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Sample records for anti-malarial drug sensitivity

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

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    Brun Reto

    2009-10-01

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

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

    OpenAIRE

    White, NJ

    2008-01-01

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

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

    OpenAIRE

    White Nicholas J

    2008-01-01

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

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

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    Avinaba Mukherjee

    2016-03-01

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

  5. Artemisinin anti-malarial drugs in China.

    Science.gov (United States)

    Guo, Zongru

    2016-03-01

    Discovered by Youyou Tu, one of the 2015 Nobel Prize winners in Physiology or Medicine, together with many other Chinese scientists, artemisinin, artemether and artesunate, as well as other artemisinins, have brought the global anti-malarial treatment to a new era, saving millions of lives all around the world for the past 40 years. The discoveries of artemisinins were carried out beginning from the 1970s, a special period in China, by hundreds of scientists all together under the "whole nation" system. This article focusing on medicinal chemistry research, briefly introduced the discovery and invention course of the scientists according to the published papers, and highlighted their academic contribution and achievements. PMID:27006895

  6. 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

  7. 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

  8. 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

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

    OpenAIRE

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

    2010-01-01

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

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

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    Lee Sue J

    2009-11-01

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

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

    OpenAIRE

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

    2016-01-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a...... baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods: All drug shops selling...... resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug...

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

    OpenAIRE

    Greenwood Brian

    2010-01-01

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

  14. 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

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

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    Prashant Singh

    2016-03-01

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

  16. 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

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

    Science.gov (United States)

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

    2016-01-01

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

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

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    Doerig Christian

    2010-07-01

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

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

    OpenAIRE

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

    2013-01-01

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

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

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    Chavalitshewinkoon-Petmitr Porntip

    2011-08-01

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

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

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    Chance Michael L

    2011-08-01

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

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

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    McKenzie F Ellis

    2010-07-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Santoshkumar R Jeevangi; Manjunath S; Sharanabasappa M Awanti

    2010-01-01

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

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

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    Mwafongo Winfred

    2010-10-01

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

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

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    Nain Vikrant

    2010-09-01

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

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

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    Uzochukwu Benjamin

    2009-02-01

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

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

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    Dondorp Arjen M

    2009-10-01

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

  8. 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

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

    OpenAIRE

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

    2014-01-01

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

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

    OpenAIRE

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

    2014-01-01

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

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

    OpenAIRE

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

    2011-01-01

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

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

    OpenAIRE

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

    2011-01-01

    Abstract Background Artemether-lumefantrine (ALu) replaced sulphadoxine-pymimethamine (SP) as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT) is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may u...

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

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    Duchateau Luc

    2011-02-01

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

  14. 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.

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Travers Dominique

    2011-01-01

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

  17. 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.

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

    OpenAIRE

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

    2009-01-01

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

  19. 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

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

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    Rath Srikanta

    2011-05-01

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

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

    OpenAIRE

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

    2013-01-01

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

  2. 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

  3. 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.

  4. 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

  5. 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.

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

    Institute of Scientific and Technical Information of China (English)

    郭志鑫; 姜典财; 黄志禄; 范兵; 李哲媛; 刘继华; 王幸

    2011-01-01

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

  7. 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.

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

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    Ronn Anita

    2011-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Qi Weihong

    2009-12-01

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

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

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    Sow Diarietou

    2009-06-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite......In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ) remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1...... resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma....

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

    Directory of Open Access Journals (Sweden)

    Khodakarim Nastaran

    2010-05-01

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

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

    OpenAIRE

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

    2009-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  15. 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

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

    OpenAIRE

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

    2014-01-01

    BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceutica...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

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    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

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

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    M. Akkawi

    2014-10-01

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

  20. 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.

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

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    Cravo Pedro VL

    2009-04-01

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

  3. Analysis of an ordinal outcome in a multicentric randomized controlled trial: application to a 3- arm anti- malarial drug trial in Cameroon

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    Gwét Henri

    2010-06-01

    Full Text Available Abstract Background Malaria remains a burden in Sub-Saharan Countries. The strategy proposed by the World Health Organization (WHO is to systematically compare the therapeutic efficacy of antimalarial drugs using as primary outcome for efficacy, a four-category ordered criterion. The objective of the present work was to analyze the treatment effects on this primary outcome taking into account both a center-effect and individual covariates. A three-arm, three-centre trial of Amodiaquine (AQ, sulfadoxine-pyrimethamine (SP and their combination (AQ + SP, conducted by OCEAC-IRD in 2003, in 538 children with uncomplicated Plasmodium falciparum malaria, is used as an illustration. Methods Analyses were based on ordinal regression methods, assuming an underlying continuous latent variable, using either the proportional odds (PO or the proportional hazards (PH models. Different algorithms, corresponding to both frequentist- and bayesian-approaches, were implemented using the freely available softwares R and Winbugs, respectively. The performances of the different methods were evaluated on a simulated data set, and then they were applied on the trial data set. Results Good coverage probability and type-1 error for the treatment effect were achieved. When the methods were applied on the trial data set, results highlighted a significance decrease of SP efficacy when compared to AQ (PO, odds ratio [OR] 0.14, 95% confidence interval [CI] 0.04-0.57; hazard ratio [HR] 0.605, 95% CI 0.42-0.82, and an equal effectiveness between AQ + SP and AQ (PO, odds ratio [OR] 1.70, 95% confidence interval [CI] 0.25-11.44; hazard ratio [HR] 1.40, 95% CI 0.88-2.18. The body temperature was significantly related to the responses. The patient weights were marginally associated to the clinical response. Conclusion The proposed analyses, based on usual statistical packages, appeared adapted to take into account the full information contained in the four categorical outcome in

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

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    Croft Simon L

    2012-08-01

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

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

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    Sevcsik Ann-Marie

    2010-04-01

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

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

    OpenAIRE

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

    2015-01-01

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

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

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    Huang Fang

    2012-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Wells Timothy NC

    2011-03-01

    Full Text Available Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal

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

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    Mullié Catherine

    2012-03-01

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

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

    DEFF Research Database (Denmark)

    Mangesho, Peter E; Reynolds, Joanna; Lemnge, Martha; Vestergaard, Lasse S; Chandler, Clare I R

    2014-01-01

    . However, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. CONCLUSIONS: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease...

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

    OpenAIRE

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

    2011-01-01

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

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

    OpenAIRE

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Tonlong WANGPAN

    2016-03-01

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

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

    OpenAIRE

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

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

    Directory of Open Access Journals (Sweden)

    Abiodun Oyindamola O

    2013-01-01

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

  19. 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

  20. 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...

  1. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*

    OpenAIRE

    Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara

    2010-01-01

    Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low ...

  2. Acyclic Nucleoside Phosphonates as Potential Anti-Malarial Agents

    Czech Academy of Sciences Publication Activity Database

    Janeba, Zlatko; Hocková, Dana; Holý, Antonín; Česnek, Michal; Baszczyňski, Ondřej; Tichý, Tomáš; Krečmerová, Marcela; Naesens, L.; Skinner-Adams, T. S.; Edstein, M.; Keough, D. T.; de Jersey, J.; Guddat, L. W.

    Riviera Maya: -, 2011. s. 21-21. [Zing Conferences 2011. Drug Discovery - Tropical Diseases Conference. 11.12.2011-15.12.2011, Riviera Maya] R&D Projects: GA ČR GAP207/11/0108; GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : acyclic nucleoside phosphonates * HGXPRT * malaria * Plasmodium Subject RIV: CC - Organic Chemistry

  3. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Institute of Scientific and Technical Information of China (English)

    Phitsinee; Thipubon; Wachiraporn; Tipsuwan; Chairat; Uthaipibull; Sineenart; Santitherakul; Somdet; Srichiratanakool

    2015-01-01

    Objective: To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one(CM1) iron chelator and green tea extract(GTE) as anti-malarial activity in Plasmodium berghei(P. berghei) infected mice.Methods: The CM1(0–100 mg/kg/day) and GTE(0–100 mg(-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells(PRBC) were enumerated by using Giemsa staining microscopic method.Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine(PYR)(ED50= 0.76 mg/kg).GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity.Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron cstitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

  4. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Institute of Scientific and Technical Information of China (English)

    Phitsinee Thipubon; Wachiraporn Tipsuwan; Chairat Uthaipibull; Sineenart Santitherakul; Somdet Srichiratanakool

    2015-01-01

    Objective:To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) iron chelator and green tea extract (GTE) as anti-malarial activity in Plasmodium berghei (P. berghei ) infected mice. Methods:The CM1 (0–100 mg/kg/day) and GTE (0–100 mg (-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells (PRBC) were enumerated by using Giemsa staining microscopic method. Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine (PYR) (ED50=0.76 mg/kg). GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity. Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron constitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

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

    Directory of Open Access Journals (Sweden)

    Evans Lawrence

    2012-06-01

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

  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. Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Nana O Wilson

    Full Text Available Despite appropriate anti-malarial treatment, cerebral malaria (CM-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10 and increasing angiogenic factor (VEGF production. Treatment with a combination of atorvastatin and artemether improved survival (100% when compared with artemether monotherapy (70%, p<0.05. Thus, adjunctively

  8. A new class of anti-malarial therapeutics that inhibit nucleotide synthesis in Plasmodium falciparum and vivax

    Czech Academy of Sciences Publication Activity Database

    Keough, D. T.; Hocková, Dana; Holý, Antonín; Naesens, L.; Skinner-Adams, T. S.; de Jersey, J.; Guddat, L. W.

    Lorne : The University of Queensland, 2009. -. [Lorne Conference on Protein Structure and Function /34./. 08.02.2009-12.02.2009, Lorne] Institutional research plan: CEZ:AV0Z40550506 Keywords : Plasmodium falciparum * anti-malarial therapeutics * nucleotide synthesis Subject RIV: CC - Organic Chemistry

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

    Science.gov (United States)

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

    2016-01-01

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

  10. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Jr., Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara; Garuti, Helen; Wittlin, Sergio; Papastogiannidis, Petros; Lin, Jing-wen; Janse, Chris J.; Khan, Shahid M.; Duraisingh, Manoj; Coleman, Bradley; Goldsmith, Elizabeth J.; Phillips, Margaret A.; Munoz, Benito; Wirth, Dyann F.; Klinger, Jeffrey D.; Wiegand, Roger; Sybertz, Edmund (Leiden-MC); (Puerto Rico); (STPHI); (Harvard); (GSK); (Genzyme); (UTSMC)

    2010-11-22

    Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED{sub 50} values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

  11. Effect of selenium (Se) deficiency on the anti-malarial action of Qinghaosu (QHS) in mice

    Energy Technology Data Exchange (ETDEWEB)

    Levander, O.A.; Ager, A.L.; May, R.

    1986-03-01

    QHS is an endoperoxide, so it occurred to the authors that its anti-malarial action might be potentiated by low glutathione peroxidase (GSH-Px) activity. Weanling female mice were fed 1 of 4 diets: chow or a Torula yeast-based diet supplemented with 0, 0.1 or 0.5 ppm Se as Na/sub 2/SeO/sub 3/. After 6 weeks, mean hepatic GSH-Px activities and plasma Se levels in these 4 dietary groups were 17.3, 0.1, 5.4, and 14.5 munits/mg protein and 242, 4, 230, and 532 ng/ml, respectively. At this time, all mice were inoculated i.p. with asexual blood stages of Plasmodium yoelii. Then groups of 7 or 8 mice fed each diet were given 0, 4, 16, or 64 mg QHS/kg orally bid at 3, 4, and 5 days post inoculation. On the 6th day, blood films were taken and antimalarial activity was assessed by determining % parasitemia (% PARA). Mice given 0 or 4 mg QHS/kg averaged 47% PARA and this was not affected by diet. Mice receiving 64 mg QHS/kg averaged about 1% PARA irrespective of diet. However, mice given 16 mg QHS/kg had 25% PARA when fed chow but only 8 to 11% PARA when fed the Torula diet, regardless of Se intake. Thus, while Se status did not appear to influence the antimalarial potency of QHS, some factor(s) in the Torula diet enhanced its activity at intermediate doses vs. the chow diet.

  12. Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience

    Directory of Open Access Journals (Sweden)

    Sebbag Robert

    2011-05-01

    Full Text Available Abstract Background This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. Case description In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and sanofi-aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop" which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and sanofi-aventis to ensure: 1 the adoption of this new medicine by malaria-endemic countries, 2 its appropriate usage through a broad range of information tools, and 3 the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. Discussion and evaluation The partnership between DNDi and sanofi-aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. Conclusions The

  13. 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

  14. Acyclic Nucleoside Phosphonates as Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: New Anti-Malarial Chemotherapy Leads

    Czech Academy of Sciences Publication Activity Database

    Hocková, Dana; Holý, Antonín; Česnek, Michal; Baszczyňski, Ondřej; Tichý, Tomáš; Krečmerová, Marcela; Janeba, Zlatko; Skinner-Adams, T. S.; Naesens, L.; Keough, D. T.; de Jersey, J.; Guddat, L. W.

    Praha : Institute of Organic Chemistry and Biochemistry AS CR, v. v. i., 2011 - (Hocek, M.), s. 171-174 ISBN 978-80-86241-37-1. - (Collection Symposium Series. 12). [Chemistry of Nucleic Acid Components /15./. Český Krumlov (CZ), 05.06.2011-10.06.2011] R&D Projects: GA MŠk 1M0508; GA ČR GAP207/11/0108 Institutional research plan: CEZ:AV0Z40550506 Keywords : ANPs * acyclic nucleoside phosphonates * anti-malarial * Plasmodium * HGXPRTase Subject RIV: CC - Organic Chemistry

  15. Site-specific integration and expression of an anti-malarial gene in transgenic Anopheles gambiae significantly reduces Plasmodium infections.

    Directory of Open Access Journals (Sweden)

    Janet M Meredith

    Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    O'Connell Kathryn A

    2011-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.

  18. In vitro genotoxicity of the West African anti-malarial herbal Cryptolepis sanguinolenta and its major alkaloid cryptolepine.

    Science.gov (United States)

    Ansah, Charles; Khan, Ayesha; Gooderham, Nigel J

    2005-03-01

    Cryptolepine (CLP), the major alkaloid of the West African anti-malarial herbal Cryptolepis sanguinolenta (Periplocaceae) is a DNA intercalator that exhibits potent toxicity to a variety of mammalian cells in vitro. We have hypothesized that the DNA intercalating properties of cryptolepine could trigger genetic damage in mammalian cells. The objective of the present study was therefore to assess the ability of both cryptolepine (CLP) and the traditional anti-malarial formulation, the aqueous extract from the roots (CSE) to induce mutation at the hprt locus and micronuclei (MN) formation in V79, a Chinese hamster fibroblast cell line commonly used in genetic toxicity studies. CSE at a high concentration (50 microg/ml) induced an apparent significant ten fold increase in mutant frequency compared to vehicle control (mean of 38 versus 4 mutant clones/10(6) surviving cells) but, this concentration of CSE was very toxic (<15% cell survival). CLP did not appear to be mutagenic in the dosage range used (up to 2.5 microM, equivalent to 1.1 microg/ml). However, after 24h treatment of V79 cells both CSE and CLP induced a dose-dependent increase in micronuclei of 4.15% and 6.43% (25 microg/ml CSE and 2.5 microM, equivalent to 1.1 microg/ml CLP, respectively) compared to 0.36% in vehicle control. These results show that treatment of mammalian cells with CSE and CLP can lead to DNA damage and we suggest that the routine use of CSE and the potential use of CLP derivatives in malaria chemotherapy could carry a genotoxic risk. PMID:15664441

  19. 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

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

    Directory of Open Access Journals (Sweden)

    Jason P Wendler

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

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

    OpenAIRE

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

    2014-01-01

    Background 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...

  2. Genetic polymorphisms associated with anti-malarial antibody levels in a low and unstable malaria transmission area in southern Sri Lanka

    OpenAIRE

    Dewasurendra Rajika L; Suriyaphol Prapat; Fernando Sumadhya D; Carter Richard; Rockett Kirk; Corran Patrick; Kwiatkowski Dominic; Karunaweera Nadira D

    2012-01-01

    Abstract Background The incidence of malaria in Sri Lanka has significantly declined in recent years. Similar trends were seen in Kataragama, a known malaria endemic location within the southern province of the country, over the past five years. This is a descriptive study of anti-malarial antibody levels and selected host genetic mutations in residents of Kataragama, under low malaria transmission conditions. Methods Sera were collected from 1,011 individuals residing in Kataragama and anti-...

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

    OpenAIRE

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

    2013-01-01

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

  4. In vitro and in vivo anti-malarial activity of limonoids isolated from the residual seed biomass from Carapa guianensis (andiroba) oil production

    OpenAIRE

    Pereira, Tiago B; Rocha e Silva, Luiz F.; Amorim, Rodrigo CN; Melo, Márcia RS; Zacardi de Souza, Rita C; Marcos N. Eberlin; Emerson S. Lima; Vasconcellos, Marne C.; Pohlit, Adrian M.

    2014-01-01

    Background Carapa guianensis is a cultivable tree used by traditional health practitioners in the Amazon region to treat several diseases and particularly symptoms related to malaria. Abundant residual pressed seed material (RPSM) results as a by-product of carapa or andiroba oil production. The objective of this study was to evaluate the in vitro and in vivo anti-malarial activity and cytotoxicity of limonoids isolated from C. guaianensis RPSM. Methods 6α-acetoxyepoxyazadiradione (1), andiro...

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

    OpenAIRE

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

    2012-01-01

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

  6. Synthesis and pharmacokinetics of radioisotope labeled anti-malarial agent in Sprague-Dawley rats

    Energy Technology Data Exchange (ETDEWEB)

    Kannanpalli, Pradeep; Park, Sang Hyun [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2008-04-15

    Pyro naridine tetraphosphate is a new synthetic drug which is currently being investigated for use in the treatment of malaria. The main objective of this investigation was to synthesize [{sup 14}C]pyro naridine tetraphosphate and to determine its absorption, distribution, excretion and pharmacokinetics in to male and female Sprague-Dawley rats following a single oral administration (10 mg/kg). To overcome the disadvantages posed by the classical method, a novel and efficient method using microwave irradiation was employed for the synthesis of pyro naridine tetraphosphate. Use of microwave irradiation decreased the reaction time considerably, used less of the starting material and also increased the yield when compared with the classical method. [{sup 14}C]Pyro naridine tetraphosphate thus synthesized had a high degree of purity and showed satisfactory {sup 1}H NMR, {sup 13}C NMR, mass spectra (MS), infrared (IR) and elemental analysis data. The distribution of [{sup 14}C]pyro naridine tetraphosphate in various tissues like the blood, plasma, liver, lung, heart, spleen, kidney, brain, stomach, small intestine and large intestine were determined at 1, 4, 8, 24, 48, 96, 144, 192 and 240 h post administration of the drug to rats. Mass balance excretion of [{sup 14}C]pyro naridine tetraphosphate in urine, faeces and in breath as {sup 14}CO{sub 2} were also determined at different time intervals post administration of the drug. We observed that [{sup 14}C]pyro naridine tetraphosphate was readily absorbed and widely distributed within 1 h following oral administration as it was determined by the presence of radioactivity in various tissues investigated. The absorption, distribution and excretion of the drug was found to be gender independent as both male and female rats showed a similar pattern of radioactivity. [{sup 14}C]Pyro naridine tetraphosphate was absorbed mainly from the small intestine upon oral administration. The major route of excretion for [{sup 14}C

  7. How sulfadoxine-pyrimethamine (SP was perceived in some rural communities after phasing out chloroquine (CQ as a first-line drug for uncomplicated malaria in Tanzania: lessons to learn towards moving from monotherapy to fixed combination therapy

    Directory of Open Access Journals (Sweden)

    Nsimba Stephen ED

    2006-01-01

    health workers considered the drug to be good and effective against malaria. Such negative perception towards SP highlights the need to start earlier sensitization and educational campaigns to the rural communities for a new drug program to ensure its success. Messages should clearly state what should be expected from the new drug (Coartem, before its introduction. This is important especially as Tanzania is expected to move towards the expensive but efficacious and effective fixed-combination (Coartem anti-malarial therapy early next year (2006.

  8. The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

    OpenAIRE

    Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

    2013-01-01

    Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are ...

  9. Acyclic nucleoside phosphonates as a new class of anti-malarial compounds: Inhibition of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase by 9-[2-(2-phosphonoethoxy)ethyl]-purines and their branched derivatives

    Czech Academy of Sciences Publication Activity Database

    Hocková, Dana; Holý, Antonín; Keough, D. T.; Naesens, L.; Skinner-Adams, T. S.; de Jersey, J.; Guddat, L. W.

    Praha : -, 2009. -. ISBN 978-80-02-02160-5. [ESOC 2009. European Symposium on Organic Chemistry /16./. 12.07.2009-16.07.2009, Praha] Institutional research plan: CEZ:AV0Z40550506 Keywords : acyclic nucleoside phosphonates * anti-malarial compounds Subject RIV: CC - Organic Chemistry

  10. Ex vivo drug sensitivity profiles of Plasmodium falciparum field isolates from Cambodia and Thailand, 2005 to 2010, determined by a histidine-rich protein-2 assay

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    Tyner Stuart D

    2012-06-01

    Full Text Available Abstract Background In vitro drug susceptibility assay of Plasmodium falciparum field isolates processed “immediate ex vivo” (IEV, without culture adaption, and tested using histidine-rich protein-2 (HRP-2 detection as an assay, is an expedient way to track drug resistance. Methods From 2005 to 2010, a HRP-2 in vitro assay assessed 451 P. falciparum field isolates obtained from subjects with malaria in western and northern Cambodia, and eastern Thailand, processed IEV, for 50% inhibitory concentrations (IC50 against seven anti-malarial drugs, including artesunate (AS, dihydroartemisinin (DHA, and piperaquine. Results In western Cambodia, from 2006 to 2010, geometric mean (GM IC50 values for chloroquine, mefloquine, quinine, AS, DHA, and lumefantrine increased. In northern Cambodia, from 2009–2010, GM IC50 values for most drugs approximated the highest western Cambodia GM IC50 values in 2009 or 2010. Conclusions Western Cambodia is associated with sustained reductions in anti-malarial drug susceptibility, including the artemisinins, with possible emergence, or spread, to northern Cambodia. This potential public health crisis supports continued in vitro drug IC50 monitoring of P. falciparum isolates at key locations in the region.

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

  12. 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

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

    Science.gov (United States)

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

    2016-09-01

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

  14. Frequency of glucose-6-phosphate dehydrogenase deficiency in malaria patients from six African countries enrolled in two randomized anti-malarial clinical trials

    Directory of Open Access Journals (Sweden)

    Duparc Stephan

    2011-08-01

    Full Text Available Abstract Background Glucose-6-phosphate dehydrogenase (G6PD deficiency is common in populations living in malaria endemic areas. G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone-artesunate (CDA phase III clinical trial programme. Methods Study participants, aged > 1 year, with microscopically confirmed uncomplicated Plasmodium falciparum malaria, and haemoglobin ≥ 70 g/L or haematocrit ≥ 25%, were recruited into two clinical trials conducted in six African countries (Burkina Faso, Ghana, Kenya, Nigeria, Tanzania, Mali. G6PD genotype of the three most common African forms, G6PD*B, G6PD*A (A376G, and G6PD*A- (G202A, A542T, G680T and T968C, were determined and used for frequency estimation. G6PD phenotype was assessed qualitatively using the NADPH fluorescence test. Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration, temperature, asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg (both given once daily for three days or six-dose artemether-lumefantrine. Results Of 2264 malaria patients enrolled, 2045 had G6PD genotype available and comprised the primary analysis population (1018 males, 1027 females. G6PD deficiency prevalence was 9.0% (184/2045; 7.2% [N = 147] male hemizygous plus 1.8% [N = 37] female homozygous, 13.3% (273/2045 of patients were heterozygous females, 77.7% (1588/2045 were G6PD normal. All deficient G6PD*A- genotypes were A376G/G202A. G6PD phenotype was available for 64.5% (1319/2045 of patients: 10.2% (134/1319 were G6PD deficient, 9.6% (127/1319 intermediate, and 80.2% (1058/1319 normal. Phenotype test specificity in detecting hemizygous males was 70.7% (70/99 and 48.0% (12/25 for homozygous females. Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin (p = 0.154, adjusted mean baseline temperature (p = 0

  15. 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....

  16. Therapeutic and prophylactic effect of intermittent preventive anti-malarial treatment in infants (IPTi from Ghana and Gabon

    Directory of Open Access Journals (Sweden)

    Kreuels Benno

    2008-10-01

    Full Text Available Abstract Background Intermittent preventive treatment in infants (IPTi with sulphadoxine-pyrimethamine (SP reduces the incidence of malaria episodes in young children. The exact mechanism by which the protective effect is mediated needs to be defined. This study aimed to investigate therapeutic, prophylactic, and possible exceeding effects of SP-based IPTi in two clinical trials. Methods Protective efficacies from two IPTi trials performed in Kumasi, Ghana, and Lambaréné, Gabon, were assessed for overlapping time series of 61 days. For six-months periods after each of three IPTi doses a multivariate Poisson regression model with the respective cohort as co-variate was generated and effect modification of protective efficacy with time strata was evaluated by log-likelihood tests. Results Protective efficacies were not significantly different between the two study cohorts. Study-cohort corrected protective efficacy was highest for the first 61 days after each IPTi application and decreased continuously. For the first 61 days after IPTi-1, IPTi-2, and IPTi-3 the protective efficacy was 71%, 44%, and 43%, respectively. A reduction of the malaria incidence rate was detectable for the first 60, 30 and 40 days after IPTi-1, IPTi-2 and IPTi-3 drug application, respectively. After IPTi-3 a higher risk for malaria could be seen after day 60. This effect was mainly based on the overwhelming influence of the Kumasi cohort. Conclusion The results suggest that SP-based IPTi mainly works through a therapeutic and prophylactic effect over 30 to 60 days after drug application and that a sustained effect beyond post-treatment prophylaxis might be very low. Trial registration Data analysis from clinical trials NCT ID # 00206739 (Kumasi Trial and NCT ID # 00167843 (Lambaréné Trial, http://www.clinicaltrials.gov.

  17. Aqueous Root Extract of the Anti-Malarial Herbal Cryptolepis sangunolenta (Lindl Schltr Inhibits Ovulation in Rabbits

    Directory of Open Access Journals (Sweden)

    Charles Ansah

    2012-10-01

    Full Text Available The objective of the present study was to assess the effect of the aqueous root extract of Cryptolepis sanguinolenta (cryptolepis, a popular West Africa antimalarial agent on ovulation in rabbits. We demonstrated previously that the aqueous root extract of the plant inhibits reproduction and foetal development in mice. The possible mechanism involved in this reproductive effect and whether the effect is species dependent has yet to be elucidated. Using the rabbit, the present study examined the effect of cryptolepis on pre and post ovulatory events to explore further the mechanism of the reproductive toxicity of cryptolepis. Cryptolepis (62.5-500 mg/kg; p.o administered five hours before ovulation inhibited ovulation in rabbits as ovarian histology showed dilated but unraptured ovum. The effects of cryptolepis were similar to diclofenac, an NSAID used as a reference drug. Post ovulatory treatment with cryptolepis (62.5-500 mg/kg; p.o had little effect on ovarian histology but decreased the implantation index. This study shows that the anti-conceptive effects of cryptolepis involve inhibition of ovulation and early post ovulatory events in the rabbit.

  18. Haemoglobin interference and increased sensitivity of fluorimetric assays for quantification of low-parasitaemia Plasmodium infected erythrocytes

    Directory of Open Access Journals (Sweden)

    Puyet Antonio

    2009-12-01

    Full Text Available Abstract Background Improvements on malarial diagnostic methods are currently needed for the correct detection in low-density Plasmodium falciparum infections. Microfluorimetric DNA-based assays have been previously used for evaluation of anti-malarial drug efficacy on Plasmodium infected erythrocytes. Several factors affecting the sensitivity of these methods have been evaluated, and tested for the detection and quantification of the parasite in low parasitaemia conditions. Methods Parasitaemia was assessed by measuring SYBRGreen I® (SGI and PicoGreen® (PG fluorescence of P. falciparum Dd2 cultures on human red blood cells. Different modifications of standard methods were tested to improve the detection sensitivity. Calculation of IC50 for chloroquine was used to validate the method. Results Removal of haemoglobin from infected red-blood cells culture (IRBC increased considerably the fluorescent signal obtained from both SGI and PG. Detergents used for cell lysis also showed to have an effect on the fluorescent signal. Upon depletion of haemoglobin and detergents the fluorescence emission of SGI and PG increased, respectively, 10- and 60-fold, extending notably the dynamic range of the assay. Under these conditions, a 20-fold higher PG vs. SGI fluorescent signal was observed. The estimated limits of detection and quantification for the PG haemoglobin/detergent-depleted method were 0.2% and 0.7% parasitaemia, respectively, which allow the detection of ~10 parasites per microliter. The method was validated on whole blood-infected samples, displaying similar results as those obtained using IRBC. Removal of white-blood cells prior to the assay allowed to increase the accuracy of the measurement, by reducing the relative uncertainty at the limit of detection from 0.5 to 0.1. Conclusion The use of PG microassays on detergent-free, haemoglobin-depleted samples appears as the best choice both for the detection of Plasmodium in low-density infections

  19. Treatment of fevers prior to introducing rapid diagnostic tests for malaria in registered drug shops in Uganda

    OpenAIRE

    Mbonye, AK; Lal, S; Cundill, B; Hansen, KS; Clarke, S.; Magnussen, P

    2013-01-01

    Background: Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of...

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

    Institute of Scientific and Technical Information of China (English)

    Satyajit; Tripathy; Somenath; Roy

    2014-01-01

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

  1. New Anti-malarial Drug Leads: N-Branched Acyclic Nucleoside Phosphonates as Inhibitors of the Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases

    Czech Academy of Sciences Publication Activity Database

    Hocková, Dana; Keough, D. T.; Janeba, Zlatko; Naesens, L.; Edstein, M. D.; Chavchich, M.; Wang, T. H.; de Jersey, J.; Guddat, L. W.

    Istanbul : IUPAC, 2013. s. 1629-1629. [World Chemistry Congress /44./. 11.08.2013-16.08.2013, Istanbul] R&D Projects: GA ČR GAP207/11/0108 Grant ostatní: NHMRC(AU) 1030353 Institutional support: RVO:61388963 Keywords : nucleotide analogues * enzyme inhibitors * Plasmodium Subject RIV: CC - Organic Chemistry

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

    OpenAIRE

    Rath Srikanta; Singh Prabhat; Mishra Shrawan

    2011-01-01

    Abstract Background Amodiaquine (AQ) along with sulphadoxine-pyrimethamine (SP) offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following e...

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

    Institute of Scientific and Technical Information of China (English)

    Satyajit Tripathy; Somenath Roy

    2014-01-01

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

  4. Comparative transcriptomics and metabolomics in a rhesus macaque drug administration study

    OpenAIRE

    Lee, Kevin J.; Yin, Weiwei; Arafat, Dalia; Tang, Yan; Uppal, Karan; Tran, ViLinh; Cabrera-Mora, Monica; Lapp, Stacey; Moreno, Alberto; Meyer, Esmeralda; DeBarry, Jeremy D.; Pakala, Suman; Nayak, Vishal; Kissinger, Jessica C; Jones, Dean P.

