma/erythroleukemia cells. Here, we review accumulating knowledge on its working mechanisms and evaluate PP as a novel anti-cancer drug that targets mitochondrial respiration.

  14. Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration.

    Directory of Open Access Journals (Sweden)

    Isao eIshii

    2012-10-01

    Full Text Available Pyrvinium pamoate (PP is an FDA-approved classical anthelmintic, but is now attracting particular attention as an anti-cancer drug after recent findings of its potent cytotoxicity against various cancer cell lines only during glucose starvation, as well as its anti-tumor activity against hypovascular pancreatic cancer cells transplanted in mice. The molecular mechanisms by which PP promotes such preferential toxicity against cancer cells are currently under extensive investigation. PP suppressed the NADH-fumarate reductase system that mediates a reverse reaction of the mitochondrial electron-transport chain complex II in anaerobic organisms such as parasitic helminthes or mammalian cells under tumor microenvironment-mimicking hypoglycemic/hypoxic conditions, thereby inhibiting efficient ATP production. PP also inhibited the unfolded protein response induced by glucose starvation, thereby inhibiting the proliferation of pancreatic cancer cells. Even under normoglycemic/normoxic conditions, PP suppressed the mitochondrial electron-transport chain complex I and thereby STAT3, inhibiting the proliferation of myeloma/erythroleukemia cells. Here, we review accumulating knowledge on its working mechanisms and evaluate PP as a novel anti-cancer drug that targets mitochondrial respiration.

  15. Reprofiling a classical anthelmintic, pyrvinium pamoate, as an anti-cancer drug targeting mitochondrial respiration

    International Nuclear Information System (INIS)

    Ishii, Isao; Harada, Yasuo; Kasahara, Tadashi

    2012-01-01

    Pyrvinium pamoate (PP) is an FDA-approved classical anthelmintic, but is now attracting particular attention as an anti-cancer drug after recent findings of its potent cytotoxicity against various cancer cell lines only during glucose starvation, as well as its anti-tumor activity against hypovascular pancreatic cancer cells transplanted in mice. The molecular mechanisms by which PP promotes such preferential toxicity against cancer cells are currently under extensive investigation. PP suppressed the NADH-fumarate reductase system that mediates a reverse reaction of the mitochondrial electron-transport chain complex II in anaerobic organisms such as parasitic helminthes or mammalian cells under tumor microenvironment-mimicking hypoglycemic/hypoxic conditions, thereby inhibiting efficient ATP production. PP also inhibited the unfolded protein response induced by glucose starvation, thereby inhibiting the proliferation of pancreatic cancer cells. Even under normoglycemic/normoxic conditions, PP suppressed the mitochondrial electron-transport chain complex I and thereby STAT3, inhibiting the proliferation of myeloma/erythroleukemia cells. Here, we review accumulating knowledge on its working mechanisms and evaluate PP as a novel anti-cancer drug that targets mitochondrial respiration.

  16. Effects of chloroquine, mefloquine and quinine on natural killer cell activity in vitro. An analysis of the inhibitory mechanism

    DEFF Research Database (Denmark)

    Pedersen, B K; Bygbjerg, I C; Theander, T G

    1986-01-01

    ) or interleukin 2 (Il-2); preincubation of mononuclear cells with IF or Il-2 followed by addition of anti-malarial drugs decreased the inhibitory effects of the drugs. The drug-induced inhibition of the NK cell activity was not dependent on the presence of monocytes. Using monocyte depleted Percoll fractionated......Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF...

  17. An Overview of Application of Nanotechnology in Malaria Control

    Directory of Open Access Journals (Sweden)

    Pam DD

    2017-07-01

    Full Text Available Infectious diseases caused by parasites are of immense global significance as about 30% of world’s population experiences parasitic infections. malaria is the most life threatening disease and accounts for one to two million deaths round the globe every year. Currently, there is no available effective vaccine against malaria. The shortcomings of malaria preventive and curative drug treatments have become a major reason for the failure to eradicate the disease. There is an urgent need for an effective antimalarial agent due to increasing drug resistance of Plasmodium falciparum. Nanotechnology has been identified as the new frontier in the fight against this disease. Nanomedicine is a new technology utilizing nanometer scale drug delivery systems as therapeutics, able to confer advantages which include improved drug pharmacokinetic profiles, organ, cell and parasite targeted drug delivery, reduce doses and reduction in drug toxicity. Nanomedicine can address the challenges associated with current anti-malarial drugs by reformulating the drugs in nanomedicine drug delivery systems (NMDDS. The development of these particulate carriers as vehicles for delivery of active compounds is a novel area of research that provides a new hope in malarial chemotherapy.

  18. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    International Nuclear Information System (INIS)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

    2013-01-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

  19. Effect of anti-obesity drug on cardiovascular risk factors: a systematic review and meta-analysis of randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Yu-Hao Zhou

    Full Text Available BACKGROUND: Anti-obesity drugs are widely used to prevent the complications of obesity, however, the effects of anti-obesity drugs on cardiovascular risk factors are unclear at the present time. We carried out a comprehensively systematic review and meta-analysis to assess the effects of anti-obesity drugs on cardiovascular risk factors. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures. We included randomized placebo-controlled trials that reported the effects of anti-obesity drugs on cardiovascular risk factors compared to placebo. Overall, orlistat produced a reduction of 2.39 kg (95%CI-3.34 to -1.45 for weight, a reduction of 0.27 mmol/L (95%CI: -0.36 to -0.17 for total cholesterol, a reduction of 0.21 mmol/L (95%CI: -0.30 to -0.12 for LDL, a reduction of 0.12 mmol/L (95%CI: -0.20 to -0.04 for fasting glucose, 1.85 mmHg reduction (95%CI: -3.30 to -0.40 for SBP, and a reduction of 1.49 mmHg (95%CI: -2.39 to -0.58 for DBP. Sibutramine only showed effects on weight loss and triglycerides reduction with statistical significances. Rimonabant was associated with statistically significant effects on weight loss, SBP reduction and DBP reduction. No other significantly different effects were identified between anti-obesity therapy and placebo. CONCLUSION/SIGNIFICANCE: We identified that anti-obesity therapy was associated with a decrease of weight regardless of the type of the drug. Orlistat and rimonabant could lead to an improvement on cardiovascular risk factors. However, Sibutramine may have a direct effect on cardiovascular risk factors.

  20. Prescription Pattern Analysis of Nonsteroidal Anti-inflammatory Drugs in the Northeastern Iranian Population

    NARCIS (Netherlands)

    Zeinali, Majid; Tabeshpour, Jamshid; Maziar, Seyed Vahid; Taherzadeh, Zhila; Zirak, Mohammad Reza; Sent, Danielle; Azarkhiavi, Kamal Razavi; Eslami, Saeid

    2017-01-01

    Inappropriate nonsteroidal anti-inflammatory drugs (NSAIDs) therapy is a common cause of actual and potential adverse effects, such as bleeding and gastrointestinal ulceration, which exacerbates the patient's medical condition and might even be life threatening. We aimed to evaluate and analyze the