    2014-01-01

    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 (BM) RNA-Seq and plasma metabolome profiles (each with over 15,000 features) have been generated for five naïve individuals at up to seven timepoints before, during and after three rounds of drug administration. Linear modeling and Bayesian network analyses are both considered, alongside investigation...

  5. Analysis of ex vivo drug response data of Plasmodium clinical isolates: the pros and cons of different computer programs and online platforms.

    OpenAIRE

    Wirjanata, G; Handayuni, I; Zaloumis, SG; Chalfein, F.; Prayoga, P; Kenangalem, E.; Poespoprodjo, JR; Noviyanti, R.; Simpson, Ja; Price, RN; Marfurt, J

    2016-01-01

    Background In vitro drug susceptibility testing of malaria parasites remains an important component of surveillance for anti-malarial drug resistance. The half-maximal inhibition of growth (IC50) is the most commonly reported parameter expressing drug susceptibility, derived by a variety of statistical approaches, each with its own advantages and disadvantages. Methods In this study, licensed computer programs WinNonlin and GraphPad Prism 6.0, and the open access programs HN-NonLin, Antimalar...

  6. Sensitive radioenzymatic assay for catechol drugs

    International Nuclear Information System (INIS)

    This assay measures picogram quantities of catechol drugs and endogenous catecholamines in body tissues and fluids. The catechols are converted to their 3H-O-methyl metabolites during incubation with 3H-S-adenosylmethionine then separated by solvent extraction and thin-layer chromatography. Most drugs containing the catechol structure can be radiolabeled and separated from norepinephrine and epinephrine by this technique to provide simultaneous measurement of endogenous and exogenously administered catechols. The disposition of isoproterenol in tissues and fluids of man and experimental animals is measured to illustrate the utility of this assay. The reactivity of several commonly administered catechol drugs with COMT is described and the possible implications discussed

  7. Molecular modeling, in silico screening and molecular dynamics of PfPRL-PTP of P. falciparum for identification of potential anti-malarials.

    Science.gov (United States)

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

    2016-06-01

    Millions of deaths occur every year due to malaria. Growing resistance against existing drugs for treatment of malaria has exaggerated the problem further. There is an intense demand of identifying drug targets in malaria parasite. PfPRL-PTP protein is PRL group of phosphatase, and one of the interesting drug targets being involved in three important pathways of malaria parasite (secretion, phosphorylation, and prenylation). Therefore, in this study, we have modeled three-dimensional structure of PfPRL-PTP followed by validation of 3D structure using RAMPAGE, verify3D, and other structure validation tools. We could identify 12 potential inhibitory compounds using in silico screening of NCI library against PfPRL-PTP with Glide. The molecular dynamics simulation was also performed using GROMACS on PfPRL-PTP model alone and PfPRL-PTP-inhibitor complex. This study of identifying potential drug-like molecules would add up to the process of drug discovery against malaria parasite. PMID:26313238

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

    International Nuclear Information System (INIS)

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

    Science.gov (United States)

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

    2015-01-01

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

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

    OpenAIRE

    Abiodun Oyindamola O; Brun Reto; Wittlin Sergio

    2013-01-01

    Abstract Background Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+−ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin der...

  11. Gene sensitizes cancer cells to chemotherapy drugs

    Science.gov (United States)

    NCI scientists have found that a gene, Schlafen-11 (SLFN11), sensitizes cells to substances known to cause irreparable damage to DNA.  As part of their study, the researchers used a repository of 60 cell types to identify predictors of cancer cell respons

  12. Repurposing of antiparasitic drugs: the hydroxy-naphthoquinone buparvaquone inhibits vertical transmission in the pregnant neosporosis mouse model

    OpenAIRE

    Müller, Joachim; Aguado-Martínez, Adriana; Manser, Vera; Wong, Ho Ning; Haynes, Richard K.; Hemphill, Andrew

    2016-01-01

    The three anti-malarial drugs artemiside, artemisone, and mefloquine, and the naphthoquinone buparvaquone known to be active against theileriosis in cattle and Leishmania infections in rodents, were assessed for activity against Neospora caninum infection. All four compounds inhibited the proliferation of N. caninum tachyzoites in vitro with IC50 in the sub-micromolar range, but artemisone and buparvaquone were most effective (IC50 = 3 and 4.9 nM, respectively). However, in a neosporosis mous...

  13. Biological studies of matrix metalloproteinase sensitive drug delivery systems

    DEFF Research Database (Denmark)

    Johansen, Pia Thermann

    for delivery of drugs to specific tissues or cells utilizing biological knowledge of cancer tissue is getting increased attention. In this thesis a novel matrix metalloproteinase-2 (MMP-2) sensitive poly-ethylene glycol (PEG) coated liposomal drug delivery system for treatment of cancer was developed......Cancer, which is a group of diseases characterized by cells with elevated replication rate and compromised DNA damage response, is often treated with cytotoxic drugs, chemotherapeutics, inducing DNA damage that results in cell death. The use of chemotherapeutics in the clinic, however, is limited...... due to severe side effects as a result of drug distribution to healthy tissues. To enhance ecacy of treatment and improve life quality of patients, tumor specific drug delivery strategies, such as liposome encapsulated drugs, which accumulate in tumor tissue, has gained increased attention. Several...

  14. The Drug Sensitivity of Cyclosporine A Combined with Antineoplastic Drugs in Retinoblastoma in Vitro

    Institute of Scientific and Technical Information of China (English)

    Wanli Liu; Zhongyao Wu

    2005-01-01

    Purpose: To study cyclosporine A inhibition on the fresh retinoblastoma cells in vitro and increasing the drug sensitivity after combined with different antineoplastic drugs.Methods: To study the growth curve of cyclosporine A on 27 samples of primary retinoblastoma cells by MTT assay and to study the change of the drug sensitivity by cyclosporine A combined with seven antineoplastic drugs.Results: The average IC50 of cyclosporine A on the 27 retinoblastoma cells is 67.81μg/ml and the average inhibitive rate of these samples is 26.1% when cyclosporine A is in the concentration of 2μg/ml. The inhibitive rates all got improved after the seven antineoplastic drugs combined with cyclosporine A and the increasing average inhibitive rate is more than 5.Conclusion: Cyclosporine A can inhibit retinoblastoma cells in vitro and its inhibitive effect is dose dependent. Moreover it can enhance the inhibition of multiple antineoplastic drugs on retinoblastoma cells.

  15. 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. PMID:19191252

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

    International Nuclear Information System (INIS)

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

  17. Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective

    Directory of Open Access Journals (Sweden)

    Dillip Angel

    2010-06-01

    Full Text Available Abstract Background To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP to artemether-lumefantrine (ALu in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania. Methods The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS and in Ifakara town. Data collection consisted of: 1 yearly censuses of shops selling drugs; 2 collection of monthly data on availability of anti-malarials in public health facilities; and 3 retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data. Results Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008 and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008 of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock, but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock, but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti-malarial

  18. Different combination of drugs regarding the damage on organs targeting salt sensitivity or non-salt-sensitive hypertension

    Institute of Scientific and Technical Information of China (English)

    吴琪

    2013-01-01

    Objective To study the damage on organs from salt sensitivity hypertension or non-salt-sensitive hypertension and the selection of drug combination.Methods 120 hypertensive patients including 60 cases salt-sensitive(SS)

  19. Multiple cutaneous sensitization to nonsteroidal anti-inflammatory drugs.

    Science.gov (United States)

    Gonzalo, M A; Revenga, F

    1996-01-01

    The use of topical nonsteroidal anti-inflammatory drugs is widespread (particularly in countries bordering the Mediterranean). Compared to their wide use, the incidence of published adverse cutaneous effects appears minimal, although they are increasing. Most of them are a form of allergic contact dermatitis (ACD). Multiple sensitization and/or cross-reactions are rarely reported. Interestingly, our patient presented ACD with diclofenac and etofenamate (both from different chemical groups) and, furthermore, patch tests were positive with bencydamine and indomethacin (both indolacetic acid derivatives), piroxicam and fepradinol. We think that our results could not be explained due to cross-reactivity, and that multiple sensitization was more likely. PMID:8864624

  20. Prescription patterns and drug use among pregnant women with febrile illnesses in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Birungi, Josephine; Yanow, Stephanie;

    2013-01-01

    Malaria is a public health problem in Uganda; affecting mainly women and children. Effective treatment has been hampered by over-diagnosis and over-treatment with anti-malarial drugs among patients presenting with fever. In order to understand the effect of drug pressure on sulfadoxine......-pyrimethamine (SP) resistance in pregnancy, a sample of pregnant women presenting with fever in out-patient clinics was studied. The main objective was to assess prescription patterns and drug use in pregnancy especially SP; and draw implications on the efficacy of SP for intermittent preventive treatment of...... malaria in pregnancy (IPTp)....

  1. Stimuli-sensitive hydrogels: A novel ophthalmic drug delivery system

    Directory of Open Access Journals (Sweden)

    Singh Vinod

    2010-01-01

    Full Text Available Background: Stimuli-sensitive hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids on stimulation, such as pH, temperature and ionic change. Aim: To develop hydrogels that are sensitive to stimuli, i.e. pH, in the cul-de-sac of the eye for providing a prolonged effect and increased bioavailability with reduction in frequency of administration. Materials and Methods: Hydrogels were formulated by using timolol maleate as the model drug, polyacrylic acid as the gelling agents, hydroxyl ethyl cellulose as the viscolizer and sodium chloride as the isotonic agent. Stirring of ingredients in pH 4 phosphate buffer at high speed was carried out. The dynamic dialysis technique was used for drug release studies. In vivo study for reduction in intraocular pressure was carried out by using albino rabbits. Statistical Analysis: Drug release studies data were used for statistical analysis in first-order plots, Higuchi plots and Peppas exponential plots. Student t-test was performed for in vivo study. Results: Viscosity of the hydrogel increases from 3.84 cps to 9.54 cps due to change in pH 4 to pH 7.4. The slope value of the Peppas equation was found to be 0.3081, 0.3743 and 0.2964. Up to 80% of drug was released in an 8 h drug release study. Sterile hydrogels with no ocular irritation were obtained. Conclusions: Hydrogels show increase in viscosity due to change in pH. Hydrogels were therapeutically effacious, stable, non-irritant and showed Fickian diffusion. In vivo results clearly show a prolonged reduction in intraocular pressure, which was helpful for reduction in the frequency of administration.

  2. Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection [v2; ref status: indexed, http://f1000r.es/53d

    Directory of Open Access Journals (Sweden)

    Veljko Veljkovic

    2015-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Veljko Veljkovic

    2015-02-01

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

  4. Distribution and drug sensitivity of pathogens in diabetic foot ulcer secretions

    Institute of Scientific and Technical Information of China (English)

    李惠琴

    2013-01-01

    Objective To investigate the distribution and drug sensitivity of pathogens isolated from diabetic foot ulcer(DFU) secretions. Methods A retrospective study was carried out on the distribution and drug sensitivity of pathogens isolated from the secretions of 218 DFU

  5. ph Sensitive hydrogel as colon specific drug delivery

    International Nuclear Information System (INIS)

    γ-radiation induced graft copolymerization and crosslinking was for the synthesis of ph-sensitive hydrogels composed of poly (vinyl pyrrolidone) acrylic acid. The prepared hydrogels were subjected to swelling test to evaluate the effects of ph and ionic strength of the surrounding solution. Drastic changes in the swelling parameters where observed by changing the surrounding solution ph values. The release of ibuprofen from hydrogels was monitored as a function of time at ph 1 and ph 7 in order to evaluate the prepared copolymer ability for colon- specific drug carrier uses.

  6. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

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

    2016-01-01

    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. PMID:26858018

  7. A Cluster Randomised Trial Introducing Rapid Diagnostic Tests into Registered Drug Shops in Uganda: Impact on Appropriate Treatment of Malaria

    OpenAIRE

    Mbonye, AK; Magnussen, P; Lal, S; Hansen, KS; Cundill, B; Chandler, C.; Clarke, SE

    2015-01-01

    Background Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therap...

  8. Roles of sildenafil in enhancing drug sensitivity in cancer.

    Science.gov (United States)

    Shi, Zhi; Tiwari, Amit K; Patel, Atish S; Fu, Li-Wu; Chen, Zhe-Sheng

    2011-06-01

    The phenomenon of multidrug resistance (MDR) has decreased the hope for successful cancer chemotherapy. The ATP-binding cassette (ABC) transporter superfamily is the largest transmembrane family. The overexpression of ABC transporters is a major determinant of MDR in cancer cells both in vitro and in vivo. Unfortunately, until recently, most of the strategies used to surmount ABC-transporter-mediated MDR have had limited success. An ideal modulator of MDR would be one that has a low liability to induce toxicity and alter the pharmacokinetic profile of antineoplastic drugs. Sildenafil, an inhibitor of cGMP-specific phosphodiesterase type 5, was found to significantly reverse ABC-transporter-mediated MDR. Our results indicate that sildenafil has differential inhibitory effects on ABC transporters: It significantly decreases the efflux activity of ABCB1 and ABCG2, but has no significant effects on ABCC1. Emerging evidence indicates that sildenafil and other phosphodiesterase type 5 inhibitors may enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs. PMID:21610107

  9. Metabolic engineering of E.coli for the production of a precursor to artemisinin, an anti-malarial drug [Chapter 25 in Manual of Industrial Microbiology and Biotechnology, 3rd edition

    Energy Technology Data Exchange (ETDEWEB)

    Petzold, Christopher; Keasling, Jay

    2011-07-18

    This document is Chapter 25 in the Manual of Industrial Microbiology and Biotechnology, 3rd edition. Topics covered include: Incorporation of Amorpha-4,11-Diene Biosynthetic Pathway into E. coli; Amorpha-4,11-Diene Pathway Optimization; "-Omics" Analyses for Increased Amorpha-4,11-Diene Production; Biosynthetic Oxidation of Amorpha-4,11-Diene.

  10. Microfluidic Synthesis of pH-Sensitive Multicompartmental Microparticles for Multimodulated Drug Release.

    Science.gov (United States)

    Kim, Hyeon Ung; Choi, Dae Gun; Roh, Yoon Ho; Shim, Min Suk; Bong, Ki Wan

    2016-07-01

    Stimuli-responsive carriers releasing multiple drugs have been researched for synergistic combinatorial cancer treatment with reduced side-effects. However, previously used drug carriers have limitations in encapsulating multiple drug components in a single carrier and releasing each drug independently. In this work, pH-sensitive, multimodulated, anisotropic drug carrier particles are synthesized using an acid-cleavable polymer and stop-flow lithography. The particles exhibit a faster drug release rate at the acidic pH of tumors than at physiological pH, demonstrating their potential for tumor-selective drug release. The drug release rate of the particles can be adjusted by controlling the monomer composition. To accomplish multimodulated drug release, multicompartmental particles are synthesized. The drug release profile of each compartment is programmed by tailoring the monomer composition. These pH-sensitive, multicompartmental particles are promising drug carriers enabling tumor-selective and multimodulated release of multiple drugs for synergistic combination cancer therapy. PMID:27197594

  11. Modelling the impact of intermittent preventive treatment for malaria on selection pressure for drug resistance

    Directory of Open Access Journals (Sweden)

    Cissé Badara

    2007-01-01

    Full Text Available Abstract Background Intermittent preventive treatment (IPT is a promising intervention for malaria control, although there are concerns about its impact on drug resistance. Methods The key model inputs are age-specific values for a baseline anti-malarial dosing rate, b parasite prevalence, and c proportion of those treated with anti-malarials (outside IPT who are infected. These are used to estimate the immediate effect of IPT on the genetic coefficient of selection (s. The scenarios modelled were year round IPT to infants in rural southern Tanzania, and three doses at monthly intervals of seasonal IPT in Senegal. Results In the simulated Tanzanian setting, the model suggests a high selection pressure for drug resistance, but that IPTi would only increase this by a small amount (4.4%. The percent change in s is larger if parasites are more concentrated in infants, or if baseline drug dosing is less common or less specific. If children aged up to five years are included in the Tanzanian scenario then the predicted increase in s rises to 31%. The Senegalese seasonal IPT scenario, in children up to five years, results in a predicted increase in s of 16%. Conclusion There is a risk that the useful life of drugs will be shortened if IPT is implemented over a wide childhood age range. On the other hand, IPT delivered only to infants is unlikely to appreciably shorten the useful life of the drug used.

  12. Development of an in vitro drug sensitivity assay for Trichuris muris first-stage larvae

    OpenAIRE

    Wimmersberger, David; Tritten, Lucienne; Keiser, Jennifer

    2013-01-01

    Background Trichuriasis represents a major public health problem in the developing world and is regarded as a neglected disease. Albendazole and mebendazole, the two drugs of choice against trichuriasis display only moderate cure rates, hence alternative drugs are needed. To identify candidate compounds, in vitro drug sensitivity testing currently relies on the adult Trichuris muris motility assay. The objective of the present study was to develop a simple and cost-effective drug sensitivity ...

  13. Protein microarray: sensitive and effective immunodetection for drug residues

    Directory of Open Access Journals (Sweden)

    Zer Cindy

    2010-02-01

    Full Text Available Abstract Background Veterinary drugs such as clenbuterol (CL and sulfamethazine (SM2 are low molecular weight ( Results The artificial antigens were spotted on microarray slides. Standard concentrations of the compounds were added to compete with the spotted antigens for binding to the antisera to determine the IC50. Our microarray assay showed the IC50 were 39.6 ng/ml for CL and 48.8 ng/ml for SM2, while the traditional competitive indirect-ELISA (ci-ELISA showed the IC50 were 190.7 ng/ml for CL and 156.7 ng/ml for SM2. We further validated the two methods with CL fortified chicken muscle tissues, and the protein microarray assay showed 90% recovery while the ci-ELISA had 76% recovery rate. When tested with CL-fed chicken muscle tissues, the protein microarray assay had higher sensitivity (0.9 ng/g than the ci-ELISA (0.1 ng/g for detection of CL residues. Conclusions The protein microarrays showed 4.5 and 3.5 times lower IC50 than the ci-ELISA detection for CL and SM2, respectively, suggesting that immunodetection of small molecules with protein microarray is a better approach than the traditional ELISA technique.

  14. Deficient supplies of drugs for life threatening diseases in an African community

    Directory of Open Access Journals (Sweden)

    Andrew Marit

    2007-06-01

    Full Text Available Abstract Background In Malawi essential drugs are provided free of charge to patients at all public health facilities in order to ensure equitable access to health care. The country thereby spends about 30% of the national health budget on drugs. In order to investigate the level of drug shortages and eventually find the reasons for the drugs shortages in Malawi, we studied the management of the drug supplies for common and life threatening diseases such as pneumonia and malaria in a random selection of health centres. Methods In July and August 2005 we visited eight out of a total of 37 health centres chosen at random in the Lilongwe District, Malawi. We recorded the logistics of eight essential and widely used drugs which according to the treatment guidelines should be available at all health centres. Five drugs are used regularly to treat pneumonia and three others to treat acute malaria. Out-of-stock situations in the course of one year were recorded retrospectively. We compared the quantity of each drug recorded on the Stock Cards with the actual stock of the drug on the shelves at the time of audit. We reviewed 8,968 Patient Records containing information on type and amount of drugs prescribed during one month. Results On average, drugs for treating pneumonia were out of stock for six months during one year of observation (median value 167 days; anti-malarial drugs were lacking for periods ranging from 42 to138 days. The cross-sectional audit was even more negative, but here too the situation was more positive for anti-malarial drugs. The main reason for the shortage of drugs was insufficient deliveries from the Regional Medical Store. Benzyl penicillin was in shortest supply (4% received. The median value for non-availability was 240 days in the course of a year. The supply was better for anti-malarial drugs, except for quinine injections (9 %. Only 66 % of Stock Card records of quantities received were reflected in Patient Records

  15. Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Pascual Aurélie

    2012-02-01

    Full Text Available Abstract Background The aim of the present work was to assess i ex vivo activity of pyronaridine (PND and piperaquine (PPQ, as new components of artemisinin-based combination therapy (ACT, to define susceptibility baseline, ii their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ, lumefantrine (LMF, mefloquine (MQ, artesunate (AS and dihydroartemisinin (DHA against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii in vitro cross-resistance with other quinoline drugs, chloroquine (CQ or quinine (QN. Methods The susceptibility of the 181 P. falciparum isolates to the nine anti-malarial drugs was assessed using the standard 42-hours 3H-hypoxanthine uptake inhibition method. Results The IC50 values for PND ranged from 0.55 to 80.0 nM (geometric mean = 19.9 nM and from 11.8 to 217.3 nM for PPQ (geometric mean = 66.8 nM. A significant positive correlation was shown between responses to PPQ and PND responses (rho = 0.46 and between PPQ and MDAQ (rho = 0.30. No significant correlation was shown between PPQ IC50 and responses to other anti-malarial drugs. A significant positive correlation was shown between responses to PND and MDAQ (rho = 0.37, PND and LMF (rho = 0.28, PND and QN (rho = 0.24, PND and AS (rho = 0.19, PND and DHA (rho = 0.18 and PND and CQ (rho = 0.16. All these coefficients of correlation are too low to suggest cross-resistance between PPQ or PND and the other drugs. Conclusions In this study, the excellent anti-malarial activity of PPQ and PND was confirmed. The absence of cross-resistance with quinolines and artemisinin derivatives is consistent with the efficacy of the combinations of PPQ and DHA or PND and AS in areas where parasites are resistant to conventional anti-malarial drugs.

  16. [Immunotropic and antihypoxant therapy of experimental drug-sensitive and drug-resistant tuberculosis].

    Science.gov (United States)

    Sukhanov, D S; Vinogradova, T I; Demidik, S N; Zabolotnyh, N V; Vasilieva, S N; Kovalenko, A L; Vitovskaya, M L

    2013-01-01

    The results of pre-clinical research of cycloferon, remaxol and runihol on the model of experimental generalized tuberculosis, caused by the MBT with a different spectrum of drug sensitivity are presented. A considerable increase of the curative effect of the therapy with the used of cycloferon and remaxol. There was manifested the strengthening of lung clearance from the office, reducing the prevalence of specific inflammation in the lungs of the index of lung damage, stimulation of sorption and destructive ability of peritoneal macrophages, inhibited in the course of development of experimental tuberculosis infection. Runihol has no impact on the effectiveness of chemotherapy in the absence of a stimulating influence on the phagocytic function of the peritoneal macrophages. PMID:23805718

  17. Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Freundlich, Joel S.; Wang, Feng; Vilchèze, Catherine; Gulten, Gulcin; Langley, Robert; Schiehser, Guy A.; Jacobus, David P.; Jacobs, Jr., William R.; Sacchettini, James C.; (Einstein); (TAM); (Jacobus)

    2009-06-30

    Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis. Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC{sub 50} value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 {mu}g mL{sup -1} (13 {mu}M), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.

  18. Pressure-sensitive adhesives for transdermal drug delivery systems.

    Science.gov (United States)

    Tan; Pfister

    1999-02-01

    Adhesives are a critical component in transdermal drug delivery (TDD) devices. In addition to the usual requirements of functional adhesive properties, adhesives for TDD applications must have good biocompatibility with the skin, chemical compatibility with the drug, various components of the formulation, and provide consistent, effective delivery of the drug. This review discusses the three most commonly used adhesives (polyisobutylenes, polyacrylates and silicones) in TDD devices, and provides an update on recently introduced TDD products and recent developments of new adhesives. PMID:10234208

  19. 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.......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...... 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...

  20. Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells.

    LENUS (Irish Health Repository)

    Doherty, Ben

    2014-01-01

    KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer.

  1. Shear-stress sensitive lenticular vesicles for targeted drug delivery

    Science.gov (United States)

    Holme, Margaret N.; Fedotenko, Illya A.; Abegg, Daniel; Althaus, Jasmin; Babel, Lucille; Favarger, France; Reiter, Renate; Tanasescu, Radu; Zaffalon, Pierre-Léonard; Ziegler, André; Müller, Bert; Saxer, Till; Zumbuehl, Andreas

    2012-08-01

    Atherosclerosis results in the narrowing of arterial blood vessels and this causes significant changes in the endogenous shear stress between healthy and constricted arteries. Nanocontainers that can release drugs locally with such rheological changes can be very useful. Here, we show that vesicles made from an artificial 1,3-diaminophospholipid are stable under static conditions but release their contents at elevated shear stress. These vesicles have a lenticular morphology, which potentially leads to instabilities along their equator. Using a model cardiovascular system based on polymer tubes and an external pump to represent shear stress in healthy and constricted vessels of the heart, we show that drugs preferentially release from the vesicles in constricted vessels that have high shear stress.

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

    OpenAIRE

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

    2013-01-01

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

  3. A cluster randomised trial introducing rapid diagnostic tests into registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Magnussen, Pascal; Lal, Sham; Hansen, Kristian S; Cundill, Bonnie; Chandler, Clare; Clarke, Siân E

    2015-01-01

    introducing mRDTs in registered drug shops was implemented in 20 geographical clusters of drug shops in Mukono district, central Uganda. Ten clusters were randomly allocated to the intervention (diagnostic confirmation of malaria by mRDT followed by ACT) and ten clusters to the control arm (presumptive......BACKGROUND: Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the...... impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. METHODS: A cluster-randomized trial of...

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

    Directory of Open Access Journals (Sweden)

    Wurtz Nathalie

    2012-06-01

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

  5. Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking

    OpenAIRE

    Wheeler, Daniel S.; Robble, Mykel A.; Hebron, Emily M.; Dupont, Matthew J.; Ebben, Amanda L.; Wheeler, Robert A

    2015-01-01

    Drug-associated cues have profound effects on an addict's emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all exper...

  6. Repurposing of antiparasitic drugs: the hydroxy-naphthoquinone buparvaquone inhibits vertical transmission in the pregnant neosporosis mouse model.

    Science.gov (United States)

    Müller, Joachim; Aguado-Martínez, Adriana; Manser, Vera; Wong, Ho Ning; Haynes, Richard K; Hemphill, Andrew

    2016-01-01

    The three anti-malarial drugs artemiside, artemisone, and mefloquine, and the naphthoquinone buparvaquone known to be active against theileriosis in cattle and Leishmania infections in rodents, were assessed for activity against Neospora caninum infection. All four compounds inhibited the proliferation of N. caninum tachyzoites in vitro with IC50 in the sub-micromolar range, but artemisone and buparvaquone were most effective (IC50 = 3 and 4.9 nM, respectively). However, in a neosporosis mouse model for cerebral infection comprising Balb/c mice experimentally infected with the virulent isolate Nc-Spain7, the three anti-malarial compounds failed to exhibit any activity, since treatment did not reduce the parasite burden in brains and lungs compared to untreated controls. Thus, these compounds were not further evaluated in pregnant mice. On the other hand, buparvaquone, shown earlier to be effective in reducing the parasite load in the lungs in an acute neosporosis disease model, was further assessed in the pregnant mouse model. Buparvaquone efficiently inhibited vertical transmission in Balb/c mice experimentally infected at day 7 of pregnancy, reduced clinical signs in the pups, but had no effect on cerebral infection in the dams. This demonstrates proof-of-concept that drug repurposing may lead to the discovery of an effective compound against neosporosis that can protect offspring from vertical transmission and disease. PMID:26883424

  7. Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

    Science.gov (United States)

    Jarrett, Angela M; Gao, Yajing; Hussaini, M Yousuff; Cogan, Nicholas G; Katz, David F

    2016-05-01

    Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization. PMID:27012224

  8. Drug predictive cues activate aversion-sensitive striatal neurons that encode drug seeking.

    Science.gov (United States)

    Wheeler, Daniel S; Robble, Mykel A; Hebron, Emily M; Dupont, Matthew J; Ebben, Amanda L; Wheeler, Robert A

    2015-05-01

    Drug-associated cues have profound effects on an addict's emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, self-administration sessions were preceded by a taste cue that signaled delayed drug availability. Assessments of hedonic responses indicated that this delay cue became aversive during training. Both the self-administration behavior and the immediate cue were subsequently extinguished in the absence of cocaine. After extinction of self-administration behavior, the presentation of the aversive delay cue reinstated drug seeking. In vivo electrophysiology and voltammetry recordings in the nucleus accumbens measured the neural responses to both the delay and immediate drug cues after extinction. Interestingly, the presentation of the delay cue simultaneously decreased dopamine signaling and increased excitatory encoding of the immediate cue. Most importantly, the delay cue selectively enhanced the baseline activity of neurons that would later encode drug seeking. Together these observations reveal how cocaine cues can modulate not only affective state, but also the neurochemical and downstream neurophysiological environment of striatal circuits in a manner that promotes drug seeking. PMID:25948270

  9. Delivering anti-cancer drugs with endosomal pH-sensitive anti-cancer liposomes.

    Science.gov (United States)

    Moku, Gopikrishna; Gulla, Suresh Kumar; Nimmu, Narendra Varma; Khalid, Sara; Chaudhuri, Arabinda

    2016-04-22

    Numerous prior studies have been reported on the use of pH-sensitive drug carriers such as micelles, liposomes, peptides, polymers, nanoparticles, etc. that are sensitive to the acidic (pH = ∼6.5) microenvironments of tumor tissues. Such systems have been primarily used in the past as effective drug/gene/microRNA carriers for releasing their anti-cancer payloads selectively to tumor cells/tissues. Herein, we report on the development of new liposomal drug carriers prepared from glutamic acid backbone-based cationic amphiphiles containing both endosomal pH-sensitive histidine as well as cellular uptake & solubility enhancing guanidine moieties in their polar head-group regions. The most efficient one among the four presently described endosomal pH-sensitive liposomal drug carriers not only effectively delivers potent anti-cancer drugs (curcumin & paclitaxel) to mouse tumor, but also significantly contributes to inhibiting mouse tumor growth. The findings in the in vitro mechanistic studies are consistent with apoptosis of tumor cells being mediated through increased cell cycle arrest in the G2/M phase. Findings in the FRET assay and in vitro drug release studies conducted with the liposomes of the most efficient pH-sensitive lipid demonstrated its pH dependent fusogenic and controlled curcumin release properties. Importantly, the presently described liposomal formulation of curcumin & paclitaxel enhanced overall survivability of tumor bearing mice. To the best of our knowledge, the presently described system (curcumin, paclitaxel and liposomal carrier itself) is the first of its kind pH-sensitive liposomal formulation of potent chemotherapeutics in which the liposomal drug itself exhibits significant mouse tumor growth inhibition properties. PMID:26806172

  10. Integrating Domain Specific Knowledge and Network Analysis to Predict Drug Sensitivity of Cancer Cell Lines.

    Science.gov (United States)

    Kim, Sebo; Sundaresan, Varsha; Zhou, Lei; Kahveci, Tamer

    2016-01-01

    One of fundamental challenges in cancer studies is that varying molecular characteristics of different tumor types may lead to resistance to certain drugs. As a result, the same drug can lead to significantly different results in different types of cancer thus emphasizing the need for individualized medicine. Individual prediction of drug response has great potential to aid in improving the clinical outcome and reduce the financial costs associated with prescribing chemotherapy drugs to which the patient's tumor might be resistant. In this paper we develop a network based classifier (NBC) method for predicting sensitivity of cell lines to anticancer drugs from transcriptome data. In the literature, this strategy has been used for predicting cancer types. Here, we extend it to estimate sensitivity of cells from different tumor types to various anticancer drugs. Furthermore, we incorporate domain specific knowledge such as the use of apoptotic gene list and clinical dose information in our method to impart biological significance to the prediction. Our experimental results suggest that our network based classifier (NBC) method outperforms existing classifiers in estimating sensitivity of cell lines for different drugs. PMID:27607242

  11. Drug sensitivity patterns of HHV8 carrying body cavity lymphoma cell lines

    Directory of Open Access Journals (Sweden)

    Konya Jozsef

    2011-10-01

    Full Text Available Abstract Background Primary effusion lymphoma (PEL is a rare KSHV/HHV8-associated high-grade non-Hodgkin's lymphoma (NHL of B-cell origin, characterized by serous effusions in body cavities. Most patients are HIV-infected men with severe immunosuppression and other HHV8-associated diseases such as Kaposi's sarcoma (KS. The prognosis for those infected is poor, with a median survival of less than 6 months in most cohorts. Sustained complete remission is rare. High-dose chemotherapy regimens are used to improve remission rate and survival. The aim of the present study was to compare the drug sensitivity pattern of the available primary effusion (body cavity based lymphoma-derived cell lines in order to find additional, potentially effective drugs that are not included in current chemotherapy treatment protocols. Methods We have analyzed 11 cell lines against 27 frequently used cytostatic drugs in short term (3 days survival assays using automated high throughput confocal microscopy. Results All cell lines showed a distinct, individual drug sensitivity pattern. Considering the in vitro used and clinically achieved drug concentration, Vinorelbine, Paclitaxel, Epirubicin and Daunorubicin were the most effective drugs. Conclusions We suggest that inclusion of the above drugs into PEL chemotherapy protocols may be justified. The heterogeneity in the drug response pattern however indicated that assay-guided individualized therapy might be required to optimize therapeutic response.

  12. Use of drugs, perceived drug efficacy and preferred providers for febrile children: implications for home management of fever

    Directory of Open Access Journals (Sweden)

    Rutebemberwa Elizeus

    2009-06-01

    Full Text Available Abstract Background Community distribution of anti-malarials and antibiotics has been recommended as a strategy to reduce the under-five mortality due to febrile illnesses in sub-Saharan Africa. However, drugs distributed in these interventions have been considered weak by some caretakers and utilization of community medicine distributors has been low. The aim of the study was to explore caretakers' use of drugs, perceptions of drug efficacy and preferred providers for febrile children in order to make suggestions for community management of pneumonia and malaria. Methods The study was conducted in eastern Uganda using four focus group discussions with fathers and mothers of children under five; and eight key informant interviews with health workers in government and non-governmental organization facilities, community medicine distributors, and attendants in drug shops and private clinics. Caretakers were asked the drugs they use for treatment of fever, why they considered them efficacious, and the providers they go to and why they go there. Health providers were interviewed on their opinions of caretakers' perceptions of drugs and providers. Analysis was done using content analysis. Results Drugs that have been phased out as first-line treatment for malaria, such as chloroquine and sulphadoxine/pyrimethamine, are still perceived as efficacious. Use of drugs depended on perception of the disease, cost and drug availability. There were divergent views about drug efficacy concerning drug combinations, side effects, packaging, or using drugs over time. Bitter taste and high cost signified high efficacy for anti-malarials. Government facilities were preferred for conducting diagnostic investigations and attending to serious illnesses, but often lacked drugs and did not treat people fast. Drug shops were preferred for having a variety of drugs, attending to clients promptly and offering treatment on credit. However, drug shops were considered

  13. Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells

    OpenAIRE

    Ayako Nakano; Daisuke Tsuji; Hirokazu Miki; Qu Cui; Salah Mohamed El Sayed; Akishige Ikegame; Asuka Oda; Hiroe Amou; Shingen Nakamura; Takeshi Harada; Shiro Fujii; Kumiko Kagawa; Kyoko Takeuchi; Akira Sakai; Shuji Ozaki

    2011-01-01

    Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) suppressed ATP production in malignant cells, and restored the retention of daunorubic...

  14. PRECLINICAL DRUG TRIALS IN THE mdx MOUSE: ASSESSMENT OF RELIABLE AND SENSITIVE OUTCOME MEASURES

    OpenAIRE

    SPURNEY, CHRISTOPHER F.; Gordish-Dressman, Heather; Alfredo D Guerron; Sali, Arpana; Gouri S Pandey; Rawat, Rashmi; van der Meulen, Jack H; Cha, Hee-Jae; Pistilli, Emidio E.; Partridge, Terence A.; Hoffman, Eric P; Nagaraju, Kanneboyina

    2009-01-01

    The availability of animal models for Duchenne muscular dystrophy has led to extensive preclinical research on potential therapeutics. Few studies have focused on reliability and sensitivity of endpoints for mdx mouse drug trials. Therefore, we sought to compare a wide variety of reported and novel endpoint measures in exercised mdx and normal control mice at 10, 20, and 40 weeks of age. Statistical analysis as well as power calculations for expected effect sizes in mdx preclinical drug trial...

  15. Lactate as a Novel Quantitative Measure of Viability in Schistosoma mansoni Drug Sensitivity Assays

    OpenAIRE

    Howe, Stephanie; Zöphel, Dorina; Subbaraman, Harini; Unger, Clemens; Held, Jana; Engleitner, Thomas; Hoffmann, Wolfgang H.; Kreidenweiss, Andrea

    2014-01-01

    Whole-organism compound sensitivity assays are a valuable strategy in infectious diseases to identify active molecules. In schistosomiasis drug discovery, larval-stage Schistosoma allows the use of a certain degree of automation in the screening of compounds. Unfortunately, the throughput is limited, as drug activity is determined by manual assessment of Schistosoma viability by microscopy. To develop a simple and quantifiable surrogate marker for viability, we targeted glucose metabolism, wh...

  16. A pH-Sensitive Injectable Nanoparticle Composite Hydrogel for Anticancer Drug Delivery

    OpenAIRE

    Yuanfeng Ye; Xiaohong Hu

    2016-01-01

    According to previous reports, low pH-triggered nanoparticles were considered to be excellent carriers for anticancer drug delivery, for the reason that they could trigger encapsulated drug release at mild acid environment of tumor. Herein, an acid-sensitive β-cyclodextrin derivative, namely, acetalated-β-cyclodextrin (Ac-β-CD), was synthesized by acetonation and fabricated to nanoparticles through single oil-in-water (o/w) emulsion technique. At the same time, camptothecin (CPT), a hydrophob...

  17. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. PMID:26939698

  18. Tetrathiomolybdate sensitizes ovarian cancer cells to anticancer drugs doxorubicin, fenretinide, 5-fluorouracil and mitomycin C

    International Nuclear Information System (INIS)

    Our recent study showed that tetrathiomolybdate (TM), a drug to treat copper overload disorders, can sensitize drug-resistant endometrial cancer cells to reactive oxygen species (ROS)-generating anticancer drug doxorubicin. To expand these findings in the present study we explore TM efficacy in combination with a spectrum of ROS-generating anticancer drugs including mitomycin C, fenretinide, 5-fluorouracil and doxorubicin in ovarian cancer cells as a model system. The effects of TM alone or in combination with doxorubicin, mitomycin C, fenretinide, or 5-fluorouracil were evaluated using a sulforhodamine B assay. Flow cytometry was used to detect the induction of apoptosis and ROS generation. Immunoblot analysis was carried out to investigate changes in signaling pathways. TM potentiated doxorubicin-induced cytotoxicity and modulated key regulators of apoptosis (PARP, caspases, JNK and p38 MAPK) in SKOV-3 and A2780 ovarian cancer cell lines. These effects were linked to the increased production of ROS, as shown in SKOV-3 cells. ROS scavenging by ascorbic acid blocked the sensitization of cells by TM. TM also sensitized SKOV-3 to mitomycin C, fenretinide, and 5-fluorouracil. The increased cytotoxicity of these drugs in combination with TM was correlated with the activity of ROS, loss of a pro-survival factor (e.g. XIAP) and the appearance of a pro-apoptotic marker (e.g. PARP cleavage). Our data show that TM increases the efficacy of various anticancer drugs in ovarian cancer cells in a ROS-dependent manner

  19. Drug procurement, the Global Fund and misguided competition policies

    Directory of Open Access Journals (Sweden)

    Hess Kimberly

    2009-12-01

    Full Text Available Abstract In an effort to increase competition and decrease price, the Global Fund to Fight AIDS, Tuberculosis and Malaria recently began asking some grant recipients to use international competitive bidding processes for certain drug purchases. Unfortunately, for countries like Kenya, this request has caused more harm than good. After awarding the tender for its annual supply of the anti-malarial artemether-lumefantrine to the lowest bidder, Ajanta Pharma, Kenya experienced wide stock-outs in part due to the company's inability to supply the order in full and on time. Similar problems could arise in Uganda. Despite Kenya's experience, Uganda has awarded its next tender for artemether-lumefantrine to Ajanta Pharma. Uganda is already facing wide stock-outs and risks exacerbating an already dire situation the longer it takes to fulfil the procurement contract. A tender process based primarily on price cannot account for a company's ability to consistently supply sufficient product in time.

  20. Triclosan derivatives: Towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis

    OpenAIRE

    Joel S. Freundlich; Wang, Feng; Vilchèze, Catherine; Gulten, Gulcin; Langley, Robert; Schiehser, Guy A.; Jacobus, David P.; Jacobs, William R.; Sacchettini, James C.

    2009-01-01

    Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase of mycolic acid biosynthesis, whose inhibition leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted derivatives of triclosan was developed. Two groups of triclosan derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibi...

  1. New double-walled PH-sensitive hydrogel systems containing nanoparticle drug for colon-specific drug delivery

    International Nuclear Information System (INIS)

    Double-walled (DW) with a Core of mixture of nano or microparticles of carboxymethyl cellulose sodium (CMC) salt and model drug olsalazine [3, 3-azobis (6-hydroxy benzoic acid)] (OSZ) as an azo derivatives of 5-aminosalicylic acid (5-ASA) and an external coat of cross-linked copolymers of (acrylamido methyl) cellulose acetate butyrate (AMCAB) and methacrylic acid (MAA) with various amounts of 1, 6-hexandiol diacrylate (HDD) are considered cross-linking agents (CA). The core with nano composite was prepared by freeze drying method and then used as nuclei for subsequent shell copolymerization. The structure of core was characterized with scanning electron microscopy. The double-walled hydrogels were characterized by differential scanning colorimetry and FT-IR. Studies of drug release were carried out in enzyme-free , simulated gastric and intestinal fluids (SGF and SIF, respectively). The drug-release profiles indicated that the amount of drug released depended ed on the shell layer composition. The releasing was modulated by the amount of cross-linking in shell layer. Bused on the great difference in hydrolysis rates at pH 1 and 7.4, these pH-sensitive hydrogels appear to be good candidates, for colon-specific drug delivery

  2. Anticancer drug clustering in lung cancer based on gene expression profiles and sensitivity database

    International Nuclear Information System (INIS)

    The effect of current therapies in improving the survival of lung cancer patients remains far from satisfactory. It is consequently desirable to find more appropriate therapeutic opportunities based on informed insights. A molecular pharmacological analysis was undertaken to design an improved chemotherapeutic strategy for advanced lung cancer. We related the cytotoxic activity of each of commonly used anti-cancer agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin (CDDP), and carboplatin (CBDCA)) to corresponding expression pattern in each of the cell lines using a modified NCI program. We performed gene expression analysis in lung cancer cell lines using cDNA filter and high-density oligonucleotide arrays. We also examined the sensitivity of these cell lines to these drugs via MTT assay. To obtain our reproducible gene-drug sensitivity correlation data, we separately analyzed two sets of lung cancer cell lines, namely 10 and 19. In our gene-drug correlation analyses, gemcitabine consistently belonged to an isolated cluster in a reproducible fashion. On the other hand, docetaxel, paclitaxel, 5-FU, SN-38, CBDCA and CDDP were gathered together into one large cluster. These results suggest that chemotherapy regimens including gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Gene expression-drug sensitivity correlations, as provided by the NCI program, may yield improved therapeutic options for treatment of specific tumor types

  3. Thermo-sensitive and photoluminescent hydrogels: Synthesis, characterization, and their drug-release property

    International Nuclear Information System (INIS)

    Multifunctional hydrogels that simultaneously possess semi-interpenetrating networks structure, strong photoluminescence, and temperature sensitivity were successfully fabricated based on the crosslink of poly(acrylamide) (PAAm) in the presence of poly(N-isopropylacrylamide) (PNIPAM) and CdTe quantum dots (QDs) at a mild condition. With the increase of external temperature, the photoluminescence (PL) intensity and emission peak of the hydrogels gradually decreased and red-shifted, respectively. Decreasing the temperature, the PL intensity and emission peak of the hydrogels could back to their initial values again. Moreover, drug-release experiments on the multifunctional hydrogels demonstrated that the release rate can be tuned by the environmental temperature and the content of PNIPAM. In addition, biocompatible hyperbranched polyglycerol functionalized QDs (QD-HPGs) instead of pristine QDs can also be incorporated into the hydrogels, affording biocompatible hydrogels which could still exhibit temperature-sensitive photoluminescence and drug-release behaviors. Highlights: → Multifunctional hydrogels that simultaneously possess semi-interpenetrating networks structure, strong photoluminescence, and thermo-sensitive optical and drug-release behaviors were presented for the first time. → These multifunctional hydrogels can be facilely fabricated through the crosslink of poly(acrylamide) in the presence of poly(N-isopropylacrylamide) and CdTe quantum dots at a mild condition. → It is believed that the multifunctional hydrogels will find potential applications in thermo-sensitive devices and drug delivery.

  4. Nosocomial Infections and Drug Susceptibility Patterns in Methicillin Sensitive and Methicillin Resistant Staphylococcus aureus

    OpenAIRE

    Sharma, Nitish Kumar; Garg, Raina; Baliga, Shrikala; Bhat K., Gopalkrishna

    2013-01-01

    Aim: Staphylococcus aureus is one of the leading causes of nosocomial infections and is known for its ability to develop resistance to antibiotics. The drug susceptibility pattern of Methicillin Sensitive S. aureus (MSSA) and Methicillin Resistant S. aureus (MRSA) may vary.

  5. Study on Drug Delivery Systems (II) : Synthesis of Stimule Sensitive Polymers for Intelligent Drug Delivery Systems

    OpenAIRE

    Kaetsu, Isao; Morita, Yasuji

    1991-01-01

    [Abstract] The stimule-sensitive and responsive hydrogels were synthesized by radiation polymerization. The effects of copolymer composition, hydrolysis and crosslinking monomers on the electrical responsiveness were investigated and compared with those on the temperature responsiveness. It was observed that the content of electrolytic component strongly affected on the stimule responsiveness and the responses showed a maximum at a certain copolymer composition. It was suggested that the resp...

  6. Polypyrrole nanoparticles for tunable, pH-sensitive and sustained drug release

    Science.gov (United States)

    Samanta, Devleena; Meiser, Jana L.; Zare, Richard N.

    2015-05-01

    We report the development of a generalized pH-sensitive drug delivery system that can release any charged drug preferentially at the pH range of interest. Our system is based on polypyrrole nanoparticles (PPy NPs), synthesized via a simple one-step microemulsion technique. These nanoparticles are highly monodisperse, stable in solution over the period of a month, and have good drug loading capacity (~15 wt%). We show that PPy NPs can be tuned to release drugs at both acidic and basic pH by varying the pH, the charge of the drug, as well as by adding small amounts of charged amphiphiles. Moreover, these NPs may be delivered locally by immobilizing them in a hydrogel. Our studies show encapsulation within a calcium alginate hydrogel results in sustained release of the incorporated drug for more than 21 days. Such a nanoparticle-hydrogel composite drug delivery system is promising for treatment of long-lasting conditions such as cancer and chronic pain which require controlled, localized, and sustained drug release.

  7. Does the drug sensitivity of malaria parasites depend on their virulence?

    Directory of Open Access Journals (Sweden)

    Chan Brian HK

    2008-12-01

    Full Text Available Abstract Background Chemotherapy can prompt the evolution of classical drug resistance, but selection can also favour other parasite traits that confer a survival advantage in the presence of drugs. The experiments reported here test the hypothesis that sub-optimal drug treatment of malaria parasites might generate survival and transmission advantages for virulent parasites. Methods Two Plasmodium chabaudi lines, one derived from the other by serial passage, were used to establish avirulent and virulent infections in mice. After five days, infections were treated with various doses of pyrimethamine administered over 1 or 4 days. Virulence measures (weight and anaemia, parasite and gametocyte dynamics were followed until day 21. Results All treatment regimes reduced parasite and gametocyte densities, but infections with the virulent line always produced more parasites and more gametocytes than infections with the avirulent line. Consistent with our hypothesis, drug treatment was disproportionately effective against the less virulent parasites. Treatment did not affect the relative transmission advantage of the virulent line. Neither of the lines contained known mutations conferring classical drug resistance. Conclusion Drug-sensitivity of malaria parasites can be virulence-dependent, with virulent parasites more likely to survive sub-optimal treatment. If this proves to be general for a variety of drugs and parasite species, selection imposed by sub-optimal drug treatment could result in the evolution of more aggressive malaria parasites.

  8. Synthesis, characterization, and controllable drug release of pH-sensitive hybrid magnetic nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Zhou Lilin [Key Laboratory of Organic Optoelectronics and Molecular Engineering of the Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084 (China); Yuan Jinying [Key Laboratory of Organic Optoelectronics and Molecular Engineering of the Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084 (China)], E-mail: yuanjy@mail.tsinghua.edu.cn; Yuan Weizhong; Sui Xiaofeng [Key Laboratory of Organic Optoelectronics and Molecular Engineering of the Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084 (China); Wu Sizhu [Key Laboratory of Science and Technology of Controlled Chemical Reactions, Beijing University of Chemical Technology, Beijing 100029 (China); Li Zhaolong [Key Laboratory of Organic Optoelectronics and Molecular Engineering of the Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084 (China); Shen Dezhong [Department of Chemistry, Tsinghua University, Beijing 100084 (China)

    2009-09-15

    The synthesis of magnetite nanoparticles coated with pH-sensitive poly((2-dimethylamino) ethyl methacrylate) (PDMAEMA) via atom transfer radical polymerization (ATRP) for use as novel potential carriers for targeted drug delivery and controllable release is reported. The organic/inorganic hybrid nanoparticles were obtained with a narrow molecular weight distribution. The pH-sensitivity of the nanoparticles was investigated by the measurement of the pH dependence of hydrodynamic radius and the superparamagnetism was illustrated by vibrating sample magnetometer (VSM). The behavior of model drug phenolphthalein released from the nanoparticles indicated that the rate of drug release could be effectively controlled by altering the pH values of the environment.

  9. Synthesis and evaluation of sensitizer drug photorelease chemistry: Micro-optic method applied to singlet oxygen generation and drug delivery

    Science.gov (United States)

    Ghosh, Goutam

    This thesis summarizes a new micro-optic method for singlet oxygen generation and sensitizer drug delivery, which include i) synthesis and evaluation of a first generation device for drug delivery from native and fluorinated silica probe tips, ii) synthesis of PEG conjugated sensitizers to study phototoxicity in ovarian cancer cells, and iii) synthesis and evaluation of tris-PEGylated chlorin conjugated fluorinated silica for its future integration into the device to use as a 2nd generation device. A first generation micro-optic device was developed that works by sparging O2 gas and light generating cytotoxic singlet oxygen that cleaves the covalently attached drug (sensitizer) from the probe tip at the distal end of the fiber. The aim is to develop a 1st and 2nd generation device for site specific delivery of photosensitizer and singlet oxygen to overcome the challenges involved in systemic administration of the sensitizer. Synthesis and evaluation of drug (pheophorbide-a) delivery applying micro-optic method from native and fluorinated silica probe tip was achieved. The amount of sensitizer photocleavage depends on the loading level of sensitizer onto the probe tips. We also found that photorelease efficiency depends on the nature of the solvents where sensitizer is photocleaved. For example, no photorelease was observed in an aqueous solvent where sensitizer remained adsorbed to the native silica probe-tip. But, 90% photocleavage was obtained in octanol. A significant amount of photosensitizer (formate ester of pyropheophorbide- a) diffused into the liposome when photocleavage study was carried out in liposome. Substantial increase of photorelease was observed in organic solvent when pyropheophorbide-a (PPa) sensitizer was attached to the partially fluorinated porous Vycor glass. We also explored sensitizer photorelease from the fluorinated silica surface at various temperatures and we found that autocatalytic photorelease happened at room temperature and above

  10. Release study of Naproxen, A Modern drug from pH Sensitive Pullulan Acetate Microsphere

    Directory of Open Access Journals (Sweden)

    Mishra Bishwambhar

    2012-12-01

    Full Text Available The current study represents the latest and new advances in the investigations and applications of the pullulan the wonderful biomaterial which is produced from microbes (generally Aureobasidium sps. and its derivatives for its applications in the development of various therapeutic formulations. Basically pullulan is an exo-polysacharides which is non-carcinogenic, non-immunogenic and non-mutagenic without having any types of toxicological activities. Similar to dextran and other biopolymer it can be used as a plasma expander. The model drug for this studies i.e Naproxen was used which is one of the most potent non-steroid and anti-inflammatory drug for the treatment of various bone related diseases .In our study we have prepared pH sensitive naproxen-pullulan delivery system in which Pullulan acetate was synthesized by treating 2.5 gm of crude pullulan with 25 ml of formamide at 50°C. For the loading of drug 50 mg of Pullulan acetate was dissolved 5 ml of dichloromethane and to it 80 mg of Naproxen was added. The drug loading efficiency of the prepared microparticle was found to be 80%. The microsphere was also showing a pH sensitive swelling behaviour in Phosphate Buffer Saline (PBS buffer. The release profile of the drug loaded microsphere reveals that pH of the medium was influencing it at in vitro condition. Moreover the released amount of drug from the pullulan based microsphere at pH 7.2 was 75 times more than that at the pH 1.2. Therefore Pullulan acetate loaded with Naproxen is a useful polymerised materials for the development and formulation of pH sensitive drug.

  11. 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.

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

    Science.gov (United States)

    Flusberg, Deborah A.; Sorger, Peter K.

    2013-06-01

    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.

  13. The absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs.

    Science.gov (United States)

    Veldman, Robert Jan; Mita, Alain; Cuvillier, Olivier; Garcia, Virginie; Klappe, Karin; Medin, Jeffrey A; Campbell, John D; Carpentier, Stéphane; Kok, Jan Willem; Levade, Thierry

    2003-06-01

    Conversion of ceramide, a putative mediator of anticancer drug-induced apoptosis, into glucosylceramide, by the action of glucosylceramide synthase (GCS), has been implicated in drug resistance. Herein, we compared GM95 mouse melanoma cells deficient in GCS activity, with cells stably transfected with a vector encoding GCS (GM95/GCS). Enzymatic and metabolic analysis demonstrated that GM95/GCS cells expressed a fully functional enzyme, resulting in normal ceramide glycosylation. However, cytotoxicity assays, as well as caspase activation and cytochrome c release studies, did not reveal any difference between the two cell lines with respect to their sensitivity toward doxorubicin, vinblastine, paclitaxel, cytosine arabinoside, or short-chain ceramide analogs. Administration of doxorubicin resulted in ceramide accumulation in both cell lines, with similar kinetics and amplitude. Although glucosylceramide formation was detected in doxorubicin-treated GM95/GCS cells, metabolism of drug-induced ceramide did not appear to be instrumental in cell survival. Furthermore, N-(n-butyl)deoxynojirimycin, a potent and non-toxic GCS inhibitor, had no chemosensitizing effect on wild-type melanoma cells. Altogether, both genetic and pharmacological alterations of the cellular ceramide glycosylation capacity failed to sensitize melanoma cells to anticancer drugs, therefore moderating the importance of ceramide glucosylation in drug-resistance mechanisms. PMID:12692077

  14. The sensitivity of human tumour cells to quinone bioreductive drugs: what role for DT-diaphorase?

    Science.gov (United States)

    Robertson, N; Stratford, I J; Houlbrook, S; Carmichael, J; Adams, G E

    1992-08-01

    15 human tumour cell lines (lung, breast and colon) have been evaluated for their sensitivity to the quinone based anti-cancer drugs Mitomycin C, Porfiromycin, and EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-(IH-indole-4,7-dione)prop-beta- en-alpha-ol). Sensitivity has been compared with the intra-cellular levels of DT-diaphorase, an enzyme thought to be important in the reductive activation of these quinones. No correlation exists between levels of DT-diaphorase and sensitivity to Mitomycin C or Porfiromycin. However, for EO9 those cell lines showing highest levels of DT-diaphorase activity tend to be the most sensitive. PMID:1510692

  15. Presynaptic muscarinic receptors: Change of sensitivity during long-term drug treatment

    International Nuclear Information System (INIS)

    The authors investigate some of the characteristics of auto- and heteroreceptors from different brain areas in male rats; their alteration in sensitivity following chronic drug treatment is monitored. The synaptosomes were prelabeled with tritium-choline or tritium-dopamine and the release of tritium-acetylcholine and tritium-DA was studied in superfusion. It is shown that the difference in susceptibility between auto- and heteroreceptors with respect to changes of sensitivity may represent a further criterion to discriminate between muscarinic receptor subtypes

  16. On the Comparison of Interpersonal Sensitivity and Assertiveness between Drug-Dependent Persons and Ordinary People

    OpenAIRE

    Babak Vojudi; Nastaran Otared; Hamid poursharifi

    2015-01-01

    Objective: The present study was aimed at comparing interpersonal sensitivity and assertiveness between drug-dependent persons and ordinary people. Method: The research method was causal-comparative. The statistical population of the study consisted of all narcotic addicts of Tabriz City who referred to Addiction Treatment Centers while the research was being conducted. The number of 30 addicted persons was selected through cluster sampling and 30 ordinary persons as control group through con...

  17. Formulation and characterization of sustained release dosage form of moisture sensitive drug

    OpenAIRE

    Patel, Priya; Dave, Abhishek; Vasava, Amit; Patel, Paresh

    2015-01-01

    Objective: The purpose of this study was to prepare sustained release tablet of moisture sensitive drug like Ranitidine Hydrochloride for treatment of gastroesophageal reflux disease along with the improvement of moisture stability to get better therapeutic efficacy. Materials and Methods: Pan coating technique was used for coating of the tablet. Film coating was done using Eudragit RLPO and Eugragit EPO as coating polymer. 32 full factorial design was applied for optimization purpose, and 9 ...

  18. Kinetic Degradation and Controlled Drug Delivery System Studies for Sensitive Hydrogels Prepared by Gamma Irradiation

    International Nuclear Information System (INIS)

    Ternary mixtures of N-vinyle-2-pyrrolidone(NVP ), itaconic acid (IA) and gelatin (G) were gamma irradiated to prepared poly(NVP/IA/G) hydrogels. The equilibrium kinetic swelling, drug release behavior, Scan Electron Microscope (SEM) and the swelling-degradation kinetics were studied. Both the diffusion exponent and the diffusion coefficient increase with increasing content of (IA). Also, the swelling behavior of copolymer hydrogels in response to ph value of the external media was studied, it is noted that the highest swelling values at ph 4. The in vitro drug release behavior of these hydrogels was examined by quantification analysis with a UV/VIS spectrophotometers. Chlorpromazine hydrochloride was loaded into dried hydrogels to investigate the stimuli-sensitive property at the specific ph. The release studies show that the highest value of release was at ph 4 which can be used for drug delivery system

  19. Sensitive, resistant and multi-drug resistant Acinetobacter baumanii at Saudi Arabia hospital eastern region.

    Science.gov (United States)

    Ahmed, Mughis Uddin; Farooq, Reshma; Al-Hawashim, Nadia; Ahmed, Motasim; Yiannakou, Nearchos; Sayeed, Fatima; Sayed, Ali Rifat; Lutfullah, Sualiha

    2015-05-01

    Since the Physicians start use of antibiotics long ago with un-notice drug resistance. However actual problem was recognized about 85 years ago. Antibiotic resistant and Multi-drug resistant bacterial strains are at rise throughout the world. It is physicians and researchers to take scientific research based appropriate action to overcome this ever-spreading problem. This study is designed to find out sensitive (S), resistant (R) and multi-drug resistant (MDR) Acinetobacter baumanii strain along with other isolates in the resident patients of Eastern Region of Saudi Arabia. Pseudomonas aeruginosa is excluded from other gram-negative organisms isolated from different sites as it will be dealt separately. This study is based in was retrospective observations designed to collect data of different stains of Acinetobacter baumanii with reference to their Sensitivity (S), Resistance (R), Multi-Drug Resistance (MDR) along with other Gram negative isolated from different sites (from 1st January 2004 to 31st December 2011) at King Abdulaziz Hospital located Eastern Region of Kingdom of Saudi Arabia (KSA). All necessary techniques were used to culture and perform sensitivity of these isolates. There were 4532 isolates out of which 3018 (67%) were from patients. Out of Acinetobacter baumanii infected were 906 (20%) while other 3626 (80%) isolates were miscellaneous. Numbers of patients or cases were 480 (53%) out of 906 isolates and numbers of patients or cases in other organisms were 2538 (70%) out of 3626 isolates. Acinetobacter baumanii infected patients 221 (46%) were male and 259 (54%) were female and the male and female ratio of 1:1.2. In other organisms this male female ratio was almost same. There was steady rise in number of patients and the hence the isolates from 2004 to 2011. Majority of the bacterial strains were isolated as single organism but some were isolated as double or triple or quadruple or more organisms from different sites. Sensitive, Resistant and

  20. Sensitizing nanoparticle based platinum(IV) drugs by curcumin for better chemotherapy.

    Science.gov (United States)

    Kang, Xiang; Zhao, Chen; Yan, Lesan; Qi, Ruogu; Jing, Xiabin; Wang, Zehua

    2016-09-01

    A polymer-cisplatin(IV) conjugate was prepared by attaching Pt(IV)-COOH to a biodegradable amphiphilic block copolymer containing pendant OH groups. The conjugate can assemble into micelles (M(Pt)) with a mean diameter of ca. 169nm. Further, curcumin (CM) was used to sensitize platinum drug based nanoparticles to overcome cisplatin resistance and enhance antitumor efficacy. In vitro studies showed that M(Pt)/CM combinations had great synergistic effect both on cisplatin sensitive and cisplatin resistant cell lines (A2780 and A2780DDP). In vivo studies showed that M(Pt)/CM had a much lower systemic toxicity and an enhanced antitumor efficacy compared to cisplatin alone or the corresponding cisplatin/CM combinations. Therefore, polymer-cisplatin(IV) conjugate with small molecules that serve as a non-cytotoxic or minimally cytotoxic sensitizer or enhancer provide a promising strategy, which may have potential clinical implications in the near future. PMID:27311131

  1. NOVEL pH-SENSITIVE DRUG DELIVERY SYSTEM BASED ON NATURAL POLYSACCHARIDE FOR DOXORUBICIN RELEASE

    Institute of Scientific and Technical Information of China (English)

    Dian-xiang Lu; Xian-tao Wen; Jie Liang; Xing-dong Zhang; Zhong-wei Gu; Yu-jiang Fan

    2008-01-01

    A novel pH-sensitive nanoparticle drug delivery system (DDS) derived from natural polysaccharide pullulan for doxorubicin (DOX) release was prepared. Pullulan was functionalized by successive carboxymethylization and amidation to introduce hydrazide groups. DOX was then grafted onto pullulan backbone through the pH-sensitive hydrazone bond to form a pullulan/DOX conjugate. This conjugate self-assembled to form nano-sized particles in aqueous solution as a result of the hydrophobic interaction of the DOX. Transmission electron microscope (TEM) and dynamic light scattering (DLS)characterization showed that the nanoparticles were spherical and their size was less than 100 nm. The DOX released from the nanoparticles in a pH-sensitive manner. In vitro cytotoxicity assay indicated the pullulan/DOX nanoparticles showed comparable cytotoxicity effect with free DOX on the 4T1 mouse breast cancer cells.

  2. Design and assembly of pH-sensitive lipidic cubic phase matrices for drug release.

    Science.gov (United States)

    Nazaruk, Ewa; Szlęzak, Monika; Górecka, Ewa; Bilewicz, Renata; Osornio, Yazmin M; Uebelhart, Peter; Landau, Ehud M

    2014-02-11

    Bicontinuous lipidic cubic phases (LCPs) exhibit a combination of material properties that make them highly interesting for various biomaterial applications: they are nontoxic, biodegradable, optically transparent, thermodynamically stable in excess water, and can incorporate active molecules of virtually any polarity. Here we present a molecular system comprising host lipid, water, and designed lipidic additive, which form a structured, pH-sensitive lipidic matrix for hydrophilic as well as hydrophobic drug incorporation and release. The model drug doxorubicin (Dox) was loaded into the LCP. Tunable interactions with the lipidic matrix led to the observed pH-dependent drug release from the phase. The rate of Dox release from the cubic phase at pH 7.4 was low but increased significantly at more acidic pH. A small amount of a tailored diacidic lipid (lipid 1) added to the monoolein LCP modified the release rate of the drug. Phase identity and structural parameters of pure and doped mesophases were characterized by small-angle X-ray scattering (SAXS), and release profiles from the matrix were monitored electrochemically. Analysis of the release kinetics revealed that the total amount of drug released from the LCP matrix is linearly dependent on the square root of time, implying that the release mechanism proceeds according to the Higuchi model. PMID:24443890

  3. Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML)

    International Nuclear Information System (INIS)

    Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the P-gp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts. The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test. Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp. These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients

  4. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression.

    Science.gov (United States)

    Kotsovolou, Olga; Ingelman-Sundberg, Magnus; Lang, Matti A; Marselos, Marios; Overstreet, David H; Papadopoulou-Daifoti, Zoi; Johanson, Inger; Fotopoulos, Andrew; Konstandi, Maria

    2010-08-16

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity. PMID:20595028

  5. 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.

  6. A new type of radiotherapeutic sensitizing drug: a clinical trials of sodium glycididazole

    International Nuclear Information System (INIS)

    A new type tumor radiosensitizing drug-Sodium Glycidadizole(CMNa)synthesized since 1984.Now been completed I-III clinical trials.The therapeutic efficacy and toxicity of CMNa combined with conventional radiotherapy for head neck, lung and esophagus cancer patients in phase II trial were recommended. 207 Pts: Head neck cancer(n=84), Esophagus cancer (n=61),lung cancer(n=62) were enrolled, proceeded for clinical trial phase II in five clinical hospitals denoted by National Drug Administration. Thereafter, the Pts were divided into test group (gp,n=104)and control gp(n=101) according to the rule of di blind, random and parallels. Median age of the former was 52.3±12.5; later 54.1±12.3. The Pts of the test gp was injected CMNa 800 mgs/m2/time,3/wks,then conventionally irradiated 2 Gy with 4-6 MV linear accelerator within an hour for 6-7 wks; Whereas the Pts of control gp was the same treatment as test gp but injected with only placebo, no drug. All patients were assessed by CT,or X-ray films. When the radiation doses arrived to the median dosage D4000 cGy after 6-7 wks therapy, the therapeutic efficiency (CR+PR) of the test group(CMNa+RT) increased from the 80.6%(79/98) of control gp to 92.7%(101/109)(p=0.01), and the drug did not increase the radiation effects of normal tissues by irradiation. It showed that the CMNa possessed significantly radiotherapeutic sensitizing efficacy and very low toxicity. Even some Pts were continuously injected CMNa up to 21 times, total dosage 16.8g/m2 , still did not see any remarkable side toxicities and neurotoxicity. With this protocol, injecting CMNa 800 mgs/time,3 times/week before conventional radiation for tumor Pts was safe, could increase the radiosensitization of hypoxia cells in tumor remarkable; whereas no radiosensitizing effects of normal tissues. Thus, CMNa is a new type, highly effective and of lower toxicity radiotherapeutic sensitizing drug that could enhance antitumor effects evidently. We have received the New Drug

  7. Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys1

    Institute of Scientific and Technical Information of China (English)

    Su-qing CHEN; Hai-feng ZHAI; Yan-ying CUI; Jie SHI; Bernard LE FOLL; Lin LU

    2007-01-01

    Aim: Clonidine is an α2 adrenoceptor agonist that is frequently used to reduce withdrawal symptoms during opioid detoxification in humans. The long-term effects of clonidine on withdrawal symptoms and its effects on subsequent drug exposure have not been thoroughly documented. The aim of the study was to determine if clonidine administered during morphine withdrawal in rhesus mon-keys produces long-lasting effects on withdrawal symptoms and alters the effects of subsequently taken drugs of abuse. Methods: Adult male rhesus monkeys were treated with increasing doses of morphine for 90 d to induce opiate (narcotic)dependence. The immediate and long-lasting effects of 1 week's administration of clonidine were measured via the recording of morphine withdrawal signs and the subsequent effects of challenge injections of morphine or cocaine. Results:Monkeys chronically treated with morphine displayed withdrawal signs that lasted 2 weeks after cessation of morphine administration and displayed sensitized re-sponses to subsequent morphine and cocaine injections. Clonidine significantly reduced certain morphine withdrawal signs and overall withdrawal score, but these effects did not persist upon cessation of clonidine treatment. Sensitization to the effects of morphine and cocaine were significantly reduced in monkeys previ-ously treated with clonidine. Conclusion: Our results suggest that in addition to its short-term alleviating effect on morphine withdrawal signs, clonidine may re-duce subsequent effects of drugs of abuse after prolonged abstinence.

  8. Benchmarking of gastric cancer sensitivity to anti-cancer drugs ex vivo as a basis for drug selection in systemic and intraperitoneal therapy

    OpenAIRE

    Hultman, Bo; Mahteme, Haile; Sundbom, Magnus; Ljungman, Martin; Larsson, Rolf; Nygren, Peter

    2014-01-01

    Background   The choice of drugs for treatment of advanced gastric cancer (GC) is empirical. The purpose of the current study was to benchmark ex vivo the sensitivity of GC tumor cells from patients to standard cytotoxic and some newly introduced targeted drugs (TDs), as a basis for drug selection in the treatment of GC. Methods   Tumor cell samples from patients with GC were analyzed for sensitivity to 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, mito­mycin C, doxorubicin and doceta...

  9. 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

  10. On the Comparison of Interpersonal Sensitivity and Assertiveness between Drug-Dependent Persons and Ordinary People

    Directory of Open Access Journals (Sweden)

    Babak Vojudi

    2015-02-01

    Full Text Available Objective: The present study was aimed at comparing interpersonal sensitivity and assertiveness between drug-dependent persons and ordinary people. Method: The research method was causal-comparative. The statistical population of the study consisted of all narcotic addicts of Tabriz City who referred to Addiction Treatment Centers while the research was being conducted. The number of 30 addicted persons was selected through cluster sampling and 30 ordinary persons as control group through convenience sampling method. Gmbryl & Ritchie’s assertiveness questionnaire (1975 and Boyce & Parker’s Interpersonal Sensitivity Measure (IPSM 1989 were used for data collection purposes. Results: The results showed that there was a statistically significant difference between two groups in terms of interpersonal sensitivity and assertiveness. The addicts showed less assertiveness and more interpersonal sensitivity in comparison with their healthy counterparts. Conclusion: The findings show that people who are unable to express themselves and exert sensitivity in interpersonal relationships are more likely at high risk of substance dependence. However, it is possible to prevent these persons from turning to addiction by teaching them these skills.

  11. Overexpression of the human HAP1 protein sensitizes cells to the lethal effect of bioreductive drugs.

    Science.gov (United States)

    Prieto-Alamo, M J; Laval, F

    1999-03-01

    Abasic sites (AP sites) are generated in DNA either directly by DNA-damaging agents or by DNA glycosylases acting during base excision repair. These sites are repaired in human cells by the HAP1 protein, which, besides its AP-endonuclease activity, also possesses a redox function. To investigate the ability of HAP1 protein to modulate cell resistance to DNA-damaging agents, CHO cells were transfected with HAP1 cDNA, resulting in stable expression of the protein in the cell nuclei. The sensitivity of the transfected cells to the toxic effect of various agents, e.g. methylmethane sulfonate, bleomycin and H2O2, was not modified. However, the transfected cells became more sensitive to killing by mitomycin C, porfiromycin, daunorubicin and aziridinyl benzoquinone, drugs that are activated by reduction. To test whether the redox function of HAP1 protein was involved in this increased cytotoxicity, we have constructed a mutated HAP1 protein endowed with normal AP-endonuclease activity but deleted for redox function. When this mutated protein was expressed in the cells, elevated AP-endonuclease activity was measured, but sensitization to the lethal effects of compounds requiring bioreduction was no longer observed. These results suggest that HAP1 protein, besides its involvement in DNA repair, is able to activate bioreduction of alkylating drugs used in cancer chemotherapy. PMID:10190555

  12. Impact of heterozygous mutations in BRCA1 and BRCA2. Sensitivity to genotoxic drugs

    International Nuclear Information System (INIS)

    The carriers of heterozygous mutations in BRCA1 / 2 have a high risk of developing breast cancer. The loss of the normal allele with consequent loss of function is frequently observed in tumor level. Since these genes involved in the cellular response to genetic damage, loss of function can determine differences in sensitivity to genotoxic agents. In this study investigated whether heterozygous mutations in BRCA1 / 2 modify the sensitivity to genotoxic drugs using lymphoblastic cell lines developed from individuals who carry no mutation carriers and heterozygous for BRCA1 / 2. Materials and methods. Chemo sensitivity of the cell lines was compared lymphoblastoid GM13709 (mutation in exon 11 of BRCA1 2187delA), GM14622 (level 607stop mutation in exon 11 of BRCA2) and GM 14453 (normal BRCA1 / 2) from exposure to Adriamycin (0.2-2.5 mM) and Cisplatin (0.625- 80mM) through the test of cell viability based on MTT reduction. It determined the inhibitory concentration 50 (IC50) from curves regression dose-response obtained after 24 hours of drug exposure. It 5 independent experiments performed in triplicate. Results. The line GM14622 was significantly (P = 0.003) more sensitive to Adriamycin (IC50: 0.585 mM) than the Control GM14453 (IC50: 1.364 mM) online while GM13709 was similar to the control (IC50: 1.324 mM) response. Turn the line GM14622 was also significantly (P = 0.01) more sensitive cisplatin (IC50: 12.7 mM) than the line GM14453 (IC50: 28.6mm) and GM13709 had the same response as the (IC50: 28.6 mM) control. Discussion and Conclusions. Our results suggest that mutations deleterious heterozygous BRCA2 may confer increased sensitivity to drugs genotoxic, which may have implications in the management of patients carrying or BRCA2 mutations in women with sporadic breast cancer exhibit low expression of BRCA2

  13. Monitoring drug induced apoptosis and treatment sensitivity in non-small cell lung carcinoma using dielectrophoresis.

    Science.gov (United States)

    Taruvai Kalyana Kumar, Rajeshwari; Liu, Shanshan; Minna, John D; Prasad, Shalini

    2016-09-01

    Non-invasive real time methods for characterizing biomolecular events that contribute towards apoptotic kinetics would be of significant importance in the field of cancer biology. Effective drug-induced apoptosis is an important factor for establishing the relationship between cancer genetics and treatment sensitivity. The objective of this study was to develop a non-invasive technique to characterize cancer cells that are undergoing drug-induced apoptosis. We used dielectrophoresis to determine apoptotic cells as early as 2h post drug treatment as compared to 24h with standard flow cytometry method using non-small cell lung cancer (NSCLC) adenocarcinoma cell line (HCC1833) as a study model. Our studies have shown significant differences in apoptotic cells by chromatin condensation, formation of apoptotic bodies and exposure of phosphatidylserine (PS) on the extracellular surface when the cells where treated with a potent Bcl-2 family inhibitor drug (ABT-263). Time lapse dielectrophoretic studies were performed over 24h period after exposure to ABT-263 at clinically relevant concentrations. The dielectrophoretic studies were compared to Annexin-V FITC flow assay for the detection of PS in mid-stage apoptosis using flow cytometry. As a result of physical and biochemical changes, inherent dielectric properties of cells undergoing varying stages of apoptosis showed amplified changes in their cytoplasmic and membrane capacitance. In addition, zeta potential of these fixed isolated cells was measured to obtain direct correlation to biomolecular events. PMID:27262539

  14. Swelling and drug releasing properties of poly(N-isopropylacrylamide) thermo-sensitive copolymer gels

    Institute of Scientific and Technical Information of China (English)

    Chunyue PAN; Qingde LONG; Dian YU; Yanping RAO; Nianqian WU; Xingcui LI

    2008-01-01

    A series of N,isopropylacrylamide (NIPAAm)copolymer gels with different hydrophilicities were prepared from NIPAAm, hydrophilic acrylamide (AAm) and hydrophobic butyl methacrylate (BMA). The swelling and thermo,responsive properties of PNIPAAm P (NIPAm,co,BMA) and P(NIPAm,co,AAm) copolymer hydrogels were investigated. The drug loading and releasing behaviors for two kinds of model drug with different hydrophilicities were studied. The result shows that the copolymer gels present negative thermo,sensitivities. The lower critical solution temperature (LCST), equilibrium swelling degree and the initial swelling rate increase as the hydrophilicity of gels increases when the temperature is below the LCST. With increasing gel hydrophilicity the loading ratio for sodium salicylate increases, while for salicylic acid, the reverse is observed. The initial drug releasing rate of sodium salicylate and salicylic acid also increase with increasing gel hydrophilicity. The initial drug releasing rate of sodium salicylate is significantly higher than that of salicylic acid. For salicylic acid which is less hydrophilic, the equilibrium releasing ratio at high temperature is lower than that at low temperature while for sodium salicylate which is more hydrophilic, the equilibrium releasing ratio at high temperature is almost the same as that at low temperature. Equilibrium releasing ratios of the three gels are significantly different from each other for salicylic acid when the temperature is below LCST while the equilibrium releasing ratios of the three gels are all 100% for sodium salicylate.

  15. Primary mechanisms of erythrocyte photolysis induced by biological sensitizers and phototoxic drugs

    International Nuclear Information System (INIS)

    The elucidation of the molecular mechanism of photosensitized hemolysis of red blood cells may give important clues to the primary events underlying the phototoxic reactions observed in pathological conditions such as porphyria and induced by photosensitizing drugs. Sensitizers effective in photohemolysis are porphyrins, the tryptophan metabolite kynurenic acid, and phototoxic drugs such as chlorpromazine and demethylchlortetracycline. Utilizing the singlet oxygen quenchers, β-carotene and histidine and the large deuterium effect on the lifetime of singlet oxygen previously described, good evidence of the participation of this excited molecular species in the photohemolysis in the presence of kynurenic acid was obtained. Chlorpromazine and demethylchlortetracycline clearly acted by a non-singlet oxygen pathway. The situation observed with haematoporphyrin was less clear and may have represented a mixed Type I-Type II mechanism. (author)

  16. Novel pH-sensitive polyacetal-based block copolymers for controlled drug delivery

    OpenAIRE

    Kim, Jin-Ki; Garripelli, Vivek Kumar; Jeong, Ui-Hyeon; Park, Jeong-Sook; Repka, Michael A.; Jo, Seongbong

    2010-01-01

    The principal aim of this study was to synthesize and characterize pH-sensitive biodegradable triblock copolymers containing a hydrophobic polyacetal segment for controlled drug delivery. Poly(ethylene glycol)-poly(ethyl glyoxylate)-poly(ethylene glycol) (PEG-PEtG-PEG) triblock copolymers with PEG molecular weights 500 (PEtG-PEG500) and 750 (PEtG-PEG750) were synthesized by PEtG end-capping with methoxy PEG via a carbamate linkage. Synthesized amphiphilic PEG-PEtG-PEG was characterized by 1H-...

  17. [A Case of Drug-Induced Thrombocytopenia Resulting from Sensitivity to Oxaliplatin].

    Science.gov (United States)

    Masuda, Taiki; Nagai, Kagami; Sanada, Katsuya

    2015-11-01

    A 67-year-old man was diagnosed with pulmonary metastasis from advanced transverse colon cancer. Thus, a local resection was performed. Adjuvant chemotherapy with mFOLFOX6 was started. Sixteen courses were carried out without problems. However, he complained of chills and chest discomfort 2 hours after beginning the 17th course of chemotherapy. Laboratory data showed remarkable thrombocytopenia, and platelet-associated IgG level was high. After administration of steroids and platelet transfusions, the platelet count improved. Therefore, we diagnosed drug-induced thrombocytopenia resulting from sensitivity to oxaliplatin (L-OHP). Since then, sLV5FU2 therapy was started, and the patient received the whole adjuvant chemotherapy without problems. Thrombocytopenia resulting from sensitivity to L-OHP is a relatively rare side effect. We herein report this case with a review of the relevant literature. PMID:26805296

  18. Inhibition of anaphylactic histamine release from heterologously sensitized mast cells: differential effects of drugs which interfere with calcium influx.

    OpenAIRE

    Kurose, Masao

    1981-01-01

    Drug effects were studied on anaphylactic histamine release from rat mast cells sensitized in vitro with mouse IgE antibody. When histamine release was elicited by adding Ca-++ at various times after antigen-stimulation of sensitized cells in Ca++-free medium, the drugs to be tested were added shortly before each Ca++ addition. Quercetin was effective only when added before or immediately after antigen. Theophylline and disodium cromoglycate (DSCG) were active irrespective of the time interva...

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

    Science.gov (United States)

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

    2010-03-01

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

  20. Antimicrobial sensitivity and frequency of DRUG resistance among bacterial strains isolated from cancer patients

    International Nuclear Information System (INIS)

    Blood stream infections (bacteremia) is potentially life threatening. Concomitant with a change in the incidence and epidemiology of infecting organisms, there has been an increase in resistance to many antibiotic compounds. The widespread emergence of resistance among bacterial pathogens has an impact on our ability to treat patients effectively. The changing spectrum of microbial pathogens and widespread emergence of microbial resistance to antibiotic drugs has emphasized the need to monitor the prevalence of resistance in these strains. In the present study frequency of isolation of clinically significant bacteria and their susceptibility and resistance pattern against a wide range of antimicrobial drugs from positive blood cultures collected during 2001-2003 was studied. A total of 102 consecutive isolates were found with 63% gram positive and 44% gram negative strains. The dominating pathogens were Staphylococcus aureus (51%), Streptococci (31%), Pseudomonas (40%), Proteus (13%), Klebsiella (13%). The isolated strains were tested against a wide range of antibiotics belonging to cephalosporins, aminoglycosides and quinolone derivative group by disk diffusion method. It has been observed that isolated strains among gram positive and negative strains showed different level of resistance against aminoglycosides and cephalosporin group of antibiotics with gram positives showing highest number and frequency of resistance against aminoglycosides (40-50%) and cephalosporins.(35-45%) whereas cephalosporins were found to be more effective against gram negatives with low frequency of resistant strains. Cabapenem and quinolone derivative drugs were found to be most effective among other groups in both gram positive and negative strains with 23-41% strains found sensitive to these two drugs. The frequency of sensitive strains against aminoglycoside and cephalosporin in gram negative and gram positive strains were found to be decreasing yearwise with a trend towards an

  1. Morphology and Drug Release of Ph-Sensitive Microspheres Containing Flavonoids

    Science.gov (United States)

    Paola, Scarfato; Elvira, Avallone; Pio, Lannelli; Rita, Aquino; Domenico, Acierno

    2008-08-01

    In this work we developed pH-sensitive microspherical dosage forms for poorly water soluble flavonoids (quercetin and naringenin) by using Eudragit L100 as enteric polymer. The systems were produced by water in oil (w/o) solvent evaporation method, optimizing the formulation and preparation conditions in order to obtain high encapsulation efficiency and production yield. The synthesized microspheres were characterized in terms of particle size distribution, drug loading, morphology and in vitro release properties. The performed analyses evidenced that the microspheres were free- flowing and spherical in shape, both quercetin and naringenin were microencapsulated in the amorphous state and the drug content was near to the theoretical one. Preliminary in vitro dissolution studies, carried out using a pH-change method, showed that the samples exhibit a typical biphasic drug release trend, due to the pH dependent solubility of the enteric polymers used. In particular, the samples have a fairly gastroresistance followed by an about complete release in simulated intestinal fluid.

  2. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.

    Directory of Open Access Journals (Sweden)

    Ayako Nakano

    Full Text Available Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2, KG-1 (ABCB1 and HepG2 cells (ABCB1 and ABCG2. Interestingly, although side population (SP cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

  3. A system for determining the pharmacology of indirect radiation sensitizer drugs on multicellular spheroids

    International Nuclear Information System (INIS)

    We have characterized some of the physiology of multicellular spheroids of different sizes grown from Chinese hamster lung fibroblast (V79) cells. Among the parameters studied were oxygen tension distributions within the spheroid. This was achieved using ultramicroelectrodes with tip diameters of 1-5 mu and a perfusion system whereby environmental conditions such as flow, temperature, and chemical makeup of the milieu could be measured and controlled. Plateau pO/sup 2/ values of less than 10 mm Hg were consistently obtained from spheroids under various conditions. We were able to modify these distributions by use of indirect radiation sensitizer drugs such as mechlorethamine HCl (mustargen) at nontoxic doses. We have also made determinations of the inhibitory capacities of several other drugs on the respiration rate of constituent cells of multicellular spheroids in single-cell suspensions. We have concluded that there are indeed hypoxic cells in spheroids whose radioresistance may be modified by essentially nontoxic levels of indirect radiosensitizer drugs and that the system described shows great promise for screening agents which may modify radiation response

  4. Xylan-based temperature/pH sensitive hydrogels for drug controlled release.

    Science.gov (United States)

    Gao, Cundian; Ren, Junli; Zhao, Cui; Kong, Weiqing; Dai, Qingqing; Chen, Qifeng; Liu, Chuanfu; Sun, Runcang

    2016-10-20

    Xylan-based temperature/pH sensitive hydrogels were prepared by the crosslinking copolymerization of xylan with N-isopropylacrylamide (NIPAm) and acrylic acid (AA) using N,Ń-methylenebis-acrylamide (MBA) as a cross-linker and 2,2-dimethoxy-2-phenylacetophenone as a photoinitiator via ultraviolet irradiation. The influence of the NIPAm, AA and MBA amount on properties of xylan-based hydrogels was discussed. The morphology and interactions of hydrogels were characterized by SEM and FTIR. The lower critical solution temperature (LCST) of hydrogels was investigated by DSC. The results indicated that the LCST of hydrogels emerged at around 34°C and increased with increasing the AA content. The drug encapsulation efficiency of as-prepared hydrogels reached to 97.60% and the cumulative release rate of acetylsalicylic acid was 90.12% and 26.35% in the intestinal and gastric fluid, respectively. Xylan-based hydrogels were proved to be biocompatible with NIH3T3 cell by MTT assay and showed the promising application as drug carriers for the intestinal-targeted oral drug delivery. PMID:27474557

  5. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

    Directory of Open Access Journals (Sweden)

    Zai-Fa Hong

    Full Text Available Cholangiocarcinoma (CCA, a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K/protein kinase B (AKT/mammalian target of rapamycin (mTOR pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.

  6. The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity.

    Directory of Open Access Journals (Sweden)

    Shiau-Mei Chen

    Full Text Available MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124 participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs. We then examined which DNA repair-related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair-related genes, encoding ATM interactor (ATMIN and poly (ADP-ribose polymerase 1 (PARP1, were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

  7. A sensitive multidimensional method for the detection, characterization, and quantification of trace free drug species in antibody-drug conjugate samples using mass spectral detection.

    Science.gov (United States)

    Birdsall, Robert E; McCarthy, Sean M; Janin-Bussat, Marie Claire; Perez, Michel; Haeuw, Jean-François; Chen, Weibin; Beck, Alain

    2016-01-01

    Conjugation processes and stability studies associated with the production and shelf life of antibody-drug conjugates (ADCs) can result in free (non-conjugated) drug species. These free drug species can increase the risk to patients and reduce the efficacy of the ADC. Despite stringent purification steps, trace levels of free drug species may be present in formulated ADCs, reducing the therapeutic window. The reduction of sample preparation steps through the incorporation of multidimensional techniques has afforded analysts more efficient methods to assess trace drug species. Multidimensional methods coupling size-exclusion and reversed phase liquid chromatography with ultra-violet detection (SEC-RPLC/UV) have been reported, but offer limited sensitivity and can limit method optimization. The current study addresses these challenges with a multidimensional method that is specific, sensitive, and enables method control in both dimensions via coupling of an on-line solid phase extraction column to RPLC with mass spectral detection (SPE-RPLC/MS). The proposed method was evaluated using an antibody-fluorophore conjugate (AFC) as an ADC surrogate to brentuximab vedotin and its associated parent maleimide-val-cit-DSEA payload and the derived N-acetylcysteine adduct formed during the conjugation process. Assay sensitivity was found to be 2 orders more sensitive using MS detection in comparison to UV-based detection with a nominal limit of quantitation of 0.30 ng/mL (1.5 pg on-column). Free-drug species were present in an unadulterated ADC surrogate sample at concentrations below 7 ng/mL, levels not detectable by UV alone. The proposed SPE-RPLC/MS method provides a high degree of specificity and sensitivity in the assessment of trace free drug species and offers improved control over each dimension, enabling straightforward integration into existing or novel workflows. PMID:26651262

  8. Praziquantel sensitivity of Kenyan Schistosoma mansoni isolates and the generation of a laboratory strain with reduced susceptibility to the drug

    OpenAIRE

    Mwangi, Ibrahim N.; Sanchez, Melissa C.; Mkoji, Gerald M.; Lelo E. Agola; Steven M. Runo; Cupit, Pauline M.; Charles Cunningham

    2014-01-01

    Schistosomiasis is a neglected tropical disease caused by blood-dwelling flukes of the genus Schistosoma. While the disease may affect as many as 249 million people, treatment largely relies on a single drug, praziquantel. The near exclusive use of this drug for such a prevalent disease has led to concerns regarding the potential for drug resistance to arise and the effect this would have on affected populations. In this study, we use an in vitro assay of drug sensitivity to test the effect o...

  9. A dual drug sensitive L. major induces protection without lesion in C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Noushin Davoudi

    Full Text Available Leishmaniasis is a major health problem in some endemic areas and yet, no vaccine is available against any form of the disease. Historically, leishmanization (LZ which is an inoculation of individual with live Leishmania, is the most effective control measure at least against cutaneous leishmaniasis (CL. Due to various reasons, LZ is not used today. Several live attenuated Leishmania have been developed but their use is limited. Previously, we developed a transgenic strain of L. major that harbors two suicide genes tk and cd genes (lmtkcd+/+ for use as a challenge strain in vaccine studies. These genes render the parasite susceptible to Ganciclovir (GCV and 5-flurocytosine (5-FC. The dual drug sensitive strain of L. major was developed using gene targeting technology using a modified Herpes Simplex Virus thymidine kinase gene (hsv-tk sensitive to Ganciclovir antibiotic and Saccharomyces cerevisae cytosine deaminase gene (cd sensitive to 5-flurocytosine that were stably introduced into L. major chromosome. BALB/c mice inoculated with lmtkcd+/+ developed lesions which upon treatment with GCV and 5-FC completely healed. In the current study, the transgenic lmtkcd+/+strain was assessed as a live vaccine model to determine the time necessary to develop a protective immune response. C57BL/6 mice were inoculated with the transgenic lmtkcd+/+strain, and treated at the time of inoculation (day 0 or at day 8 after inoculation. Immunized animals were challenged with wild-type L. major, and complete protection was induced in mice that were treated at day 8. The results show that in contrast to leishmanization, in group of mice inoculated with a dual sensitive L. major development and persistence of lesion is not necessary to induce Th1 response and protection.

  10. Sense and sensitivity: physical limits to multicellular sensing and drug response

    CERN Document Server

    Varennes, Julien

    2015-01-01

    Metastasis is a process of cell migration that can be collective and guided by chemical cues. Viewing metastasis in this way, as a physical phenomenon, allows one to draw upon insights from other studies of collective sensing and migration in cell biology. Here we review recent progress in the study of cell sensing and migration as collective phenomena, including in the context of metastatic cells. We describe simple physical models of sensing and migration, and we survey the experimental evidence that cells operate near the purely physical limits to their behavior. We conclude by contrasting cells' sensory abilities with their sensitivity to drugs, and suggesting potential alternatives to cell-death-based cancer therapies.

  11. Highly Sensitive and Validated Spectrophotometric Technique for the Assay of Some Antidepressant Drugs

    Science.gov (United States)

    Deepakumari, H. N.; Prashanth, M. K.; Kumar, B. C. Vasantha; Revanasiddappa, H. D.

    2015-01-01

    The present paper describes a simple, rapid, reproducible, and highly sensitive spectrophotometric method for the determination of the tricyclic antidepressant drugs: amitriptyline hydrochloride (AMT), imipramine hydrochloride (IMH), clomipramine hydrochloride (CPH) and desipramine hydrochloride (DPH) in pure and in pharmaceutical preparations. The method is based on the bromination of the above drugs with known excess of bromine. The unreacted bromine is determined based on its ability to bleach the dye methyl red quantitatively at 520 nm. Regression analysis of Beer-Lambert plots showed a good correlation in the concentration range 0.0-2.5, 0-1.4, 0-1.4, and 0-1.0 μg/ml for AMT, IMH, CPH, and DPH, respectively. The molar absorptivity values were found to be 0.65 × 105, 1.41 × 105, 1.93 × 105, and 2.96 × 105l/mol/cm, with the corresponding Sandell's sensitivity values were 0.0048, 0.0022, 0.0018, and 0.0010 μg/cm2 for AMT, IMH, CPH, and DPH, respectively. The limits of detection (LOD) and quantification (LOQ) are also reported for the developed method. Intra- and inter-day accuracy and precision was established according to the current ICH guidelines. Application of the procedure to the analysis of various pharmaceutical preparations gave reproducible and accurate results. Further, the validity of the proposed method was confirmed by applying the standard addition technique, and the results obtained are in good agreement with those obtained by the official method.

  12. Microflora of conjunctiva in children and its sensitivity and resistance to antibacterial drugs

    Directory of Open Access Journals (Sweden)

    T. N. Vorontsova

    2012-01-01

    Full Text Available Purpose: Investigation of microflora of conjunctiva and its resistance to antibacterial drugs in healthy children and patients with various inflammatory eye diseases.Methods: We examined 402 children (421 eyes in the age from 1 month till 17 years: 62 healthy children (70 eyes and 340 pa- tients with different inflammatory diseases of anterior segment of eye (351 eyes. the smear was done in all children for plating and definition of sensitivity of microflora to antibacterial drugs by method of diffusion to agar.Results: the plating was positive even in 72.9% of healthy children who entered the hospital for the planned surgery. Most often we revealed Staphylococcus epidermidis (44.3%, Staphylococcus aureus (12.8%, Streptococcus faecalis (5.7% and Enterobacter (2.9%. In children with inflammatory diseases Staphylococcus epidermidis and Staphylococcus aureus (62.6% were found fre- quently. the analysis of data showed high level of resistance of all microflora to aminoglycosides (neomycin 37.8% and tobramycin 32.7% and chloramphenicol — 37.1%. the lowest resistance of all microflora was registered to levofloxacin (11.1% and ciprofloxacin (10.5%. In gram-negative microflora we revealed the maximal sensitivity to ciprofloxacin, in gram-positive — to levofloxacin.We detected the maximal resistance of microflora to ampicillin (66.1%, and minimal — to cephalosporines (4.5% among the antibiotics of systemic application.Conclusion: the findings allow us to recommend drops containing levofloxacin (Signicef for clinical practice in pediatric ophthalmology. 

  13. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets.

    Science.gov (United States)

    Guo, Jing; Liu, Hui; Zheng, Jie

    2016-01-01

    Synthetic lethality (SL) is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. SL reflects the biologically endogenous difference between cancer cells and normal cells, and thus the inhibition of SL partners of genes with cancer-specific mutations could selectively kill cancer cells but spare normal cells. Therefore, SL is emerging as a promising anticancer strategy that could potentially overcome the drawbacks of traditional chemotherapies by reducing severe side effects. Researchers have developed experimental technologies and computational prediction methods to identify SL gene pairs on human and a few model species. However, there has not been a comprehensive database dedicated to collecting SL pairs and related knowledge. In this paper, we propose a comprehensive database, SynLethDB (http://histone.sce.ntu.edu.sg/SynLethDB/), which contains SL pairs collected from biochemical assays, other related databases, computational predictions and text mining results on human and four model species, i.e. mouse, fruit fly, worm and yeast. For each SL pair, a confidence score was calculated by integrating individual scores derived from different evidence sources. We also developed a statistical analysis module to estimate the druggability and sensitivity of cancer cells upon drug treatments targeting human SL partners, based on large-scale genomic data, gene expression profiles and drug sensitivity profiles on more than 1000 cancer cell lines. To help users access and mine the wealth of the data, we developed other practical functionalities, such as search and filtering, orthology search, gene set enrichment analysis. Furthermore, a user-friendly web interface has been implemented to facilitate data analysis and interpretation. With the integrated data sets and analytics functionalities, SynLethDB would

  14. Construction of a novel pH-sensitive drug release system from mesoporous silica tablets coated with Eudragit

    Science.gov (United States)

    Xu, Yingpu; Qu, Fengyu; Wang, Yu; Lin, Huiming; Wu, Xiang; Jin, Yingxue

    2011-03-01

    A novel pH-sensitive drug release system has been established by coating Eudragit (Eud) on drug-loaded mesoporous silica (MS) tablets. The release rate of ibuprofen (IBU) from the MS was retarded by coating with Eudragit S-100, and the higher retardation was due to the increase of coating concentration and the coating layers. The target position of the release depended on the pH of the release medium, which was confirmed by the drug release from IBU/MS/Eud increasing rapidly with the change of medium pH from 1.2 to 7.4. This drug delivery system could prohibit irritant drug from leaking in the stomach and make it only release in the intestine. The loaded and unloaded drug samples were characterized by powder X-ray diffraction (XRD), Fourier transform infrared spectrometer (FTIR), N 2 adsorption/desorption, scanning electron microscopy (SEM), and transmission electron microscopy (TEM).

  15. [Sensitivity of clinical strains of facultatively anaerobic bacteria to antimicrobial drugs].

    Science.gov (United States)

    Bazhenov, L G; Iskhakova, Kh I

    1988-02-01

    Six hundred and sixty five samples of clinical materials from patients with various pyoinflammatory diseases were tested for obligatory anaerobes. Anaerobes were detected in 148 samples which amounted to 22.3 per cent of the total number of the samples and to 33.2 per cent of the samples with microbial growth. A total of 171 strains of obligatory anaerobes were isolated. Among them 58.5, 24.5, 16.4 and 0.6 per cent were nonsporulating gramnegative bacilli, grampositive cocci, grampositive bacilli and gramnegative cocci respectively. Sensitivity of the isolated anaerobes was tested with the disk diffusion method. The most active drugs against the tested strains were: nitroxoline, rifampicin, metronidasole, erythromycin, carbenicillin and cefotaxim (4.2, 4.5, 9.3, 10.6, 11.5 and 11.7 per cent of the resistant strains respectively). Gentamicin, polymyxin M, novobiocin and cefazoline were the least active drugs (94.6, 78.9, 65.4 and 50.0 per cent of the resistant strains respectively). Metronidasole, levomycetin, nitroxolin, rifampicin and furazolidone showed the highest activity against bacteroids of the fragilis group (0, 0, 0, 8 and 12.5 per cent of the resistant strains respectively) while gentamicin, polymyxin M, cefazolin, oxacillin, novobiocin and penicillin showed the lowest activity (100, 100, 100, 100, 87.0 and 66.7 per cent of the resistant strains respectively). PMID:3377601

  16. A simple and sensitive spectrofluorimetric method for analysis of some nitrofuran drugs in pharmaceutical preparations.

    Science.gov (United States)

    Belal, Tarek Saied

    2008-09-01

    A simple, rapid, selective and sensitive spectrofluorimetric method was described for the analysis of three nitrofuran drugs, namely, nifuroxazide (NX), nitrofurantoin (NT) and nitrofurazone (NZ). The method involved the alkaline hydrolysis of the studied drugs by warming with 0.1 M sodium hydroxide solution then dilution with distilled water for NX or 2-propanol for NT and NZ. The formed fluorophores were measured at 465 nm (lambda (Ex) 265 nm), 458 nm (lambda (Ex) 245 nm) and 445 nm (lambda (Ex) 245 nm) for NX, NT and NZ, respectively. The reaction pathway was discussed and the structures of the fluorescent products were proposed. The different experimental parameters were studied and optimized. Regression analysis showed good correlation between fluorescence intensity and concentration over the ranges 0.08-1.00, 0.02-0.24 and 0.004-0.050 microg ml(-1) for NX, NT and NZ, respectively. The limits of detection of the method were 8.0, 1.9 and 0.3 ng ml(-1) for NX, NT and NZ, respectively. The proposed method was validated in terms of accuracy, precision and specificity, and it was successfully applied for the assay of the three nitrofurans in their different dosage forms. No interference was observed from common pharmaceutical adjuvants. The results were favorably compared with those obtained by reference spectrophotometric methods. PMID:18246413

  17. Highly sensitive quantitative imaging for monitoring single cancer cell growth kinetics and drug response.

    Directory of Open Access Journals (Sweden)

    Mustafa Mir

    Full Text Available The detection and treatment of cancer has advanced significantly in the past several decades, with important improvements in our understanding of the fundamental molecular and genetic basis of the disease. Despite these advancements, drug-screening methodologies have remained essentially unchanged since the introduction of the in vitro human cell line screen in 1990. Although the existing methods provide information on the overall effects of compounds on cell viability, they are restricted by bulk measurements, large sample sizes, and lack capability to measure proliferation kinetics at the individual cell level. To truly understand the nature of cancer cell proliferation and to develop personalized adjuvant therapies, there is a need for new methodologies that provide quantitative information to monitor the effect of drugs on cell growth as well as morphological and phenotypic changes at the single cell level. Here we show that a quantitative phase imaging modality known as spatial light interference microscopy (SLIM addresses these needs and provides additional advantages over existing proliferation assays. We demonstrate these capabilities through measurements on the effects of the hormone estradiol and the antiestrogen ICI182,780 (Faslodex on the growth of MCF-7 breast cancer cells. Along with providing information on changes in the overall growth, SLIM provides additional biologically relevant information. For example, we find that exposure to estradiol results in rapidly growing cells with lower dry mass than the control population. Subsequently blocking the estrogen receptor with ICI results in slower growing cells, with lower dry masses than the control. This ability to measure changes in growth kinetics in response to environmental conditions provides new insight on growth regulation mechanisms. Our results establish the capabilities of SLIM as an advanced drug screening technology that provides information on changes in proliferation

  18. pH sensitive core-shell magnetic nanoparticles for targeted drug delivery in cancer therapy.

    Science.gov (United States)

    Lungu, Iulia Ioana; Rădulescu, Marius; Mogoşanu, George Dan; Grumezescu, Alexandru Mihai

    2016-01-01

    In the last decade, nanobiotechnology has evolved rapidly with an extensive impact on biomedical area. In order to improve bioavailability and minimize adverse effects, drug delivery systems based on magnetic nanocomposites are under development mainly for cancer imaging and antitumor therapy. In this regard, pH sensitive core-shell magnetic nanoparticles (NPs) with accurate controlled size and shape are synthesized by various modern methods, such as homogeneous precipitation, coprecipitation, microemulsion or polyol approaches, high temperature and hydrothermal reactions, sol-gel reactions, aerosol÷vapor processes and sonolysis. Due to their unique combined physico-chemical and biological properties (such as higher dispensability, chemical and thermal stability, biocompatibility), pH responsive core-shell magnetic NPs are widely investigated for controlled release of cytostatic drugs into the tumor site by means of pH change: magnetite@silicon dioxide (Fe3O4@SiO2), Fe3O4@titanium dioxide (TiO2), β-thiopropionate-polyethylene glycol (PEG)-modified Fe3O4@mSiO2, Fe3O4 NPs core coated with SiO2 with an imidazole group modified PEG-polypeptide (mPEG-poly-L-Asparagine), polyacrylic acid (PAA) and folic acid (FA) coating of the iron oxide NP core, methoxy polyethylene glycol-block-polymethacrylic acid-block-polyglycerol monomethacrylate (MPEG-b-PMAA-b-PGMA) attached by a PGMA block to a Fe3O4 core, PEG-modified polyamidoamine (PAMAM) dendrimer shell with Fe3O4 core and mesoporous silica coated on Fe3O4, mostly coated with an anticancer drug. This review paper highlights the modern research directions currently employed to demonstrate the utility of the pH responsive core-shell magnetic NPs in diagnosis and treatment of oncological diseases. PMID:27151685

  19. In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by ethnobotanically selected South African plants.

    Science.gov (United States)

    Lall, N; Meyer, J J

    1999-09-01

    Twenty South African medicinal plants used to treat pulmonary diseases were screened for activity against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis. A preliminary screening of acetone and water plant extracts against a drug-sensitive strain of Mycobacterium tuberculosis, H37Rv, was done by the agar plate method. Fourteen of the 20 acetone extracts showed inhibitory activity at a concentration of 0.5 mg/ml against this strain. Acetone as well as water extracts of Cryptocarya latifolia, Euclea natalensis, Helichrysum melanacme, Nidorella anomala and Thymus vulgaris inhibited the growth of M. tuberculosis. Given the activity of 14 acetone extracts at 0.5 mg/ml against the drug-sensitive strain by the agar plate method, a further study was done employing a rapid radiometric method to confirm the inhibitory activity. These active acetone extracts were screened against the H37Rv strain as well as a strain resistant to the drugs isoniazid and rifampin. The minimal inhibitory concentration of Croton pseudopulchellus, Ekebergia capensis, Euclea natalensis, Nidorella anomala and Polygala myrtifolia was 0.1 mg/ml against the H37Rv strain by the radiometric method. Extracts of Chenopodium ambrosioides, Ekebergia capensis, Euclea natalensis, Helichrysum melanacme, Nidorella anomala and Polygala myrtifolia were active against the resistant strain at 0.1 mg/ml. Eight plants showed activity against both strains at a concentration of 1.0 mg/ml. PMID:10473184

  20. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  1. High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs

    OpenAIRE

    D’Angelo, Daniela; Mussnich, Paula; De Rosa, Roberta; Bianco, Roberto; Tortora, Giampaolo; Fusco, Alfredo

    2014-01-01

    Background Development of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenocarcino...

  2. Novel multifunctional pH-sensitive nanoparticles loaded into microbubbles as drug delivery vehicles for enhanced tumor targeting.

    Science.gov (United States)

    Lv, Yongjiu; Hao, Lan; Hu, Wenjing; Ran, Ya; Bai, Yan; Zhang, Liangke

    2016-01-01

    This study fabricated novel multifunctional pH-sensitive nanoparticles loaded into microbubbles (PNP-MB) with the combined advantages of two excellent drug delivery vehicles, namely, pH-sensitive nanoparticles and microbubbles. As an antitumor drug, resveratrol (RES) was loaded into acetylated β-cyclodextrin nanoparticles (RES-PNP). The drug-loaded nanoparticles were then encapsulated into the internal space of the microbubbles. The characterization and morphology of this vehicle were investigated through dynamic light scattering and confocal laser scanning microscopy, respectively. In vitro drug release was performed to investigate the pH sensitivity of RES-PNP. The antitumor property of RES-loaded PNP-MB (RES-PNP-MB) was also analyzed in vivo to evaluate the antitumor effect of RES-PNP-MB. Results suggested that PNP exhibited pH sensitivity, and was successfully encapsulated into the microbubbles. RES-PNP-MB exhibit effective tumor growth suppressing in vivo. Therefore, such drug delivery vehicle should be of great attention in tumor therapy. PMID:27378018

  3. Monitoring for Plasmodium falciparum drug resistance to artemisinin and artesunate in Binh Phuoc Province, Vietnam: 1998-2009

    Directory of Open Access Journals (Sweden)

    Phuc Bui Q

    2010-06-01

    Full Text Available Abstract Background Artemisinin derivatives have been used for malaria treatment in Vietnam since 1989. Reported malaria cases have decreased from 1,672,000 with 4,650 deaths in 1991, to 91,635 with 43 deaths in 2006. Current national guidelines recommend artemisinin-based combination therapy (ACT, although artesunate is still available as monotherapy through the private sector. Recent reports suggest that effectiveness of ACT and artesunate monotherapy has declined in western Cambodia. This study examined Plasmodium falciparum resistance patterns over 10 years in southwest Vietnam in infected patients treated with artemisinin compounds. Methods The study was conducted in two communes in Phuoc Long district, Binh Phuoc province, 100 km west of the Cambodian border. This was chosen as a likely site for emerging artemisinin resistance because of the high prevalence of P. falciparum malaria, and the length of time that artemisinin had been in use. In vivo and in vitro monitoring of P. falciparum susceptibility to anti-malarial drugs was conducted in 1998, 2001, 2004/5, and 2008/9. Patients with confirmed P. falciparum malaria received therapy with 5 or 7 days of artemisinin (1998 and 2001 respectively or 7 days of artesunate Results In the four surveys, 270 patients were recruited and treated. The mean parasite clearance times differed between 1998, 2001 and 2004/5 (1.8, 2.3 and 2.1 days, P P. falciparum to artemisinin in in vitro tests was stable during the period, except for a rise in EC90 and EC99 in 2001. Conclusions This study showed stable levels of P. falciparum sensitivity to artemisinin compounds in the two sites over a ten-year period. The introduction of ACT in this area in 2003 may have protected against the development of artemisinin resistance. Adherence to the latest WHO and Vietnamese guidelines, which recommend ACT as first-line therapy in all malarious areas, and continued monitoring along the Vietnam-Cambodia border will be

  4. Haemophilus paragallinarum in chickens in Indonesia: III. Antimicrobial drug sensitivity test ofHaemophilus paragallinarum from chickens suffering of coryza

    OpenAIRE

    Sri Poernomo; Sutarma Sutarma; Sang Ayu Ketut Dewi Silawatri

    1998-01-01

    An agar disc diffusion method was used to examine the sensitivity of 27 Haemophilus paragallinarum (Hpg) isolates consisted of 23 local isolates, 4 standard isolates (serotype A) and Escherichia coli ATCC 24922 as a control to eight antimicrobial drugs (ampicillin, erythromycin, oxytetracycline, doxycycline, neomycin, streptomycin, colistine and sulphanlethoxazole-trimethoprim) . Twenty one out of 23 local isolates of Hpg were sensitive to doxycycline, 19 isolates to ampsllin, 18 isolates to ...

  5. A Genomewide Screen in Schizosaccharomyces pombe for Genes Affecting the Sensitivity of Antifungal Drugs That Target Ergosterol Biosynthesis

    OpenAIRE

    Fang, Yue; Hu, Lingling; Zhou, Xin; Jaiseng, Wurentuya; Zhang, Ben; Takami, Tomonori; Kuno, Takayoshi

    2012-01-01

    We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that target ergosterol biosynthesis using a Schizosaccharomyces pombe gene deletion library consisting of 3,004 nonessential haploid deletion mutants. We identified 109 mutants that were hypersensitive and 11 mutants that were resistant to these antifungals. Proteins whose absence rendered cells sensitive to these antifungals were classified into various functional categories,...

  6. The role of impulsivity in the aetiology of drug dependence: reward sensitivity versus automaticity

    OpenAIRE

    Hogarth, Lee

    2011-01-01

    Rationale Impulsivity has long been known as a risk factor for drug dependence, but the mechanisms underpinning this association are unclear. Impulsivity may confer hypersensitivity to drug reinforcement which establishes higher rates of instrumental drug-seeking and drug-taking behaviour, or may confer a propensity for automatic (non-intentional) control over drug-seeking/taking and thus intransigence to clinical intervention. Method The current study sought to distinguish these two accounts...

  7. Overexpression of Bax induces apoptosis and enhances drug sensitivity of hepatocellular cancer-9204 cells

    Institute of Scientific and Technical Information of China (English)

    Jian-Yong Zheng; Guang-Shun Yang; Wei-Zhong Wang; Jiang Li; Kai-Zong Li; Wen-Xian Guan; Wen-Liang Wang

    2005-01-01

    AIM: To investigate the role of overexpression of Bax in apoptotic pathways and the response of human hepatocellular cancer (HCC)-9204 cells to cell death induced by adriamycin.METHODS: The whole length of Bax cDNA was transfectrd into human HCC-9204 cells by the method of lipofectamine transfection. An inducible MT-Ⅱ regulatory system was constructed, which allowed controlled expression of protein upon addition of ZnSO4 (100 μmol/L) as an external inducer. Stable transfecting inducible expression vector containing Bax gene was performed. Expression of Bax in protein was analyzed by immunohistochemistry and Western blotting. TUNEL and flow cytometry were used to assess the effect of Bax on apoptosis. Colony assay and tetrazolium blue (MTT) assay were used to evaluate the difference in drug sensitivity of HCC-9204 cells after Bax-transfection.RESULTS: Immunohistochemistry and Western blotting demonstrated that the expression of Bax protein markedly increased in Bax-transfected cells 4 h after the addition cytoplasm and perinuclear region of HCC-9404 cells, and there was ectopic expression in cells with marked condensation of chromatin and cytoplasm (apoptotic cells). Apoptotic index significantly increased in Bax-transfected HCC-9204/Bax cells (3.6 vs 27.2, 4.2 vs 32.3, P<0.05).Flow cytometry analysis showed a significant sub-G1 peak and apoptosis in 15.4% HCC-9204/Bax cells 24 h after treatment. Furthermore, colony survival rate decreased from 66% (HCC-9204/pMD) to 45% (HCC-9204/Bax) 2 dafter ADR withdrawal. MTT assay result showed that the effects of Bax on cell viability following ADR exposure were significant as compared to the vehicle-transfected HCC-9204/pMD cells (21% vs 44%, P<0.01).CONCLUSION: Overexpression of Bax not only induces apoptosis, but also sensitizes HCC-9204 cells to cell death induced by adriamycin.

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

    Directory of Open Access Journals (Sweden)

    Madeeha Malik

    2013-01-01

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

  9. Design and synthesis of pH-sensitive polymeric micelles for oral delivery of poorly water-soluble drugs.

    Science.gov (United States)

    Yang, Xiaolan; Fan, Rongrong; Wang, Wenlong; Wang, Jiexin; Le, Yuan

    2016-09-01

    pH-sensitive polymer poly (polylactide-co-methacrylic acid)-b-poly (acrylic acid) was synthesized using atom transfer radical polymerization and ring-opening polymerization and characterized by gel permeation chromatography and (1)H NMR. The polymers can self-assemble to form micelles in aqueous medium, which respond rapidly to pH change within the gastrointestinal relevant pH range. Critical micelle concentrations and pH response behavior of the polymeric micelle were investigated. Water-insoluble drug nifedipine was loaded and the drug-loading content can be controlled by tuning the composition of the polymers. The in vitro release studies indicate pH sensitivity enabled rapid drug release at the environment of simulated intestinal fluid (pH 7.36), the cumulative released amount of NFD reached more than 80% within 24 h, while only 35% in the simulated gastric fluid (pH 1.35). All the results showed that the pH-sensitive P(PLAMA-co-MAA)-b-PAA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior. PMID:27342342

  10. Peroxiredoxin 1 knockdown sensitizes cancer cells to reactive oxygen species-generating drugs - an alternative approach for chemotherapy.

    Science.gov (United States)

    He, Tiantian; Hatem, Elie; Vernis, Laurence; Huang, Meng-Er

    2014-10-01

    Peroxiredoxins have multiple cellular functions as major antioxidants, signaling regulators and tumor suppressors. Peroxiredoxin 1 (PRX1) is the most abundant among the six isoforms of human peroxiredoxins, catalyzing the reduction of peroxides utilizing thioredoxin 1as an electron donor. PRX1 is frequently over-expressed in various cancer cells, which is thought to be associated with carcinogenesis, metastasis and resistance to radiotherapy or chemotherapy. We investigated how modulations of intracellular redox system, especially PRX1, affect cancer cell sensitivity to reactive oxygen species (ROS)-generating drugs. We observed that stable and transient Prx1 knockdown (Prx1-) significantly enhances HeLa cell sensitivity to β-lapachone (β-lap), a potential anticancer agent, and to other ROS-generating molecules. ROS accumulation played a crucial role in drug-enhanced Prx1- cell death. For β-lap, Prx1- cells sensitization is achieved through combined action of accumulation of ROS and enhancement of mitogen-activated protein kinase pathway activation. The effect of other ROS-inducing drugs on Prx1- cell survival will also be presented and discussed. Taken together, our data provide evidence that PRX1 could be an interesting anticancer target and modulation of intracellular redox states through PRX1 inhibition could be an alternative approach to enhance cancer cell sensitivity to ROS-generating drugs. PMID:26461286

  11. Swelling characteristics of hydroxyethylmethacrylate/ methacrylic acid pH -sensitive hydrogel as a drug delivery system

    Directory of Open Access Journals (Sweden)

    M. Falamarzian- J. Varshosaz

    1996-08-01

    Full Text Available Hydroxyethyl methacrylate /methacrylic acid (HEMA/MAA copolymer cross-linked with ethylenglycol dimethacrylate was prepared by a bulk.free radical polymerization method. The results indicate that this polymer is a pH -sensitive hydrogel which is collapsed in the acidic medium but completely swollen in the alkaline and neutral pH . it was determined that a proportion of 40% of MAA, the ionizing monomer of this hydrogel, was the best concentration among the different percentages used which showed a non-Fickian water transport mechanism. Increasing MAA content from 20 to 70% was accompanied with a change in water transport mechanism from Fickian to non-Fickian. However, increasing the percentage of MAA from 40 to 70 didn't improve the swelling capacity of this polymer. Pore size determination by a solute exclusion technique, showed the greatest distribution in the hydrogel with 40% MAA compared to other percentages of this monomer used. About 75% of the pores were less than 16.5 A in diameter in this polymer which is important specially in loading the hydrogel with macromoiecular drugs like proteines.

  12. Functionalized chalcones with basic functionalities have antibacterial activity against drug sensitive Staphylococcus aureus.

    Science.gov (United States)

    Liu, X L; Xu, Y J; Go, M L

    2008-08-01

    A library of chalcones with basic functionalities were evaluated for antibacterial activity against drug sensitive strains of Staphylococcus aureus and Escherichia coli. The most active compounds were 2-52 and 2-57 (MIC 6.3 microM S. aureus). These compounds had no activity against E. coli (MIC>100 microM). Both compounds were characterized by a ring A that was substituted with 2-hydroxy-4,6-dimethoxy-3-(1-methylpiperidin-4-yl) groups. The phenolic OH and 1-methylpiperidinyl groups were required for activity but the phenolic OH may play a more critical role. While the compounds were comparable to licochalcone A in terms of antibacterial activity, they caused less hemolysis of sheep erythrocytes at high concentrations (100 microM). It was noted that the structural requirements for limiting hemolytic activity were less stringent than those required for antibacterial activity. The present findings suggest that the chalcone framework is an attractive template for optimization to achieve better potency, lower toxicity and a wider spectrum of antibacterial activity. PMID:18031869

  13. Aerosol-Assisted Fast Formulating Uniform Pharmaceutical Polymer Microparticles with Variable Properties toward pH-Sensitive Controlled Drug Release

    Directory of Open Access Journals (Sweden)

    Hong Lei

    2016-05-01

    Full Text Available Microencapsulation is highly attractive for oral drug delivery. Microparticles are a common form of drug carrier for this purpose. There is still a high demand on efficient methods to fabricate microparticles with uniform sizes and well-controlled particle properties. In this paper, uniform hydroxypropyl methylcellulose phthalate (HPMCP-based pharmaceutical microparticles loaded with either hydrophobic or hydrophilic model drugs have been directly formulated by using a unique aerosol technique, i.e., the microfluidic spray drying technology. A series of microparticles of controllable particle sizes, shapes, and structures are fabricated by tuning the solvent composition and drying temperature. It is found that a more volatile solvent and a higher drying temperature can result in fast evaporation rates to form microparticles of larger lateral size, more irregular shape, and denser matrix. The nature of the model drugs also plays an important role in determining particle properties. The drug release behaviors of the pharmaceutical microparticles are dependent on their structural properties and the nature of a specific drug, as well as sensitive to the pH value of the release medium. Most importantly, drugs in the microparticles obtained by using a more volatile solvent or a higher drying temperature can be well protected from degradation in harsh simulated gastric fluids due to the dense structures of the microparticles, while they can be fast-released in simulated intestinal fluids through particle dissolution. These pharmaceutical microparticles are potentially useful for site-specific (enteric delivery of orally-administered drugs.

  14. Imipramine is an orally active drug against both antimony sensitive and resistant Leishmania donovani clinical isolates in experimental infection.

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    Sandip Mukherjee

    Full Text Available BACKGROUND: In an endeavor to find an orally active and affordable antileishmanial drug, we tested the efficacy of a cationic amphiphilic drug, imipramine, commonly used for the treatment of depression in humans. The only available orally active antileishmanial drug is miltefosine with long half life and teratogenic potential limits patient compliance. Thus there is a genuine need for an orally active antileishmanial drug. Previously it was shown that imipramine, a tricyclic antidepressant alters the protonmotive force in promastigotes, but its in vivo efficacy was not reported. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the drug is highly active against antimony sensitive and resistant Leishmania donovani in both promastigotes and intracellular amastigotes and in LD infected hamster model. The drug was found to decrease the mitochondrial transmembrane potential of Leishmania donovani (LD promastigotes and purified amastigotes after 8 h of treatment, whereas miltefosine effected only a marginal change even after 24 h. The drug restores defective antigen presenting ability of the parasitized macrophages. The status of the host protective factors TNF α, IFN γ and iNOS activity increased with the concomitant decrease in IL 10 and TGF β level in imipramine treated infected hamsters and evolution of matured sterile hepatic granuloma. The 10-day therapeutic window as a monotherapy, showing about 90% clearance of organ parasites in infected hamsters regardless of their SSG sensitivity. CONCLUSIONS: This study showed that imipramine possibly qualifies for a new use of an old drug and can be used as an effective orally active drug for the treatment of Kala-azar.

  15. Single-cell analysis of targeted transcriptome predicts drug sensitivity of single cells within human myeloma tumors.

    Science.gov (United States)

    Mitra, A K; Mukherjee, U K; Harding, T; Jang, J S; Stessman, H; Li, Y; Abyzov, A; Jen, J; Kumar, S; Rajkumar, V; Van Ness, B

    2016-05-01

    Multiple myeloma (MM) is characterized by significant genetic diversity at subclonal levels that have a defining role in the heterogeneity of tumor progression, clinical aggressiveness and drug sensitivity. Although genome profiling studies have demonstrated heterogeneity in subclonal architecture that may ultimately lead to relapse, a gene expression-based prediction program that can identify, distinguish and quantify drug response in sub-populations within a bulk population of myeloma cells is lacking. In this study, we performed targeted transcriptome analysis on 528 pre-treatment single cells from 11 myeloma cell lines and 418 single cells from 8 drug-naïve MM patients, followed by intensive bioinformatics and statistical analysis for prediction of proteasome inhibitor sensitivity in individual cells. Using our previously reported drug response gene expression profile signature at the single-cell level, we developed an R Statistical analysis package available at https://github.com/bvnlabSCATTome, SCATTome (single-cell analysis of targeted transcriptome), that restructures the data obtained from Fluidigm single-cell quantitative real-time-PCR analysis run, filters missing data, performs scaling of filtered data, builds classification models and predicts drug response of individual cells based on targeted transcriptome using an assortment of machine learning methods. Application of SCATT should contribute to clinically relevant analysis of intratumor heterogeneity, and better inform drug choices based on subclonal cellular responses. PMID:26710886

  16. Development and Application of Zirconia Coated Paper Substrate for High Sensitivity Analysis of Therapeutic Drugs in Dried Blood Spots.

    Science.gov (United States)

    Zheng, Yajun; Wang, Qian; Wang, Xiaoting; Chen, Ying; Wang, Xuan; Zhang, Xiaoling; Bai, Zongquan; Han, Xiaoxiao; Zhang, Zhiping

    2016-07-19

    Paper spray mass spectrometry has been demonstrated to be promising for direct analysis of therapeutic drugs in dried blood spots (DBS); however, the strong hydrogen bond and van de Waals interactions between paper substrate and analytes containing polar functional groups (e.g., therapeutic drugs) affect greatly the elution behavior and analysis sensitivity of compounds of interest during paper spray. Herein, we developed a one-sided ZrO2 coated paper substrate through a facile vacuum filtration approach using commercial ZrO2 particles as coating material and soluble starch as adhesive agent. Owing to the unique surface properties, as-prepared ZrO2 paper substrate has been shown to have excellent performance for analysis of therapeutic drugs in DBS during paper spray mass spectrometry. In contrast to original cellulose paper substrates, improvements of 43-189-fold in lower limit of quantitation (LLOQ) were obtained for the tested drugs using ZrO2 coated paper for paper spray. In comparing with the previously reported grade SG81 paper and one-sided silica coated paper, the LLOQs of the tested drugs with as-prepared ZrO2 paper decreased 1.5-16.5-fold relative to those from the above two, revealing that ZrO2 coated paper is a good candidate for paper spray in high sensitivity analysis of therapeutic drugs in DBS. PMID:27314839

  17. Combating malaria with nanotechnology-based targeted and combinatorial drug delivery strategies.

    Science.gov (United States)

    Thakkar, Miloni; S, Brijesh

    2016-08-01

    Despite the advancement of science, infectious diseases such as malaria remain an ongoing challenge globally. The main reason this disease still remains a menace in many countries around the world is the development of resistance to many of the currently available anti-malarial drugs. While developing new drugs is rather expensive and the prospect of a potent vaccine is still evading our dream of a malaria-free world, one of the feasible options is to package the older drugs in newer ways. For this, nano-sized drug delivery vehicles have been used and are proving to be promising prospects in the way malaria will be treated in the future. Since, monotherapy has given way to combination therapy in malaria treatment, nanotechnology-based delivery carriers enable to encapsulate various drug moieties in the same package, thus avoiding the complications involved in conjugation chemistry to produce hybrid drug molecules. Further, we envisage that using targeted delivery approaches, we may be able to achieve a much better radical cure and curb the side effects associated with the existing drug molecules. Thus, this review will focus on some of the nanotechnology-based combination and targeted therapies and will discuss the possibilities of better therapies that may be developed in the future. PMID:27067712

  18. 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

  19. New amphiphilic glycopolypeptide conjugate capable of self-assembly in water into reduction-sensitive micelles for triggered drug release

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Hui-Kang [DSAPM Lab and PCFM Lab, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275 (China); Zhang, Li-Ming, E-mail: ceszhlm@mail.sysu.edu.cn [DSAPM Lab and PCFM Lab, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275 (China); Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006 (China)

    2014-08-01

    For the development of biomimetic carriers for stimuli-sensitive delivery of anticancer drugs, a novel amphiphilic glycopolypeptide conjugate containing the disulfide bond was prepared for the first time by the ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of (propargyl carbamate)ethyl dithio ethylamine and then click conjugation with α-azido dextran. Its structure was characterized by Fourier-transform infrared spectroscopy and nuclear magnetic resonance analyses. Owing to its amphiphilic nature, such a conjugate could self assemble into nanosize micelles in aqueous medium, as confirmed by fluorometry, transmission electron microscopy and dynamic light scattering. For the resultant micelles, it was found to encapsulate poorly water-soluble anticancer drug (methotrexate, MTX) with the loading efficiency of 45.2%. By the in vitro drug release tests, the release rate of encapsulated MTX was observed to be accelerated significantly in the presence of 10 mM 1,4-dithio-DL-threitol (DTT), analogous to the intracellular redox potential. - Graphical abstract: New amphiphilic glycopolypeptide conjugate containing the disulfide bond could self-assemble in aqueous solution into reduction-sensitive micelles for triggered release of an anticancer drug (methotrexate, MTX) in the presence of 10 mM 1,4-dithio-DL-threitol (DTT). - Highlights: • Amphiphilic glycopolypeptide conjugate containing disulfide bond was prepared. • Such a conjugate self assembled in aqueous solution into nanosize micelles. • The resultant micelles could encapsulate effectively methotrexate drug. • The drug-loaded micelles showed a reduction-sensitive drug release behavior.

  20. New amphiphilic glycopolypeptide conjugate capable of self-assembly in water into reduction-sensitive micelles for triggered drug release

    International Nuclear Information System (INIS)

    For the development of biomimetic carriers for stimuli-sensitive delivery of anticancer drugs, a novel amphiphilic glycopolypeptide conjugate containing the disulfide bond was prepared for the first time by the ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of (propargyl carbamate)ethyl dithio ethylamine and then click conjugation with α-azido dextran. Its structure was characterized by Fourier-transform infrared spectroscopy and nuclear magnetic resonance analyses. Owing to its amphiphilic nature, such a conjugate could self assemble into nanosize micelles in aqueous medium, as confirmed by fluorometry, transmission electron microscopy and dynamic light scattering. For the resultant micelles, it was found to encapsulate poorly water-soluble anticancer drug (methotrexate, MTX) with the loading efficiency of 45.2%. By the in vitro drug release tests, the release rate of encapsulated MTX was observed to be accelerated significantly in the presence of 10 mM 1,4-dithio-DL-threitol (DTT), analogous to the intracellular redox potential. - Graphical abstract: New amphiphilic glycopolypeptide conjugate containing the disulfide bond could self-assemble in aqueous solution into reduction-sensitive micelles for triggered release of an anticancer drug (methotrexate, MTX) in the presence of 10 mM 1,4-dithio-DL-threitol (DTT). - Highlights: • Amphiphilic glycopolypeptide conjugate containing disulfide bond was prepared. • Such a conjugate self assembled in aqueous solution into nanosize micelles. • The resultant micelles could encapsulate effectively methotrexate drug. • The drug-loaded micelles showed a reduction-sensitive drug release behavior

  1. Anticancer drug sensitivity prediction in cell lines from baseline gene expression through recursive feature selection

    OpenAIRE

    Dong, Zuoli; Zhang, Naiqian; Li, Chun; Wang, Haiyun; Fang, Yun; Wang, Jun; Zheng, Xiaoqi

    2015-01-01

    Background An enduring challenge in personalized medicine is to select right drug for individual patients. Testing drugs on patients in large clinical trials is one way to assess their efficacy and toxicity, but it is impractical to test hundreds of drugs currently under development. Therefore the preclinical prediction model is highly expected as it enables prediction of drug response to hundreds of cell lines in parallel. Methods Recently, two large-scale pharmacogenomic studies screened mu...

  2. Cell-specific intracellular anticancer drug delivery from mesoporous silica nanoparticles with pH sensitivity.

    Science.gov (United States)

    Luo, Zhong; Cai, Kaiyong; Hu, Yan; Zhang, Beilu; Xu, Dawei

    2012-05-01

    A nanoreservoir for efficient intracellular anticancer drug delivery based on mesoporous silica nanoparticles end-capped with lactobionic acid-grafted bovine serum albumin is fabricated. It demonstrates great potential for both cell-specific endocytosis and intracellular pH-responsive controlled release of drugs. A possible endocytosis pathway/mechanism of the smart controlled drug release system is proposed. PMID:23184747

  3. Development of a glucose-sensitive drug delivery device: Microencapsulated liposomes and poly(2-ethylacrylic acid)

    Science.gov (United States)

    Kanokpanont, Sorada

    The current study is the development a self-regulated, glucose responsive drug delivery system, using dioleoylphosphatidylcholine (DOPC) liposomes, a pH sensitive polymer, poly (2-ethylacrylic acid)(PEAA), and the feed back reaction of glucose with glucose oxidase enzyme (GO). The thesis investigates the use of PEAR and liposomes to work inside a microcapsule in response to the glucose level of the environment, by following the release of fluorescence probes, 8-aminonapthalene-1,3,6-trisulfonic acid, disodium salt/p-xylene-bis-pyridimuim bromide (ANTS/DPX) and a model protein, myoglobin. The continuing studies of PEAR and liposome interaction indicated an evidence of the previous hypothesis of two-mode release at different pHs. Differential scanning calorimetric studies of DOPC and PEAA complexes revealed the possibility of polymer adsorption to the liposomes in the pH range 5.5--7.0 and insertion in the liposome bilayer at pH optimal concentration in the capsules. The pH reduction inside the capsule due to GO reaction showed positive results for the use of GO in a non-buffered system. The procedure of liquid-core alginate capsules was modified to facilitate the pH-responsive release of ANTS/DPX and myoglobin. The capsules responded to high blood glucose concentration by releasing myoglobin within 30 minutes. Although more studies are required to improve the response of the system to the normal blood glucose and to control the total protein release from negative controls, the results of in vitro release experiments confirmed the hypothesis that an idealized feedback control insulin delivery system is feasible.

  4. Mammaglobin 1 promotes breast cancer malignancy and confers sensitivity to anticancer drugs.

    Science.gov (United States)

    Picot, Nadia; Guerrette, Roxann; Beauregard, Annie-Pier; Jean, Stéphanie; Michaud, Pascale; Harquail, Jason; Benzina, Sami; Robichaud, Gilles A

    2016-07-01

    Mammaglobin 1 (MGB1), a member of the secretoglobin family, is expressed in mammary epithelial tissues and is overexpressed in most mammary carcinomas. Despite the extensive research correlating MGB1 expression profiles to breast cancer pathogenesis and disease outcome, the biological significance of MGB1 in cancer processes is still unclear. We have thus set out to conduct a functional evaluation of the molecular and cellular roles of MGB1 in breast cancer processes leading to disease progression. Using a series of breast cancer cell models with conditional MGB1 expression, we demonstrate that MGB1 promotes cancer cell malignant features. More specifically, loss of MGB1 expression resulted in a decrease of cell proliferation, soft agar spheroid formation, migration, and invasion capacities of breast cancer cells. Concomitantly, we also observed that MGB1 expression activates signaling pathways mediated by MAPK members (p38, JNK, and ERK), the focal adhesion kinase (FAK), matrix metalloproteinases (MMPs) and NFκB. Moreover, MGB1 regulates epithelial to mesenchymal (EMT) features and modulates Snail, Twist and ZEB1 expression levels. Interestingly, we also observed that expression of MGB1 confers breast cancer cell sensitivity to anticancer drug-induced apoptosis. Together, our results support a role for MGB1 in tumor malignancy in exchange for chemosensitivity. These findings provide one of the first descriptive overview of the molecular and cellular roles of MGB1 in breast cancer processes and may offer new insight to the development of therapeutic and prognostic strategies in breast cancer patients. © 2015 Wiley Periodicals, Inc. PMID:26207726

  5. Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents.

    Directory of Open Access Journals (Sweden)

    Ryan J Mailloux

    Full Text Available Uncoupling protein-2 (UCP2 is known to suppress mitochondrial reactive oxygen species (ROS production and is employed by drug-resistant cancer cells to mitigate oxidative stress. Using the drug-sensitive HL-60 cells and the drug-resistant MX2 subline as model systems, we show that genipin, a UCP2 inhibitor, sensitizes drug-resistant cells to cytotoxic agents. Increased MX2 cell death was observed upon co-treatment with genipin and different doses of menadione, doxorubicin, and epirubicin. DCFH-DA fluorimetry revealed that the increase in MX2 cell death was accompanied by enhanced cellular ROS levels. The drug-induced increase in ROS was linked to genipin-mediated inhibition of mitochondrial proton leak. State 4 and resting cellular respiratory rates were higher in the MX2 cells in comparison to the HL-60 cells, and the increased respiration was readily suppressed by genipin in the MX2 cells. UCP2 accounted for a remarkable 37% of the resting cellular oxygen consumption indicating that the MX2 cells are functionally reliant on this protein. Higher amounts of UCP2 protein were detected in the MX2 versus the HL-60 mitochondria. The observed effects of genipin were absent in the HL-60 cells pointing to the selectivity of this natural product for drug-resistant cells. The specificity of genipin for UCP2 was confirmed using CHO cells stably expressing UCP2 in which genipin induced an ∼22% decrease in state 4 respiration. These effects were absent in empty vector CHO cells expressing no UCP2. Thus, the chemical inhibition of UCP2 with genipin sensitizes multidrug-resistant cancer cells to cytotoxic agents.

  6. Development of novel polymeric materials for gene therapy and pH-sensitive drug delivery: Modeling, synthesis, characterization, and analysis

    Science.gov (United States)

    Anderson, Brian Curtis

    The aim of this work was to obtain a fundamental understanding of drug release mechanisms from polymers that undergo thermoreversible gelation and to synthesize new polymers based on these that exhibit both pH and temperature sensitivity. Novel block and random copolymers with cationic character have been developed for drug delivery and gene therapy applications. The development of these materials began with a study of the mechanism of drug release from poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers. This study revealed the release rates of drugs from water-soluble hydrogels composed of the PEO-PPO-PEO block copolymer PluronicRTM F127 was dictated almost solely by the rate of interfacial dissolution at the water/gel interface. A setup was designed to measure drug release from such soluble systems in order to avoid confounding hydrodynamic effects as a result of shear on the delicate polymer/gel interface. This study was followed by a complementary analysis of the effect ionic salts play in the phase transitions and drug release profiles in aqueous F127 solutions. In an attempt to incorporate pH sensitivity into such drug release systems, several block copolymers of poly(N,N-diethylaminoethyl methacrylate) (PDEAEM), PEO and PPO were synthesized via anionic polymerization. Diblock materials (PEO-b-PDEAEM), either with or without a carboxylic acid endcap, were synthesized and characterized. Tablet dissolution experiments demonstrated pH-sensitivity in their drug release profiles relative to PEO tablets. Pentablock materials (PDEAEM-b-PEO-b-PPO- b-PEO-b-PDEAEM) were synthesized that maintain the thermoreversible gelation and micellization properties of F127 while introducing pH-dependent release from aqueous gels of the copolymer. This is the first example of non-crosslinked materials that exhibit both pH- and temperature-sensitive behavior. Using a similar synthesis route, random copolymers of PDEAEM and poly(poly(ethylene glycol) methyl

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

    International Nuclear Information System (INIS)

    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)

  8. Haemophilus paragallinarum in chickens in Indonesia: III. Antimicrobial drug sensitivity test ofHaemophilus paragallinarum from chickens suffering of coryza

    Directory of Open Access Journals (Sweden)

    Sri Poernomo

    1998-12-01

    Full Text Available An agar disc diffusion method was used to examine the sensitivity of 27 Haemophilus paragallinarum (Hpg isolates consisted of 23 local isolates, 4 standard isolates (serotype A and Escherichia coli ATCC 24922 as a control to eight antimicrobial drugs (ampicillin, erythromycin, oxytetracycline, doxycycline, neomycin, streptomycin, colistine and sulphanlethoxazole-trimethoprim . Twenty one out of 23 local isolates of Hpg were sensitive to doxycycline, 19 isolates to ampsllin, 18 isolates to oxytetracycline, 17 isolates to sulphametoxazole-trimethoprim, 16 isolates to erythromycin, and 13 isolates to neomycin, while 13 isolates were resistance to colistine and 11 isolates were also resistance to streptomycin .

  9. Analysis of drug sensitivity of candida to antifungal drugs in 152 infected patients%152例临床念珠菌感染药敏分析

    Institute of Scientific and Technical Information of China (English)

    奚琳琳; 张群智; 李芳芹

    2011-01-01

    目的 了解医院念珠菌感染药敏情况,为临床合理用药提供实验依据.方法 从临床标本中分离培养念珠菌,进行鉴定和药敏试验.结果 1 538份临床标本中分离出念珠菌152株(9.88%);其中,白色念珠菌111株(73.03%),克柔氏念珠菌31例(20.39%),其他10(6.58%).白色念珠菌时常用抗真菌药物敏感性均较高(伊曲康唑除外),而克柔氏念珠菌则对常用抗真菌药物均有较高的敏感率.结论 白色念珠菌和克柔氏念珠菌对临床一线抗真菌药氟康哇存在耐药株,应重视对高危人群进行微生物学检测和药敏试验.%Aim To investigate drug sensitivity of candida to antibiotics in patients with candida infection.Methods Candida were isolated and cultured from clinical 152 and drug sensitivity of candida to antifungal was conducted and the results were analyzed.Results A total of 152 (9.88%)candida strains were isolated from 1 538 samples,including 111 (73.03%)Candida albicans and 31 (20.39%)Candida krusei.Candida albicans showed higher sensitive rates to conventional antifungal drugs except itraconazole.However,Candida krusei showed higher sensitive rates to antifungal agents.Conclusion Candida albicans and Candida krusei showed resistances to clinical first-line antffuangal drugs such as fluconazole.Thus srug sensitivity tests be carried out to guide clinical treatment of the infections

  10. Trafficking Microenvironmental pHs of Polycationic Gene Vectors in Drug-Sensitive and Multidrug-Resistant MCF7 Breast Cancer Cells

    OpenAIRE

    Kang, Han Chang; Samsonova, Olga; Bae, You Han

    2010-01-01

    While multidrug resistance (MDR) has been a significant issue in cancer chemotherapy, delivery resistance to various anticancer biotherapeutics, including genes, has not been widely recognized as a property of MDR. This study aims to provide a better understanding of the transfection characteristics of drug-sensitive and drug-resistant cells by tracing microenvironmental pHs of two representative polymer vectors: poly(l-lysine) and polyethyleneimine. Drug-sensitive breast MCF7 cells had four-...

  11. Apoptosis-related molecular differences for response to tyrosin kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

    Directory of Open Access Journals (Sweden)

    Jixia Li

    2013-01-01

    Full Text Available Context: The epidermal growth factor receptor (EGFR family is reportedly overexpressed in bladder cancer, and tyrosine kinaseinhibitors (TKIs have been suggested as treatment. Gefitinib is a selective inhibitor of the EGFR and lapatinib is a dual inhibitor of both the EGFR and HER2 (human EGFR type 2 receptor. Both compounds compete with the binding of adenosine triphosphate (ATP to the tyrosine kinase domain of the respective receptors to inhibit receptor autophosphorylation causing suppression of signal transduction. Unfortunately, resistance to these inhibitors is a major clinical problem. Aims: To compare the apoptosis signaling pathway(s induced by gefitinib and lapatinib, in UM-UC-5 (drug-sensitive and UM-UC-14 (drug-resistant bladder cancer cells and to identify molecular differences that might be useful predictors of their efficacy. Materials and Methods: Cell proliferation, cell cycle and apoptosis assay were used to detect the effect of TKIs on UM-UC-5 and UM-UC-14 cells. Molecular differences for response to TKIs were examined by protein array. Results: TKIs strongly inhibited cell proliferation and induced cell cycle G1 arrest and apoptosis in UM-UC-5 cells. Most notable apoptosis molecular differences included decreased claspin, trail, and survivin by TKIs in the sensitive cells. In contrast, TKIs had no effect on resistant cells. Conclusions: Claspin, trail, and survivin might be used to determine the sensitivity of bladder cancers to TKIs.

  12. New oil modified acrylic polymer for pH sensitive drug release: Experimental results and statistical analysis

    OpenAIRE

    Panja, N.; Chattopadhyay, A.K.

    2014-01-01

    We report results of an experimental study, complemented by detailed statistical analysis of the experimental data, on the development of a more effective control method of drug delivery using a pH sensitive acrylic polymer. New copolymers based on acrylic acid and fatty acid are constructed from dodecyl castor oil and a tercopolymer based on methyl methacrylate, acrylic acid and acryl amide were prepared using this new approach. Water swelling characteristics of fatty acid, acrylic acid copo...

  13. Enzyme- and pH-Sensitive Branched Polymer-Doxorubicin Conjugate-Based Nanoscale Drug Delivery System for Cancer Therapy.

    Science.gov (United States)

    Wei, Xiaoli; Luo, Qiang; Sun, Ling; Li, Xue; Zhu, Hongyan; Guan, Pujun; Wu, Min; Luo, Kui; Gong, Qiyong

    2016-05-11

    Owing to their dendritic architectural features, branched copolymers have been investigated as drug delivery systems. In this paper, an enzyme- and pH-sensitive branched poly[N-(2-hydroxypropyl)methacrylamide] (polyHPMA) copolymer-doxorubicin (DOX) conjugate possessing a molecular weight (MW) of 165 kDa was designed and prepared via a one-pot reaction and drug conjugation. This conjugate's potential as a smart, nanoscale drug delivery system (NDDS) is also investigated. The branched conjugate was capable of forming nanoparticles with a negative surface charge. The self-assembled nanoparticles were 102 nm in diameter as measured by dynamic light scattering (DLS) and 95 nm in diameter via scanning electron microscopy, respectively. The nanoparticles were degraded to low-MW products (23∼25 kDa) in the presence of papain or cathepsin B, and the degradation was monitored via DLS and size-exclusion chromatography. The nanoparticles demonstrated pH-sensitive drug release, as the DOX was attached to the branched copolymer via a hydrazone bond. In comparison to free DOX, the conjugate-based nanoparticles exhibited greater accumulation in breast tumors, resulting in enhanced antitumor therapeutic indexes. Furthermore, widespread dissemination of the conjugate among breast tumor cells was confirmed by immunohistochemical assay. Finally, no obvious systemic toxicities were observed in vivo in normal mice. Thus, the branched HPMA copolymer-DOX conjugate may be employed as a safe and efficient pH- and enzyme-responsive NDDS for cancer therapy. PMID:27102364

  14. pH-sensitive nanomicelles for controlled and efficient drug delivery to human colorectal carcinoma LoVo cells.

    Directory of Open Access Journals (Sweden)

    Shi-Ting Feng

    Full Text Available BACKGROUND: The triblock copolymers PEG-P(Asp-DIP-P(Lys-Ca (PEALCa of polyethylene glycol (PEG, poly(N-(N',N'-diisopropylaminoethyl aspartamide (P(Asp-DIP, and poly (lysine-cholic acid (P(Lys-Ca were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES, and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. METHODOLOGY/PRINCIPAL FINDINGS: The anticancer drug Paclitaxel (PTX and hydrophilic superparamagnetic iron oxide (SPIO were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells, and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. CONCLUSIONS/SIGNIFICANCE: These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy.

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

    International Nuclear Information System (INIS)

    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-1IIIB and HIV-1BaL as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1IIIB activity, whereas fusion inhibitors showed both anti-HIV-1IIIB and anti-HIV-1BaL 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.

  16. Cellular HIV type 1 DNA levels are equivalent among drug-sensitive and drug-resistant strains in newly diagnosed and antiretroviral naive patients.

    Science.gov (United States)

    Antoniadou, Zoi-Anna; Hezka, Johana; Kousiappa, Ioanna; Mamais, Ioannis; Skoura, Lemonia; Pilalas, Dimitris; Metallidis, Simeon; Nicolaidis, Pavlos; Malisiovas, Nicolaos; Kostrikis, Leondios G

    2014-03-01

    coreceptor tropism dominance suggests that both drug-resistant and drug-sensitive strains behave similarly in early infection in newly diagnosed patients. PMID:24025041

  17. pH-sensitive, polymer modified, plasma stable niosomes: promising carriers for anti-cancer drugs

    OpenAIRE

    Tila, Dena; Yazdani-Arazi, Seyede Narjes; Ghanbarzadeh, Saeed; Arami, Sanam; Pourmoazzen, Zhaleh

    2015-01-01

    The aim of this study was the design and evaluation of a novel plasma stable, pH-sensitive niosomal formulation of Mitoxantrone by a modified ethanol injection method. Cholesterol hemisuccinate was added instead of cholesterol in order to produce pH-sensitivity property and using PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymer introduced simultaneously pH-sensitivity and plasma stability properties in prepared niosomes. The pH-sensitivity and cytotoxicity of Mitoxantrone ni...

  18. PH-sensitive, polymer modified, plasma stable niosomes: promising carriers for anti-cancer drugs

    OpenAIRE

    Tila, Dena; Yazdani-Arazi, Seyede Narjes; Ghanbarzadeh, Saeed; Arami, Sanam; Pourmoazzen, Zhaleh

    2015-01-01

    The aim of this study was the design and evaluation of a novel plasma stable, pH-sensitive niosomal formulation of Mitoxantrone by a modified ethanol injection method. Cholesterol hemisuccinate was added instead of cholesterol in order to produce pH-sensitivity property and using PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymer introduced simultaneously pH-sensitivity and plasma stability properties in prepared niosomes. The pH-sensitivity and cytotoxicity of Mitoxantrone ni...

  19. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

    Science.gov (United States)

    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs. PMID:26420308

  20. Analysis of Culture and Drug Sensitivity Tests of Mycoplasmas for 387 Patients with Nongonococcal Urethritis (Cervicitis) in Chongqing

    Institute of Scientific and Technical Information of China (English)

    翟志芳; 郝飞; 钟白玉; 黄秀英; 唐书谦; 刁庆春

    2004-01-01

    Objective: To investigate the prevalence of mycoplasma infections and the sensitivity to antibiotics among patients with nongonococcal urethritis or cervicitis (NGU) in Chongqing. Methods: 387 NGU cases with mycoplasma-positive results upon culture were analysed retrospectively. RESULTS: The majority of patients with mycoplasma infections were in the 20-40 year old age group. No significant difference was found between males and females. Ureaplasma urealyticum is the main pathogen of these NGU cases and no clear relationship between its concentration and pathogenic ability was noted. Drug sensitivity was tested against nine antibiotics; the sensitivity rates to josamycin, minocycline and doxycycline were 94.06%, 88.89% and 86.82% respectively, while the resistance rates to lincomycin, ofloxacin, azithromycin and roxthromycin were 74.94%, 42.12%, 41.60% and 40.31% in turn. Conclusions: Josamycin, minocycline and doxycycline could be used as the first choice to treat NGU with mycoplasma infections in Chongqing. It is important to select antibiotics for NGU treatment with mycoplasma infections based on the results of drug sensitivity tests.

  1. Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?

    International Nuclear Information System (INIS)

    Drug resistance is a fundamental problem in the treatment of most common human cancers. Our understanding of the cellular mechanisms underlying death and survival has allowed the development of rational approaches to overcoming drug resistance. The mitogen activated protein kinase family of protein serine/threonine kinases has been implicated in this complex web of signalling, with some members acting to enhance death and other members to prevent it. A recent publication by MacKeigan et al is the first to demonstrate an enhancement of drug-induced cell death by simultaneous blockade of MEK-mediated survival signalling, and offers the potential for targeted adjuvant therapy as a means of overcoming drug resistance

  2. Graphene oxide-enhanced sol-gel transition sensitivity and drug release performance of an amphiphilic copolymer-based nanocomposite

    Science.gov (United States)

    Hu, Huawen; Wang, Xiaowen; Lee, Ka I; Ma, Kaikai; Hu, Hong; Xin, John H.

    2016-01-01

    We report the fabrication of a highly sensitive amphiphilic copolymer-based nanocomposite incorporating with graphene oxide (GO), which exhibited a low-intensity UV light-triggered sol-gel transition. Non-cytotoxicity was observed for the composite gels after the GO incorporation. Of particular interest were the microchannels that were formed spontaneously within the GO-incorporated UV-gel, which expedited sustained drug release. Therefore, the present highly UV-sensitive, non-cytotoxic amphiphilic copolymer-based composites is expected to provide enhanced photothermal therapy and chemotherapy by means of GO’s unique photothermal properties, as well as through efficient passive targeting resulting from the sol-gel transition characteristic of the copolymer-based system with improved sensitivity, which thus promises the enhanced treatment of patients with cancer and other diseases. PMID:27539298

  3. Cross-linked pH sensitive polymer micelles for drug delivery systems

    OpenAIRE

    Cajot, Sébastien; Jérôme, Christine

    2009-01-01

    Over the last decade, polymer micelles attracted an increasing interest in drug pharmaceutical research because they could be used as efficient drug delivery systems. Micelles of amphiphilic block copolymers are supramolecular core-shell type assemblies of tens of nanometers in diameter. In principle, the micelles core is usually constructed with biodegradable hydrophobic polymers such as aliphatic polyesters, e.g. poly(ɛ-caprolactone) (PCL), which serves as a reservoir for the incorpora...

  4. Konjac glucomannan/xanthan gum enzyme sensitive binary mixtures for colonic drug delivery.

    Science.gov (United States)

    Alvarez-Manceñido, Felipe; Landin, Mariana; Martínez-Pacheco, Ramón

    2008-06-01

    The polysaccharide konjac glucomannan (KGM) is degraded in the colon but not the small intestine, which makes it potentially useful as an excipient for colonic drug delivery. With xanthan gum (XG) KGM forms thermoreversible gels with hitherto unexplored biodegradation properties. In this work, rheological measurements of KGM and KGM/XG systems incubated with and without Aspergillus niger beta-mannanase (used to mimic colonic enzymes) showed that KGM was degraded by the enzyme even when interacting with XG. Tablets with KGM/XG/sucrose matrices that varied in accordance with a simplex design and bore diltiazem as a typical highly soluble drug load were prepared by wet granulation, and in most cases were found to possess satisfactory mechanical strength and exhibit slow, nearly zero-order drug release. Drug release from these tablets remained zero-order, but was accelerated (presumably due to degradation of KGM), in the presence of A. niger beta-mannanase at concentrations equivalent to human colonic conditions. However, marked differences between Japanese and American varieties of KGM as regards degree of acetylation and particle size led to significant differences in swelling rate and drug release between formulations prepared with one and the other KGM: whereas a formulation with Japanese KGM released its entire drug load within 24h in the presence of beta-mannanase, only 60% release was achieved under the same conditions by the corresponding formulation with American KGM, suggesting that with this KGM it will be necessary to optimize technological variables such as compression pressure in order to achieve suitable porosity, swelling rate, and drug release. To sum up, the results of this study suggest that sustained release of water-soluble drugs in the colon from orally administered tablets may be achieved using simple, inexpensive formulations based on combinations of KGM and XG that take the variability of KGM characteristics into account. PMID:18294827

  5. Sensitization of Candida albicans biofilms to various antifungal drugs by cyclosporine A

    Directory of Open Access Journals (Sweden)

    Shinde Ravikumar B

    2012-10-01

    Full Text Available Abstract Background Biofilms formed by Candida albicans are resistant towards most of the available antifungal drugs. Therefore, infections associated with Candida biofilms are considered as a threat to immunocompromised patients. Combinatorial drug therapy may be a good strategy to combat C. albicans biofilms. Methods Combinations of five antifungal drugs- fluconazole (FLC, voriconazole (VOR, caspofungin (CSP, amphotericin B (AmB and nystatin (NYT with cyclosporine A (CSA were tested in vitro against planktonic and biofilm growth of C. albicans. Standard broth micro dilution method was used to study planktonic growth, while biofilms were studied in an in vitro biofilm model. A chequerboard format was used to determine fractional inhibitory concentration indices (FICI of combination effects. Biofilm growth was analyzed using XTT-metabolic assay. Results MICs of various antifungal drugs for planktonic growth of C. albicans were lowered in combination with CSA by 2 to 16 fold. Activity against biofilm development with FIC indices of 0.26, 0.28, 0.31 and 0.25 indicated synergistic interactions between FLC-CSA, VOR-CSA, CSP-CSA and AmB-CSA, respectively. Increase in efficacy of the drugs FLC, VOR and CSP against mature biofilms after addition of 62.5 μg/ml of CSA was evident with FIC indices 0.06, 0.14 and 0.37, respectively. Conclusions The combinations with CSA resulted in increased susceptibility of biofilms to antifungal drugs. Combination of antifungal drugs with CSA would be an effective prophylactic and therapeutic strategy against biofilm associated C. albicans infections.

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

    International Nuclear Information System (INIS)

    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

  7. Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells.

    Science.gov (United States)

    González-Vallinas, Margarita; Molina, Susana; Vicente, Gonzalo; de la Cueva, Ana; Vargas, Teodoro; Santoyo, Susana; García-Risco, Mónica R; Fornari, Tiziana; Reglero, Guillermo; Ramírez de Molina, Ana

    2013-06-01

    5-Fluorouracil (5-FU) is the most used chemotherapeutic agent in colorectal cancer. However, resistance to this drug is relatively frequent, and new strategies to overcome it are urgently needed. The aim of this work was to determine the antitumor properties of a supercritical fluid rosemary extract (SFRE), alone and in combination with 5-FU, as a potential adjuvant therapy useful for colon cancer patients. This extract has been recognized as a healthy component by the European Food Safety Authority (EFSA). The effects of SFRE both alone and in combination with 5-FU were evaluated in different human colon cancer cells in terms of cell viability, cytotoxicity, and cell transformation. Additionally, colon cancer cells resistant to 5-FU were used to assay the effects of SFRE on drug resistance. Finally, qRT-PCR was performed to ascertain the mechanism by which SFRE potentiates the effect of 5-FU. Our results show that SFRE displays dose-dependent antitumor activities and exerts a synergistic effect in combination with 5-FU on colon cancer cells. Furthermore, SFRE sensitizes 5-FU-resistant cells to the therapeutic activity of this drug, constituting a beneficial agent against both 5-FU sensitive and resistant tumor cells. Gene expression analysis indicates that the enhancement of the effect of 5-FU by SFRE might be explained by the downregulation of TYMS and TK1, enzymes related to 5-FU resistance. PMID:23557932

  8. Sensitivity to Lovastatin of Saccharomyces cerevisiae Strains Deleted for Pleiotropic Drug Resistance (PDR) Genes

    DEFF Research Database (Denmark)

    Formenti, Luca Riccardo; Kielland-Brandt, Morten

    2011-01-01

    The use of statins is well established in human therapy, and model organisms such as Saccharomyces cerevisiae are commonly used in studies of drug action at molecular and cellular levels. The investigation of the resistance mechanisms towards statins may suggest new approaches to improve therapy...... based on the use of statins. We investigated the susceptibility to lovastatin of S. cerevisiae strains deleted for PDR genes, responsible for exporting hydrophobic and amphi-philic drugs, such as lovastatin. Strains deleted for the genes tested, PDR1, PDR3, PDR5 and SNQ2, exhibited remarkably different...

  9. Development of Nano-Liposomal Formulations of Epidermal Growth Factor Receptor Inhibitors and their Pharmacological Interactions on Drug-Sensitive and Drug-Resistant Cancer Cell Lines

    Science.gov (United States)

    Trummer, Brian J.

    , due to leaky tumor vasculature and the resulting Enhanced Permeability and Retention (EPR) phenomenon. In Chapter 2 we report that both gefitinib and the structurally similar EGFR inhibitor erlotinib display environment-dependent fluorescence properties. Peak excitation was 345 nm, and the emission peak ranged from 365 to 476 nm, depending upon the polarity of the environment and physical state of the drug. The fluorescence was negligible in aqueous solution, but intense in organic solvents or membrane bilayers. The environment-sensitive fluorescence properties of these drugs enabled rapid evaluation of numerous parameters affecting liposomal drug incorporation and performance. Up to 4-6 mol% of gefitinib could be incorporated in the liposome bilayer, based upon hydrophobic interactions with membrane bilayers. In contrast, 40-60 mol% could be loaded into the aqueous core of pre-formed liposomes at high efficiency, using a remote loading procedure. A stable formulation consisting of distearoylphosphatidylcholine: polyethylene glycol-distereoylphosphatidylethanolamine: cholesterol (DSPC:PEGDSPE:Chol, 9:1:5 mol:mol:mol) and containing drug at 50-60 mol% gefitinib (L-GEF) showed minimal leakage in serum-containing medium over 24 h at 37°C, which should be sufficient to improve biodistribution in vivo. Chapter 3 investigated the pharmacological activity of liposome-encapsulated gefitinib, alone and in combination with several prevalent anticancer agents. Experiments with MCF7 breast cancer cell lines demonstrated that liposome encapsulated gefitinib formulation (L-GEF) had a 2-fold higher IC50 (concentration of drug resulting in half-maximal growth inhibition) than free gefitinib. Lower in vitro potency would be consistent with delayed drug release from the carrier. Therapeutic effects were investigated in combination with the cytotoxic agents paclitaxel and doxorubicin. The drug-resistant MCF7R cell line was 23-fold more resistant to paclitaxel than the parental, drug-sensitive

  10. A pH-sensitive binary drug delivery system based on poly(caprolactone)-heparin conjugates.

    Science.gov (United States)

    Ye, Lin; Gao, Zemin; Zhou, Yu; Yin, Xuan; Zhang, Xinpeng; Zhang, Aiying; Feng, Zengguo

    2014-03-01

    PCL-heparin conjugates were synthesized by coupling mono-hydroxyl terminated PCL (Mn = 2000-10000 g/mol) with heparin via EDC/NHS chemistry. The conjugates enabled to self-assemble into the core-shell nanoparticles in around 100 nm diameter to load binary anti-cancer drugs. Lipophilic and neutral paclitaxel (PTX) was first encapsulated in the core, and then hydrophilic and positive charged doxorubicin (DOX) was incorporated into the negative charged shell of PTX loaded nanoparticles via the electrostatic interaction. The in vitro release profiles of the binary-drug loaded nanoparticles revealed that both PTX and DOX were sustainably released from the particles but behaved differently. The release of DOX was pH dependent, ensuring more drug to be released in the tumor cells than in the normal ones. Hence these particles were featured by a sequential controlled drug delivery behavior with a significant cytotoxicity to cervical cancer (Hela cell) and breast cancer (MDA-MB-321) cells. The CLSM observations clearly indicated that both loaded PTX and DOX aggregated in the nucleus of tumor cells to exert their anti-tumor pharmacodynamic effect on the cells. PMID:23554308

  11. Radiation synthesis of pH-sensitive hydrogels from β-cyclodextrin-grafted PEG and acrylic acid for drug delivery

    International Nuclear Information System (INIS)

    A water-soluble macromonomer (PEG-β-CD) was synthesised by reaction of β-cyclodextrin with poly(ethylene glycol) diglycidyl ether. Then, a novel hydrogel with pH-sensitivity was prepared by irradiating the mixture of acrylic acid and PEG-β-CD with electron beam. Compared with the normal PAAc hydrogel, this novel hydrogel had a higher swelling ratio at pH 3-8. 5-Fluorouracil (5-FU) was chosen as a model drug, and the kinetics of 5-FU releasing behavior was studied. Compared with the PAAc hydrogel, the results showed the release time of 5-FU from the cyclodextrin containing hydrogel was prolonged. It may be ascribed to the formation of inclusion complexes between the drug molecules and cyclodextrin groups.

  12. Changes in the sensitivity of GABAA current rundown to drug treatments in a model of temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Pierangelo eCifelli

    2013-07-01

    Full Text Available The pharmacological treatment of mesial temporal lobe epilepsy (mTLE, the most common epileptic syndrome in adults, is still unsatisfactory, as one third of the patients are or become refractory to antiepileptic agents. Refractoriness may depend upon drug-induced alterations, but the disease per se may also undergo a progressive evolution that affects the sensitivity to drugs. mTLE has been shown to be associated with a dysfunction of the inhibitory signaling mediated by GABAA receptors. In particular, the repetitive activation of GABAA receptors produces a use-dependent decrease (rundown of the evoked currents (IGABA, which is markedly enhanced in the hippocampus and cortex of drug-resistant mTLE patients. This phenomenon has been also observed in the pilocarpine model, where the increased IGABA rundown is observed in the hippocampus at the time of the first spontaneous seizure, then extends to the cortex and remains constant in the chronic phase of the disease. Here, we examined the sensitivity of IGABA to pharmacological modulation. We focused on the antiepileptic agent levetiracetam and on the neurotrophin BDNF, which were previously reported to attenuate mTLE-induced increased rundown in the chronic human tissue. In the pilocarpine model, BDNF displayed a paramount effect, decreasing rundown in the hippocampus at the time of the first seizure, as well as in the hippocampus and cortex in the chronic period. In contrast, levetiracetam did not affect rundown in the hippocampus, but attenuated it in the cortex. Interestingly, this effect of levetiracetam was also observed on the still unaltered rundown observed in the cortex at the time of the first spontaneous seizure. These data suggest that the sensitivity of GABAA receptors to pharmacological interventions undergoes changes during the natural history of mTLE, implicating that the site of seizure initiation and the timing of treatment may highly affect the therapeutic outcome.

  13. Development of Novel Polymeric Materials for Gene Therapy and pH-Sensitive Drug Delivery: Modeling, Synthesis, Characterization, and Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Brian Curtis Anderson

    2002-08-27

    The underlying theme of this thesis is the use of polymeric materials in bioapplications. Chapters 2-5 either develop a fundamental understanding of current materials used for bioapplications or establish protocols and procedures used in characterizing and synthesizing novel materials. In chapters 6 and 7 these principles and procedures are applied to the development of materials to be used for gene therapy and drug delivery. Chapter one is an introduction to the ideas that will be necessary to understand the subsequent chapters, as well as a literature review of these topics. Chapter two is a paper that has been published in the ''Journal of Controlled Release'' that examines the mechanism of drug release from a polymer gel, as well as experimental design suggestions for the evaluation of water soluble drug delivery systems. Chapter three is a paper that has been published in the ''Journal of Pharmaceutical Sciences'' that discusses the effect ionic salts have on properties of the polymer systems examined in chapter two. Chapter four is a paper published in the Materials Research Society Fall 2000 Symposium Series dealing with the design and synthesis of a pH-sensitive polymeric drug delivery device. Chapter five is a paper that has been published in the journal ''Biomaterials'' proposing a novel polymer/metal composite for use as a biomaterial in hip arthroplasty surgery. Chapter six is a paper that will appear in an upcoming volume of the Journal ''Biomaterials'' dealing with the synthesis of a novel water soluble cationic polymer with possible applications in non-viral gene therapy. Chapter seven is a paper that has been submitted to ''Macromolecules'' discussing several novel block copolymers based on poly(ethylene glycol) and poly(diethylamino ethyl methacrylate) that possess both pH-sensitive and temperature sensitive properties. Chapter eight contains a

  14. pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery

    OpenAIRE

    Wu, Hong; Zhu, Lin; Torchilin, Vladimir P.

    2012-01-01

    To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000(DSPE-PEG2000), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG3400 (DSPE-PEG3400-2C5), and poly(ethylene glycol)-coupled poly(l-histidine) (PHIS-PEG2000). The structure of PHIS-...

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

    Directory of Open Access Journals (Sweden)

    Klein Eili Y

    2012-04-01

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

  16. Neutralizing Antibodies against Plasmodium falciparum Associated with Successful Cure after Drug Therapy

    Science.gov (United States)

    Goh, Yun Shan; Peng, Kaitian; Chia, Wan Ni; Siau, Anthony; Chotivanich, Kesinee; Gruner, Anne-Charlotte; Preiser, Peter; Mayxay, Mayfong; Pukrittayakamee, Sasithon; Sriprawat, Kanlaya; Nosten, Francois; White, Nicholas J.

    2016-01-01

    An effective antibody response can assist drug treatment to contribute to better parasite clearance in malaria patients. To examine this, sera were obtained from two groups of adult patients with acute falciparum malaria, prior to drug treatment: patients who (1) have subsequent recrudescent infection, or (2) were cured by Day 28 following treatment. Using a Plasmodium falciparum antigen library, we examined the antibody specificities in these sera. While the antibody repertoire of both sera groups was extremely broad and varied, there was a differential antibody profile between the two groups of sera. The proportion of cured patients with antibodies against EXP1, MSP3, GLURP, RAMA, SEA and EBA181 was higher than the proportion of patients with recrudescent infection. The presence of these antibodies was associated with higher odds of treatment cure. Sera containing all six antibodies impaired the invasion of P. falciparum clinical isolates into erythrocytes. These results suggest that antibodies specific against EXP1, MSP3, GLURP, RAMA, SEA and EBA181 in P. falciparum infections could assist anti-malarial drug treatment and contribute to the resolution of the malarial infection. PMID:27427762

  17. Electrocardiographic study in Ghanaian children with uncomplicated malaria, treated with artesunate-amodiaquine or artemether-lumefantrine

    DEFF Research Database (Denmark)

    Adjei, George O; Oduro-Boatey, Collins; Rodrigues, Onike P;

    2012-01-01

    Several anti-malarial drugs are associated with adverse cardiovascular effects. These effects may be exacerbated when different anti-malarials are used in combination. There has been no report yet on the potential cardiac effects of the combination artesunate-amodiaquine....

  18. One-step synthesis of interpenetrating network hydrogels: Environment sensitivities and drug delivery properties

    OpenAIRE

    Lu, Jingqiong; Li, Yinhui; Hu, Deng; Chen, Xiaoling; Liu, Yongmei; Wang, Liping; Ashraf, Muhammmad Aqeel; Zhao, Yansheng

    2015-01-01

    A novel interpenetrating network hydrogel for drug controlled release, composed of modified poly(aspartic acid) (KPAsp) and carboxymethyl chitosan (CMCTS), was prepared in aqueous system. The surface morphology and composition of hydrogels were characterized by SEM and FTIR. The swelling properties of KPAsp, KPAsp/CMCTS semi-IPN and KPAsp/CMCTS IPN hydrogels were investigated and the swelling dynamics of the hydrogels was analyzed based on the Fickian equation. The pH, temperature and salt se...

  19. Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer

    DEFF Research Database (Denmark)

    Swanton, Charles; Szallasi, Zoltan Imre; Brenton, James D.;

    2008-01-01

    ) as well as endocrine therapies such as tamoxifen. Given the limited power of microarray signatures to predict therapeutic response in associative studies of small clinical trial cohorts, the use of functional genomic data combined with expression or sequence analysis of genes and microRNAs implicated...... in drug response in human tumours may provide a more robust method to guide adjuvant treatment strategies in breast cancer that are transferable across different expression platforms and patient cohorts....

  20. Mesoscale Simulations and Experimental Studies of pH-Sensitive Micelles for Controlled Drug Delivery.

    Science.gov (United States)

    Wang, Yan; Li, Qiu Yu; Liu, Xu Bo; Zhang, Can Yang; Wu, Zhi Min; Guo, Xin Dong

    2015-11-25

    The microstructures of doxorubicin-loaded micelles prepared from block polymers His(x)Lys10 (x = 0, 5, 10) conjugated with docosahexaenoic acid (DHA) are investigated under different pH conditions, using dissipative particle dynamics (DPD) simulations. The conformation of micelles and the DOX distributions in micelles were obviously influenced by pH values and the length of the histidine segment. At pH >6.0, the micelles self-assembled from the polymers were dense and compact. The drugs were entrapped well within the micellar core. The particle size increases as the histidine length increases. With the decrease of pH value to be lower than 6.0, there was no distinct difference for the micelles self-assembled from the polymer without histidine residues. However, the micelles prepared from the polymers with histidine residues shows a structural transformation from dense to swollen conformation, leading to an increased particle size from 10.3 to 14.5 DPD units for DHD-His10Lys10 micelles. This structural transformation of micelles can accelerate the DOX release from micelles under lower pH conditions. The in vitro drug release from micelles is accelerated by the decrease of pH value from 7.4 (physiological environment) to 5.0 (lysosomal environment). The integration of simulation and experiments might be a valuable method for the optimization and design of biomaterials for drug delivery with desired properties. PMID:26539742

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Inhibition of anaphylactic histamine release from heterologously sensitized mast cells: differential effects of drugs which interfere with calcium influx.

    Directory of Open Access Journals (Sweden)

    Kurose,Masao

    1981-11-01

    Full Text Available Drug effects were studied on anaphylactic histamine release from rat mast cells sensitized in vitro with mouse IgE antibody. When histamine release was elicited by adding Ca-++ at various times after antigen-stimulation of sensitized cells in Ca++-free medium, the drugs to be tested were added shortly before each Ca++ addition. Quercetin was effective only when added before or immediately after antigen. Theophylline and disodium cromoglycate (DSCG were active irrespective of the time interval between antigen and Ca++ addition. Verapamil was more effective when added before or simultaneously with antigen than when added later. When tested in the two-stage experiments, quercetin showed inhibition only in Stage 1 and verapamil was inhibitive primarily in Stage 1, while theophylline and DSCG wee only inhibitive in Stage 2. It seems that quercetin selectively and verapamil primarily act to block calcium-gate opening resulting from antigen-antibody interaction on the mast cell membrane, while theophylline and DSCG selectively inhibit the passage of calcium through open calcium channels.

  3. Dextran hydrogel coated surface plasmon resonance imaging (SPRi) sensor for sensitive and label-free detection of small molecule drugs

    Science.gov (United States)

    Li, Shaopeng; Yang, Mo; Zhou, Wenfei; Johnston, Trevor G.; Wang, Rui; Zhu, Jinsong

    2015-11-01

    The label-free and sensitive detection of small molecule drugs on SPRi is still a challenging task, mainly due to the limited surface immobilization capacity of the sensor. In this research, a dextran hydrogel-coated gold sensor chip for SPRi was successfully fabricated via photo-cross-linking for enhanced surface immobilization capacity. The density of the dextran hydrogel was optimized for protein immobilization and sensitive small molecule detection. The protein immobilization capacity of the hydrogel was 10 times greater than a bare gold surface, and 20 times greater than an 11-mercaptoundecanoic acid (MUA) surface. Such a drastic improvement in immobilization capacity allowed the SPRi sensor to detect adequate response signals when probing small molecule binding events. The binding signal of 4 nM liquid-phase biotin to streptavidin immobilized on the dextran surface reached 435 RU, while no response was observed on bare gold or MUA surfaces. The dextran hydrogel-coated SPRi sensor was also applied in a kinetic study of the binding between an immunosuppressive drug (FK506) and its target protein (FKBP12) in a high-throughput microarray format. The measured binding affinity was shown to be consistent with reported literature values, and a detection limit of 0.5 nM was achieved.

  4. Activator of G-protein Signaling 3: A Gatekeeper of Cocaine Sensitization and Drug-seeking

    OpenAIRE

    Bowers, M.S.; McFarland, K.; Lake, R.W.; Peterson, Y K; Lapish, C.C.; Gregory, M.L.; Lanier, S M; Kalivas, P.W.

    2004-01-01

    Chronic cocaine administration reduces G-protein signaling efficacy. Here we report that the expression of AGS3, which selectively binds to GiαGDP and inhibits GDP dissociation, was upregulated in the prefrontal cortex (PFC) during late withdrawal from repeated cocaine administration. Increased AGS3 was mimicked in the PFC of drug naïve rats by microinjecting a peptide containing the Giα binding domain (GPR) of AGS3 fused to the cell permeability domain of HIV-Tat. Infusion of Tat-GPR mimicke...

  5. Swelling characteristics of hydroxyethylmethacrylate/ methacrylic acid pH -sensitive hydrogel as a drug delivery system

    OpenAIRE

    M. Falamarzian- J. Varshosaz

    1996-01-01

    Hydroxyethyl methacrylate /methacrylic acid (HEMA/MAA) copolymer cross-linked with ethylenglycol dimethacrylate was prepared by a bulk.free radical polymerization method. The results indicate that this polymer is a pH -sensitive hydrogel which is collapsed in the acidic medium but completely swollen in the alkaline and neutral pH . it was determined that a proportion of 40% of MAA, the ionizing monomer of this hydrogel, was the best concentration among the different percentages used which sho...

  6. Evolving Cardiac Conduction Phenotypes in Developing Zebrafish Larvae: Implications to Drug Sensitivity

    OpenAIRE

    Yu, Fei; Huang, Jie; Adlerz, Katrina; Jadvar, Hossein; Hamdan, Mohamed H.; Chi, Neil; Chen, Jau-Nian; Hsiai, Tzung K.

    2010-01-01

    Cardiac arrhythmias include problems with impulse formation and/or conduction abnormalities. Zebrafish (Danio rerio) is an emerging model system for studying the cardiac conduction system. However, real-time recording of the electrocardiogram remains a challenge. In the present study, we assessed the feasibility of recording electrical cardiogram (ECG) signals from the zebrafish larvae using the micropipette electrodes, and demonstrated the dynamic changes in ECG signals and their sensitivity...

  7. Drug Addiction: The Relationship Between Nursing Interventions And Sensitive Outcomes. A Systematic Literature Review

    OpenAIRE

    Seabra, Paulo; Santos, Alexandra; Garcia, Lurdes; Amendoeira, José; Sá, Luís

    2012-01-01

    Background and Significance: The analysis of care contribution provided by different professionals and the results of their interventions is a recommendation that emerges from the practice stems, from costs concerns and to re-structure health services. The need to deepen the nursing contribution, to health outcomes achieved by people, is our challenge. We need to show further evidence that nursing sensitive health outcomes can contribute to health benefits of the people and pronounce today...

  8. Novel pH-sensitive polysialic acid based polymeric micelles for triggered intracellular release of hydrophobic drug.

    Science.gov (United States)

    Zhang, Wuxia; Dong, Dongqi; Li, Peng; Wang, Dongdong; Mu, Haibo; Niu, Hong; Duan, Jinyou

    2016-03-30

    Polysialic acid (PSA), a non-immunogenic and biodegradable natural polymer, is prone to hydrolysis under endo-lysosomal pH conditions. Here, we synthesized an intracellular pH-sensitive polysialic acid-ursolic acid conjugate by a condensation reaction. To further test the drug loading capability, we prepared paclitaxel-loaded polysialic acid-based amphiphilic copolymer micelle (PTX-loaded-PSAU) by a nanoprecipitation method. Results showed PTX-loaded-PSAU exhibited well-defined spherical shape and homogeneous distribution. The drug-loading was 4.5% with an entrapment efficiency of 67.5%. PTX released from PTX-loaded-PSAU was 15% and 42% in 72 h under simulated physiological condition (pH 7.4) and mild acidic conditions (pH 5.0), respectively. In addition, In vitro cytotoxicity assay showed that PTX-loaded-PSAU retained anti-tumor (SGC-7901) activity with a cell viability of 53.8% following 72 h incubation, indicating PTX-loaded-PSAU could efficiently release PTX into the tumor cells. These results indicated that the pH-responsive biodegradable PTX-loaded-PSAU possess superior extracellular stability and intracellular drug release ability. PMID:26794949

  9. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    Directory of Open Access Journals (Sweden)

    Tran TH

    2015-08-01

    Full Text Available Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.Keywords: docetaxel, polyaspartic acid, drug delivery systems, antitumor, pH-sensitive

  10. Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs.

    Science.gov (United States)

    Ma, Ming; Zhao, Lianmei; Sun, Guogui; Zhang, Chao; Liu, Lihua; Du, Yanyan; Yang, Xingxiao; Shan, Baoen

    2016-05-01

    Interleukin-24 (IL-24) is a cytokine encoded by a tumor suppressor gene of the IL-10 family, also known as the melanoma differentiation associated gene-7 (Mda-7) and first discovered in human melanoma cells. Mda-7/IL-24 has been shown to inhibit the proliferation of various human tumor cell lines, but its effect on the sensitivity of B cell lymphoma to chemotherapy agents is not yet clear. The present study investigated the effects of Mda-7/IL-24 overexpression on the sensitivity of human B cell lymphoma cells to chemotherapy, as well as its mechanism of action. The sensitivity of stable Mda-7/IL-24 overexpressing Raji and Daudi cells to cis-diamminedichloroplatinum (CDDP), epirubicin and vinblastine (VCR) were assessed by the MTS method, and the IC50 value calculated. Cell apoptosis and the intracellular accumulation of Rhodamine-123 were assayed by flow cytometry. The expression of multidrug resistance gene 1 (MDR1), B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1), topoisomerase II (Topo II) and multidrug resistance-related protein 1 (MRP1) mRNA and protein were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. In addition, western blot analysis was also used to investigate the effect of Mda-7/IL-24 on activity of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells. Growth inhibition and apoptosis rates of Mda-7/IL-24 overexpressing Raji and Daudi cells were higher than those of non-transfected cells and cells transfected with vector alone when treated with CDDP, epirubicin and VCR. The IC50 values of CDDP, epirubicin and VCR were lower for Mda-7/IL-24-overexpressing Raji and Daudi cells than for non-transfected cells and cells transfected with empty vector. Intracellular accumulation of Rhodamine-123 and the expression of Topo II were higher, while the levels of MDR1, BMI and MRP1 mRNA and protein were lower, in Mda-7/IL-24 overexpressing Raji and Daudi cells

  11. Self-assembled nanocomplexes of anionic pullulan and polyallylamine for DNA and pH-sensitive intracellular drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Vora, Lalit [University under Sect. 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, Center for Novel Drug Delivery Systems, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (India); Tyagi, Monica [Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Gupta Lab, Cancer Research Institute (India); Patel, Ketan [University under Sect. 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, Center for Novel Drug Delivery Systems, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (India); Gupta, Sanjay [Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Gupta Lab, Cancer Research Institute (India); Vavia, Pradeep, E-mail: vaviapradeep@yahoo.com [University under Sect. 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, Center for Novel Drug Delivery Systems, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (India)

    2014-12-15

    The amalgamation of chemotherapy and gene therapy is promising treatment option for cancer. In this study, novel biocompatible self-assembled nanocomplexes (NCs) between carboxylmethylated pullulan t335 (CMP) with polyallylamine (CMP–PAA NCs) were developed for plasmid DNA (pDNA) and pH-sensitive doxorubicin (DOX) delivery. DOX was conjugated to CMP (DOX–CMP) via hydrazone and confirmed by FTIR and {sup 1}H-NMR. In vitro release studies of pH-sensitive DOX–CMP conjugate showed 23 and 85 % release after 48 h at pH 7.4 (physiological pH) and pH 5 (intracellular/tumoral pH), respectively. The CMP–PAA NCs or DOX–CMP–PAA NCs self-assembled into a nanosized (<250 nm) spherical shape as confirmed by DLS and TEM. The hemolysis and cytotoxicity study indicated that the CMP–PAA NCs did not show cytotoxicity in comparison with plain polyallylamine. Gel retardation assay showed complete binding of pDNA with CMP–PAA NCs at 1:2 weight ratio. CMP–PAA NCs/pDNA showed significantly higher transfection in HEK293 cells compared to PAA/pDNA complexes. Confocal imaging demonstrated successful cellular uptake of DOX–CMP–PAA NCs in HEK293 cells. Thus, NCs hold great potential for targeted pDNA and pH-sensitive intratumoral drug delivery.

  12. Self-assembled nanocomplexes of anionic pullulan and polyallylamine for DNA and pH-sensitive intracellular drug delivery

    International Nuclear Information System (INIS)

    The amalgamation of chemotherapy and gene therapy is promising treatment option for cancer. In this study, novel biocompatible self-assembled nanocomplexes (NCs) between carboxylmethylated pullulan t335 (CMP) with polyallylamine (CMP–PAA NCs) were developed for plasmid DNA (pDNA) and pH-sensitive doxorubicin (DOX) delivery. DOX was conjugated to CMP (DOX–CMP) via hydrazone and confirmed by FTIR and 1H-NMR. In vitro release studies of pH-sensitive DOX–CMP conjugate showed 23 and 85 % release after 48 h at pH 7.4 (physiological pH) and pH 5 (intracellular/tumoral pH), respectively. The CMP–PAA NCs or DOX–CMP–PAA NCs self-assembled into a nanosized (<250 nm) spherical shape as confirmed by DLS and TEM. The hemolysis and cytotoxicity study indicated that the CMP–PAA NCs did not show cytotoxicity in comparison with plain polyallylamine. Gel retardation assay showed complete binding of pDNA with CMP–PAA NCs at 1:2 weight ratio. CMP–PAA NCs/pDNA showed significantly higher transfection in HEK293 cells compared to PAA/pDNA complexes. Confocal imaging demonstrated successful cellular uptake of DOX–CMP–PAA NCs in HEK293 cells. Thus, NCs hold great potential for targeted pDNA and pH-sensitive intratumoral drug delivery

  13. Facile synthesis of glucose-sensitive chitosan-poly(vinyl alcohol) hydrogel: Drug release optimization and swelling properties.

    Science.gov (United States)

    Abureesh, Mosab Ali; Oladipo, Akeem Adeyemi; Gazi, Mustafa

    2016-09-01

    The study describes the development of glucose-sensitive hydrogel and optimization of bovine serum albumin release profile from the hydrogel. To enhance the glucose sensitivity and improve the swelling behaviors of the hydrogel system, boric acid crosslinking, and freeze-thawing cycle techniques were used to prepare chitosan-poly(vinyl alcohol) hydrogel. The structure of the resultant hydrogel was confirmed by scanning electron microscopy and Fourier transform infrared spectroscopy. The experimental results revealed that the swelling of the hydrogel was influenced by the pH of the medium, and the hydrogel displayed explicit glucose-sensitivity under physiological conditions. The values of the diffusion exponent range between 0.34 and 0.44 and the diffusion of water into the gel system are assumed to be pseudo-Fickian in nature. Under optimized conditions, the cumulative Bovine serum albumin (BSA) drug releases ranged between 69.33±1.95% and 86.45±1.16% at 37°C in the presence of glucose and pH 7.4, respectively. PMID:26459171

  14. Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy.

    Directory of Open Access Journals (Sweden)

    Adam Szulkin

    Full Text Available BACKGROUND: Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit. MATERIALS AND METHODS: We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers. RESULTS: As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect. CONCLUSIONS: The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

  15. Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints.

    Directory of Open Access Journals (Sweden)

    Stefan Niemann

    Full Text Available BACKGROUND: Mycobacterium tuberculosis complex (MTBC, the causative agent of tuberculosis (TB, is characterized by low sequence diversity making this bacterium one of the classical examples of a genetically monomorphic pathogen. Because of this limited DNA sequence variation, routine genotyping of clinical MTBC isolates for epidemiological purposes relies on highly discriminatory DNA fingerprinting methods based on mobile and repetitive genetic elements. According to the standard view, isolates exhibiting the same fingerprinting pattern are considered direct progeny of the same bacterial clone, and most likely reflect ongoing transmission or disease relapse within individual patients. METHODOLOGY/PRINCIPAL FINDINGS: Here we further investigated this assumption and used massively parallel whole-genome sequencing to compare one drug-susceptible (K-1 and one multidrug resistant (MDR isolate (K-2 of a rapidly spreading M. tuberculosis Beijing genotype clone from a high incidence region (Karakalpakstan, Uzbekistan. Both isolates shared the same IS6110 RFLP pattern and the same allele at 23 out of 24 MIRU-VNTR loci. We generated 23.9 million (K-1 and 33.0 million (K-2 paired 50 bp purity filtered reads corresponding to a mean coverage of 483.5 fold and 656.1 fold respectively. Compared with the laboratory strain H37Rv both Beijing isolates shared 1,209 SNPs. The two Beijing isolates differed by 130 SNPs and one large deletion. The susceptible isolate had 55 specific SNPs, while the MDR variant had 75 specific SNPs, including the five known resistance-conferring mutations. CONCLUSIONS: Our results suggest that M. tuberculosis isolates exhibiting identical DNA fingerprinting patterns can harbour substantial genomic diversity. Because this heterogeneity is not captured by traditional genotyping of MTBC, some aspects of the transmission dynamics of tuberculosis could be missed or misinterpreted. Furthermore, a valid differentiation between disease relapse

  16. PES1 regulates sensitivity of colorectal cancer cells to anticancer drugs

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Wei [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China); Qu, Like, E-mail: qulike@bjcancer.org [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China); Meng, Lin; Liu, Caiyun; Wu, Jian [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China); Shou, Chengchao, E-mail: scc@bjcancer.org [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China)

    2013-02-15

    Highlights: ► PES1 was overexpressed in diverse cancer cell lines. ► PES1-ablation enhances DNA damage response by decreasing DNA repair. ► PES1-ablation increases the sensitivity of HCT116 cells to chemotherapeutic agents. ► PES1-ablation is associated with diminished nuclear entry of RAD51. -- Abstract: PES1 (also known as Pescadillo), a nucleolar protein, was involved in biogenesis of ribosomal RNA. Up-regulation of PES1 has been documented in some human cancers, indicating that PES1 may play some crucial roles in tumorigenesis. In our previous study, it was found that silencing of PES1 resulted in decreased proliferation of colorectal cancer cells. We also noticed that depletion of PES1 altered expression profiles of diverse genes. In the present study, we validated the expression changes of a subset of genotoxic stress-related genes in PES1-silenced HCT116 cells by quantitative RT-PCR. The steady and etoposide-induced phosphorylated H2AX (γ-H2AX) were higher in PES1-silenced cells than in control cells. Besides, etoposide-induced γ-H2AX persisted longer in PES1-silenced cells after removing the etoposide. Next, results of comet assay revealed decreased DNA repair after PES1-ablation. PES1-ablated cells were more sensitive to chemotherapeutic agents, which could be reversed by reconstitution with exogenous PES1. Furthermore, deletion of PES1 diminished steady and DNA damage-induced levels of nuclear RAD51. Our results uncover a potential role of PES1 in chemoresistance by regulating DNA damage response in colorectal cancer cells.

  17. Identification of genes involved in the sensitivity to antitumour drug 17-allylamino,17-demethoxygeldanamycin (17AAG).

    Science.gov (United States)

    Barresi, Vincenza; Fortuna, Cosimo G; Garozzo, Roberta; Musumarra, Giuseppe; Scirè, Salvatore; Condorelli, Daniele F

    2006-05-01

    In the present study we analysed the gene expression database provided by the National Cancer Institute in an attempt to correlate activity profiles of geldanamycin, 17AAG and 11 other analogues in 60 human tumor cell lines with their gene expression profiles determined by the cDNA microarray technique. On the basis of the activity profiles two classes of geldanamycin analogues could be distinguished, having geldanamycin and 17AAG, respectively, as prototype compounds (denominated as gelda-like and 17AAG-like classes). Application of the "soft" statistical methodology of PLS (partial least squares modelling in latent variables or projections to latent structures) allowed us to evaluate the influence of each gene expression target in determining the therapeutical responses. The transcript encoding the translocating chain-associated membrane protein (TRAM) showed a significant statistical correlation with activity profiles of 17AAG. In order to validate the role of TRAM in determining sensitivity to 17AAG we induced a selective knocking-down of this transcript by the RNA interference methodology in H226 non-small cell lung carcinoma cell line. The efficiency of double-stranded RNA oligonucleotides (short-interfering RNAs, siRNAs) was determined by measuring TRAM mRNA levels by quantitative real-time RT-PCR at different times (24-72 hours) after siRNA lipotransfection. A significant increase in chemosensitivity to 17AAG was observed in siRNA-silenced cells. Although a number of factors may affect tumour sensitivity to 17AAG the present methodology allowed us to dissect out a single parameter which may be partly responsible for its activity. PMID:16880941

  18. PES1 regulates sensitivity of colorectal cancer cells to anticancer drugs

    International Nuclear Information System (INIS)

    Highlights: ► PES1 was overexpressed in diverse cancer cell lines. ► PES1-ablation enhances DNA damage response by decreasing DNA repair. ► PES1-ablation increases the sensitivity of HCT116 cells to chemotherapeutic agents. ► PES1-ablation is associated with diminished nuclear entry of RAD51. -- Abstract: PES1 (also known as Pescadillo), a nucleolar protein, was involved in biogenesis of ribosomal RNA. Up-regulation of PES1 has been documented in some human cancers, indicating that PES1 may play some crucial roles in tumorigenesis. In our previous study, it was found that silencing of PES1 resulted in decreased proliferation of colorectal cancer cells. We also noticed that depletion of PES1 altered expression profiles of diverse genes. In the present study, we validated the expression changes of a subset of genotoxic stress-related genes in PES1-silenced HCT116 cells by quantitative RT-PCR. The steady and etoposide-induced phosphorylated H2AX (γ-H2AX) were higher in PES1-silenced cells than in control cells. Besides, etoposide-induced γ-H2AX persisted longer in PES1-silenced cells after removing the etoposide. Next, results of comet assay revealed decreased DNA repair after PES1-ablation. PES1-ablated cells were more sensitive to chemotherapeutic agents, which could be reversed by reconstitution with exogenous PES1. Furthermore, deletion of PES1 diminished steady and DNA damage-induced levels of nuclear RAD51. Our results uncover a potential role of PES1 in chemoresistance by regulating DNA damage response in colorectal cancer cells

  19. Synthesis of new thermo/pH sensitive drug delivery systems based on tragacanth gum polysaccharide.

    Science.gov (United States)

    Hemmati, Khadijeh; Ghaemy, Mousa

    2016-06-01

    In this study, new pH/temperature responsive graft copolymers were synthesized based on natural Tragacanth Gum (TG) carbohydrate and their controlled drug release was investigated. Amphiphilic alkyne terminated terpolymers (mPEG-PCL-PDMAEMA-CCH)s consist of methylated poly(ethyleneglycol) (mPEG), polycaprolactone (PCL), and poly(dimethylaminoethylmethacrylate) (PDMAEMA) were synthesized by using ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP), and then were grafted onto azide-functionalized TG molecules by click chemistry. Different techniques such as FT-IR, (1)H NMR, gel permeation chromatography (GPC), thermo-gravimetrical analysis (TGA) and scanning electron microscopy (SEM) were used to verify the successful synthesis of graft copolymers (TG-g-PDMAEMA-PCL-mPEG)s. The graft copolymers self-assembled to single micelles in aqueous solution and upon pH changes further assembled into micellar aggregates. These micelles were used to prepare quercetin loaded nanocarriers by probe sonication method. Size and morphology of the nanocarriers were studied by dynamic light scattering (DLS) and SEM. The in vitro release behavior of quercetin from these micelles showed pH-dependence. The results showed that release profile of quercetin best followed the first order model. PMID:26955747

  20. Radiation synthesis of temperature-sensitive β-cyclodextrin-grafted PEG/poly (N-isopropylacrylamide) hydrogels for drug delivery

    International Nuclear Information System (INIS)

    In this paper, β-cyclodextrin(β-CD)-based water-soluble macromonomer(PEG-β-CD) was synthesized by reaction of β-CD with poly(ethylene glycol) diglycidyl ether(PEGDE). A novel temperature-sensitive hydrogel composed of PEG-β-CD and poly(N-isopropylacrylamide)(PNIPAAm) was prepared by E-beam irradiation. Compared with the normal PNIPAAm hydrogel, the obtained hydrogel had a high swelling ratio at room temperature and exhibited faster shrinking kinetics at temperature close to the lower critical solution temperature (LCST). 5-fluorouracil (5-FU) was chosen as a model drug loaded into the hydrogels, and the release results showed the β-cyclodextrin-containing hydrogels prolonged the release time. (authors)

  1. Radiological Findings of Extensively Drug-Resistant Pulmonary Tuberculosis in Non-AIDS Adults: Comparisons with Findings of Multidrug-Resistant and Drug-Sensitive Tuberculosis

    International Nuclear Information System (INIS)

    This study was designed to describe the radiological findings of extensively drug-resistant (XDR) pulmonary tuberculosis (TB) and to compare the observed findings with findings of drug-sensitive (DS) and non-XDR multidrug- resistant (MDR) TB in non-AIDS patients. From September 1994 to December 2007, 53 MDR TB patients (M:F = 32:21; mean age, 38 years) and 15 XDR TB non-AIDS patients (M:F = 8:7; mean age, 36 years) were enrolled in the study. All of the MDR TB patients had received no treatment or less than one month of anti-TB treatment. In addition, all XDR TB patients received either no anti-TB treatment or only first-line anti-TB drugs. In addition, 141 consecutive DS TB patients (M:F = 79:62; mean age, 51 years) were also enrolled in the study for comparison. Chest radiograph, CT and demographic findings were reviewed and were compared among the three patient groups. For patients with XDR TB, the most frequent radiographic abnormalities were nodules (15 of 15 patients, 100%), reticulo-nodular densities (11 of 15, 73%), consolidation (9 of 15, 60%) and cavities (7 of 15, 47%) that were located mainly in the upper and middle lung zones. As seen on radiographs, significant differences were found for the frequency of nodules and ground-glass opacity lesions (all p < 0.001) (more frequent in DS TB patients than in MDR and XDR TB patients). For the use of CT, significant differences (more frequent in MDR and XDR TB patients) were found for the frequency of multiple cavities, nodules and bronchial dilatation (p = 0.001 or p < 0.001). Patients with MDR TB and XDR TB were younger as compared to patients with DS TB (p < 0.001). Imaging findings were not different between patients with MDR TB and XDR TB. By observation of multiple cavities, nodules and bronchial dilatation as depicted on CT in young patients with acid-fast bacilli (AFB) positive sputum, the presence of MDR TB or XDR TB rather than DS TB can be suggested. There is no significant difference in imaging

  2. Host candidate gene polymorphisms and clearance of drug-resistant Plasmodium falciparum parasites

    Directory of Open Access Journals (Sweden)

    Rockett Kirk

    2011-08-01

    Full Text Available Abstract Background Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches. Methods 3721 samples from five African countries, which were known to contain genotypically drug resistant parasites, were analysed. These parasites were collected from patients who subsequently failed to clear their infection following drug treatment, as expected, but also from patients who successfully cleared their infections with drug-resistant parasites. 67 human polymorphisms (SNPs on 17 chromosomes were analysed using Sequenom's mass spectrometry iPLEX gold platform, to identify regions of the human genome, which contribute to enhanced clearance of drug resistant parasites. Results An analysis of all data from the five countries revealed significant associations between the phenotype of ability to clear drug-resistant Plasmodium falciparum infection and human immune response loci common to all populations. Overall, three SNPs showed a significant association with clearance of drug-resistant parasites with odds ratios of 0.76 for SNP rs2706384 (95% CI 0.71-0.92, P = 0.005, 0.66 for SNP rs1805015 (95% CI 0.45-0.97, P = 0.03, and 0.67 for SNP rs1128127 (95% CI 0.45-0.99, P = 0.05, after adjustment for possible confounding factors. The first two SNPs (rs2706384 and rs1805015 are within loci involved in pro-inflammatory (interferon-gamma and anti-inflammatory (IL-4

  3. MSH3 mismatch repair protein regulates sensitivity to cytotoxic drugs and a histone deacetylase inhibitor in human colon carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Jae Myung Park

    Full Text Available BACKGROUND: MSH3 is a DNA mismatch repair (MMR gene that undergoes frequent somatic mutation in colorectal cancers (CRCs with MMR deficiency. MSH3, together with MSH2, forms the MutSβ heteroduplex that interacts with interstrand cross-links induced by drugs such as cisplatin. To date, the impact of MSH3 on chemosensitivity is unknown. METHODS: We utilized isogenic HCT116 (MLH1-/MSH3- cells where MLH1 is restored by transfer of chromosome 3 (HCT116+ch3 and also MSH3 by chromosome 5 (HCT116+3+5. We generated HCT116+3+5, SW480 (MLH1+/MSH3+ and SW48 (MLH1-/MSH3+ cells with shRNA knockdown of MSH3. Cells were treated with 5-fluorouracil (5-FU, SN-38, oxaliplatin, or the histone deacetylase (HDAC inhibitor PCI-24781 and cell viability, clonogenic survival, DNA damage and apoptosis were analyzed. RESULTS: MSH3-deficient vs proficient CRC cells showed increased sensitivity to the irinotecan metabolite SN-38 and to oxaliplatin, but not 5-FU, as shown in assays for apoptosis and clonogenic survival. In contrast, suppression of MLH1 attenuated the cytotoxic effect of 5-FU, but did not alter sensitivity to SN-38 or oxaliplatin. The impact of MSH3 knockdown on chemosensitivity to SN-38 and oxaliplatin was maintained independent of MLH1 status. In MSH3-deficient vs proficient cells, SN-38 and oxaliplatin induced higher levels of phosphorylated histone H2AX and Chk2, and similar results were found in MLH1-proficient SW480 cells. MSH3-deficient vs proficient cells showed increased 53BP1 nuclear foci after irradiation, suggesting that MSH3 can regulate DNA double strand break (DSB repair. We then utilized PCI-24781 that interferes with homologous recombination (HR indicated by a reduction in Rad51 expression. The addition of PCI-24781 to oxaliplatin enhanced cytotoxicity to a greater extent compared to either drug alone. CONCLUSION: MSH3 status can regulate the DNA damage response and extent of apoptosis induced by chemotherapy. The ability of MSH3 to regulate

  4. Effect of differentiating agents (all-trans retinoic acid and phorbol 12-myristate 13-acetate on drug sensitivity of HL60 and NB4 cells in vitro.

    Directory of Open Access Journals (Sweden)

    Jadwiga Mirecka

    2008-12-01

    Full Text Available In vitro studies have shown that human myeloid leukemia cell lines: HL60 and NB4 can be stimulated to differentiation by various agents, for example, all-trans retinoic acid (ATRA and phorbol 12-myristate 13-acetate (PMA. The purpose of this study was to investigate whether differentiation of HL60 and NB4 leukemia cell lines induced by ATRA and PMA alters their drug sensitivity. The differentiation along the neutrophil lineage (upon stimulation with ATRA and along the monocyte/macrophage lineage (upon stimulation with PMA was proved by decreased proliferative potential of cells, changes in their morphology, increased ability for NBT reduction and increased expression of CD11b and CD14 cell surface markers. The effect of drugs: cytosine arabinoside, daunorubicin, mitoxantrone and etoposide was examined by Alamar Blue test (proliferation and survival rates, as well as by evaluation of cell smears stained with Hoechst 33342 (apoptotic index. Differentiation resulted in the change of drug sensitivity in both cell lines: the differentiation along the neutrophil pathway (after stimulation with ATRA increased sensitivity to cytosine arabinoside and mitoxantrone but decreased sensitivity to etoposide; the differentiation along the monocyte/macrophage pathway (induced by PMA resulted in the decreased sensitivity of both cell lines to all drugs tested. In conclusion, we have shown that ATRA- and PMA-mediated differentiation of HL60 and NB4 cell lines results in the changes of their drug sensitivity. Our data may provide a contribution to a strategy aimed at a rational combination of differentiating agents and conventional anticancer drugs.

  5. Time-lapse imaging assay using the BioStation CT: A sensitive drug-screening method for three-dimensional cell culture

    OpenAIRE

    Sakamoto, Ruriko; Rahman, M. Mamunur; SHIMOMURA, MANAMI; Itoh, Manabu; Nakatsura, Tetsuya

    2015-01-01

    Three-dimensional (3D) cell culture is beneficial for physiological studies of tumor cells, due to its potential to deliver a high quantity of cell culture information that is representative of the cancer microenvironment and predictive of drug responses in vivo. Currently, gel-associated or matrix-associated 3D cell culture is comprised of intricate procedures that often result in experimental complexity. Therefore, we developed an innovative anti-cancer drug sensitivity screening technique ...

  6. Controlled release from thermo-sensitive PNVCL-co-MAA electrospun nanofibers: The effects of hydrophilicity/hydrophobicity of a drug.

    Science.gov (United States)

    Liu, Lin; Bai, Shaoqing; Yang, Huiqin; Li, Shubai; Quan, Jing; Zhu, Limin; Nie, Huali

    2016-10-01

    The thermo-sensitive copolymer poly(N-vinylcaprolactam-co-methacrylic acid) (PNVCL-co-MAA) was synthesized by free radical polymerization and the resulting nanofibers were fabricated using an electrospinning process. The molecular weight of the copolymer was adjusted by varying the content of methacrylic acid (MAA) while keeping that of N-vinylcaprolactam (NVCL) constant. Hydrophilic captopril and hydrophobic ketoprofen were used as model drugs, and PNVCL-co-MAA nanofibers were used as the drug carrier to investigate the effects of drug on its release properties from nanofibers at different temperatures. The results showed that slow release over several hours was observed at 40°C (above the lower critical solution temperature (LCST) of PNVCL-co-MAA), while the drugs exhibited a burst release of several seconds at 20°C (below the LCST). Drug release slowed with increasing content of the hydrophobic monomer NVCL. The hydrophilic captopril was released at a higher rate than the hydrophobic ketoprofen. The drug release characteristics were dependent on the temperature, the portion of hydrophilic groups and hydrophobic groups in the copolymer and hydrophilicity/hydrophobicity of drug. Study on the mechanism of release showed that Korsmeyer-Peppas model as a major drug release mechanism. Given these results, the PNVCL-co-MAA copolymers are proposed to have useful applications in intellectual drug delivery systems. PMID:27287157

  7. Evaluation of pH-sensitive poly(2-hydroxyethyl methacrylate-co-2-(diisopropylamino)ethyl methacrylate) copolymers as drug delivery systems for potential applications in ophthalmic therapies/ocular delivery of drugs

    OpenAIRE

    P. A. Faccia; F. M. Pardini; J. I. Amalvy

    2015-01-01

    Smart polymers like pH sensitive systems can improve different pharmacological treatment. In this work the behavior of copolymers containing 2-hydroxyethyl methacrylate (HEMA) with different proportions of 2-(diisopropylamino) ethyl methacrylate (DPA) and different amounts of cross-linker agent, ethylene glycol dimethacrylate (EGDMA) are evaluated as pH-sensitive drug delivery systems for potential application in ophthalmic therapies. A detailed characterization of the pH-responsive behavior ...

  8. miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity.

    Science.gov (United States)

    O'Brien, Keith; Lowry, Michelle C; Corcoran, Claire; Martinez, Vanesa G; Daly, Melissa; Rani, Sweta; Gallagher, William M; Radomski, Marek W; MacLeod, Roderick A F; O'Driscoll, Lorraine

    2015-10-20

    Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer. PMID:26416415

  9. ET-66ER-STRESS INDUCING DRUGS SENSITIZES GBM TO TEMOZOLOMIDE THROUGH DOWNREGULATION OF MGMT AND INDUCTION OF REGULATED NECROSIS

    Science.gov (United States)

    Xipell, Enric; Martínez-Velez, Naiara; Vera-Cano, Beatriz; Idoate, Miguel Angel; Garzón, Antonia García; Acanda, Arlet M.; Fueyo, Juan; Gomez-Manzano, Candelaria; Alonso, Marta M

    2014-01-01

    Termozolamide (TMZ) is the standard treatment against GBM, unfortunately its therapeutic effect is limited due to the expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Therefore, approaches that overcome the resistance to TMZ could be feasible therapeutic alternatives for this deadly disease. Endoplasmic reticulum (ER) stress suppresses several DNA damage proteins through the unfolding protein response. In this work we sought to evaluate whether ER-stress inducing drugs were able to downmodulate MGMT and sensitize GBM cells to TMZ treatment. Salinomycin (SLM) is a potassium ionophore that has proven effective against cancer stem cells and a possible candidate to induce ER stress. Our data showed that SLM triggered ER stress that was accompanied by the downregulation of MGMT. We obtained the same results with other ER stress inducing drugs (thapsigergin, tunicamycin) suggesting that this is a general mechanism. Chemical inhibition of ER stress reverted the abrogation of MGMT downregulation. Of importance, SLM induced an aberrant autophagic flux that led to regulated necrosis cell death mediated by the action of AIF protein, which induces DNA damage when localized in the nucleus. Combination of TMZ and SLM displayed a potent antitumor effect in vitro and in vivo in mice bearing a GBM stem cell model. Combination treatment induced a significant increase in DNA damage as shown by H2AX activation and PARP. Moreover, we observed AIF in the nucleus, as a result of the regulated necrosis, furthering favoring the DNA damage. Combination treatment showed an increment of the median survival and of long term survivors. Moreover tissue analysis confirmed a dramatic increase in the level of DNA damage. Altogether our results showed that combination treatment induces a potent antiglioma effect in vitro and in vivo. Our data uncover the possibility to exploit ER stress and regulated necrosis as therapeutic strategies for GBM treatment.

  10. Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation.

    Science.gov (United States)

    Huang, Amin; Ju, Huai-Qiang; Liu, Kaiyan; Zhan, Guilian; Liu, Daolu; Wen, Shijun; Garcia-Manero, Guillermo; Huang, Peng; Hu, Yumin

    2016-07-28

    Internal tandem duplication (ITD) of the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3) receptor is a common type of mutation in adult acute myeloid leukemia (AML), and patient response to FLT3 inhibitors appears to be transient due to the emergence of drug resistance. We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, including the murine BaF3/ITD-R and human MV4-11-R cell lines. Gene expression profile analysis of the resistant and parental cells suggests that the highest ranked molecular and cellular functions of the differentially expressed genes are related to mitochondrial dysfunction. Both murine and human resistant cell lines display a longer doubling time, along with a significant inhibition of mitochondrial respiratory chain activity and substantial upregulation of glycolysis. The sorafenib-resistant cells exhibit increased expression of a majority of glycolytic enzymes, including hexokinase 2, which is also highly expressed in the mitochondrial fraction and is associated with resistance to apoptotic cell death. The sorafenib-resistant cells are collaterally sensitive to a number of glycolytic inhibitors including 2-deoxyglucose and 3-bromopyruvate propylester. Our study reveals a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. PMID:27132990

  11. The REST Gene Signature Predicts Drug Sensitivity in Neuroblastoma Cell Lines and Is Significantly Associated with Neuroblastoma Tumor Stage

    Directory of Open Access Journals (Sweden)

    Jianfeng Liang

    2014-06-01

    Full Text Available Neuroblastoma is the most common and deadly solid tumor in children, and there is currently no effective treatment available for neuroblastoma patients. The repressor element-1 silencing transcription (REST factor has been found to play important roles in the regulation of neural differentiation and tumorigenesis. Recently, a REST signature consisting of downstream targets of REST has been reported to have clinical relevance in both breast cancer and glioblastoma. However it remains unclear how the REST signature works in neuroblastoma. Publicly available datasets were mined and bioinformatic approaches were used to investigate the utility of the REST signature in neuroblastoma with both preclinical and real patient data. The REST signature was found to be associated with drug sensitivity in neuroblastoma cell lines. Further, neuroblastoma patients with enhanced REST activity are significantly associated with higher clinical stages. Loss of heterozygosity on chromosome 11q23, which occurs in a large subset of high-risk neuroblastomas, tends to be correlated with high REST activity, with marginal significance. In conclusion, the REST signature has important implications for targeted therapy, and it is a prognostic factor in neuroblastoma patients.

  12. Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana

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    Claudia Simoes-Pires

    2014-12-01

    Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.

  13. Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase: A target for anti-malarial chemotherapy

    Czech Academy of Sciences Publication Activity Database

    Keough, D. T.; Hocková, Dana; Krečmerová, Marcela; Česnek, Michal; Holý, Antonín; Naesens, L.; Brereton, I. M.; Winzor, D. J.; de Jersey, J.; Guddat, L. W.

    2010-01-01

    Roč. 173, č. 2 (2010), s. 165-169. ISSN 0166-6851 R&D Projects: GA MŠk 1M0508 Grant ostatní: National Health and Medical Research Council(AU) 569703 Institutional research plan: CEZ:AV0Z40550506 Keywords : acyclic nucleoside phosphonates * Plasmodium vivax * 6-oxopurine phosphoribosyltransferase Subject RIV: CC - Organic Chemistry Impact factor: 2.875, year: 2010

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

    Directory of Open Access Journals (Sweden)

    Simard Frederic

    2008-03-01

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

  15. Multidrug resistance-associated protein gene overexpression and reduced drug sensitivity of topoisomerase II in a human breast carcinoma MCF7 cell line selected for etoposide resistance.

    Science.gov (United States)

    Schneider, E; Horton, J K; Yang, C H; Nakagawa, M; Cowan, K H

    1994-01-01

    A human breast cancer cell line (MCF7/WT) was selected for resistance to etoposide (VP-16) by stepwise exposure to 2-fold increasing concentrations of this agent. The resulting cell line (MCF7/VP) was 28-, 21-, and 9-fold resistant to VP-16, VM-26, and doxorubicin, respectively. MCF7/VP cells also exhibited low-level cross-resistance to 4'-(9-acridinylamino)-methanesulfon-m-anisidide, mitoxantrone, and vincristine and no cross-resistance to genistein and camptothecin. Furthermore, these cells were collaterally sensitive to the alkylating agents melphalan and chlorambucil. DNA topoisomerase II levels were similar in both wild-type MCF7/WT and drug-resistant MCF7/VP cells. In contrast, topoisomerase II from MCF7/VP cells appeared to be 7-fold less sensitive to drug-induced cleavable complex formation in whole cells and 3-fold less sensitive in nuclear extracts than topoisomerase II from MCF7/WT cells. Although this suggested that the resistant cells may contain a qualitatively altered topoisomerase II, no mutations were detected in either the ATP-binding nor the putative breakage/resealing regions of either DNA topoisomerase II alpha or II beta. In addition, the steady-state intracellular VP-16 concentration was reduced by 2-fold in the resistant cells, in the absence of detectable mdr1/P-gp expression and without any change in drug efflux. In contrast, expression of the gene encoding the MRP was increased at least 10-fold in resistant MCF7/VP cells as compared to sensitive MCF7/WT cells. These results suggest that resistance to epipodophyllotoxins in MCF7/VP cells is multifactorial, involving a reduction in intracellular drug concentration, possibly as a consequence of MRP overexpression, and an altered DNA topoisomerase II drug sensitivity. PMID:7903202

  16. Effect of anti-hyperlipidemia drugs on the alpha-tocopherol concentration and their potential for murine malaria infection.

    Science.gov (United States)

    Kume, Aiko; Herbas, Maria Shirley; Shichiri, Mototada; Ishida, Noriko; Suzuki, Hiroshi

    2016-01-01

    The current preventions of malaria are protection against mosquito bites and taking chemoprophylactic anti-malarial drugs. However, drug therapies are usually associated with adverse events and emergency of drug-resistant malaria parasites. Previous study showed that host plasma alpha-tocopherol deficiency enhanced resistance against malaria infection in mice. Here, we report a new prevention strategy against malaria by using anti-hyperlipidemia drugs, ezetimibe, berberine, cholestyramine, and probucol to modify the host plasma alpha-tocopherol concentration. The drugs were mixed with diet and fed to C57BL/6J mice for 2 weeks. Although all drugs reduced plasma alpha-tocopherol concentration after 2 weeks of feeding, probucol-treated mice showed 90 % reduction and it was the lowest alpha-tocopherol concentration among the four drugs. Ezetimibe, berberine, and combination of ezetimibe and berberine pretreatment for 2 weeks were not effective against infection of Plasmodium yoelii XL17, a lethal strain, for survival and parasitemia in mice. Two-week pretreatment and 1-week treatment after infection of cholestyramine had also no effect on malaria infection. Survival rates of cholestyramine, ezetimibe, and/or berberine treated mice were 0-22 %. However, probucol caused significant decrease in parasitemia and increased in mice survival following 2-week pretreatment and 1-week treatment after infection. All control mice died while all probucol treated mice survived during the course of infection. Thus, probucol which reduced plasma alpha-tocopherol concentration was effective in enhancing the host to resist malaria infection in mice. Our finding indicates that plasma alpha-tocopherol reducing drugs like probucol might be a candidate for beneficial prevention strategy for travelers from malaria-free area. PMID:26358099

  17. Preparation of pH-sensitive poly(ethylene oxide) hydrogels grafted by γ-ray irradiation and their applications for drug delivery system

    International Nuclear Information System (INIS)

    Hydrogels are three-dimensional networks of hydrophilic polymers held together by crosslinks of covalent bonds or ionic bonds and secondary forces in the form of hydrogen bonds or hydrophobic interactions. Environmentally sensitive hydrogels have an enormous potential for various applications. Either pH-sensitive and/or temperature- sensitive hydrogels can be used for a site-specific controlled drug delivery. Especially, pH-sensitive hydrogels have been most frequently used to develop controlled release formulations for oral administration. All the pH-sensitive hydrogels contain pendent acidic, for example carboxylic and sulfonic acids, or basic, for example ammonium salts, groups that either accept or release protons in response to changes in environmental pH[3-5]. These ionic hydrogels are the swollen polymer networks which show sudden or gradual changes in their dynamic and equilibrium swelling behavior as a result of changing the external pH. In these gels, ionization occurs when the pH of the environment is above the pKa of the ionizable group . As the degree of ionization increases (pH increase in the system), the number of fixed charges increases, resulting in increased electrostatic repulsions between the chains. Irradiation, especially if combined with simultaneous sterilization of the product, is a very convenient tool for the synthesis of hydrogels. Radiation processing has many advantages over other conventional methods. For initiation processes, radiation differs from chemical initiation. In radiation processing, no catalysts or additives are needed to initiate the reaction. The advantages of the radiation methods are that they are relatively simple, and moreover, the degree of crosslinking, which strongly determines the extent of swelling in hydrogels, can be controlled easily by varying the absorbed dose. Therefore, these methods are found to be very useful in preparing hydrogels for medical applications, where even a small contamination is

  18. Synthesis and Properties of pH-, Thermo-, and Salt-Sensitive Modified Poly(aspartic acid/Poly(vinyl alcohol IPN Hydrogel and Its Drug Controlled Release

    Directory of Open Access Journals (Sweden)

    Jingqiong Lu

    2015-01-01

    Full Text Available Modified poly(aspartic acid/poly(vinyl alcohol interpenetrating polymer network (KPAsp/PVA IPN hydrogel for drug controlled release was synthesized by a simple one-step method in aqueous system using poly(aspartic acid grafting 3-aminopropyltriethoxysilane (KH-550 and poly(vinyl alcohol (PVA as materials. The hydrogel surface morphology and composition were characterized by Fourier transform infrared spectroscopy (FTIR and scanning electron microscopy (SEM. The thermal stability was analyzed by thermogravimetric analysis (TGA. The swelling properties and pH, temperature, and salt sensitivities of KPAsp, KPAsp/PVA semi-interpenetrating polymer network (semi-IPN, and KPAsp/PVA IPN hydrogels were also investigated. All of the three hydrogels showed ampholytic pH-responsive properties, and swelling behavior was also extremely sensitive to the temperature, ionic strength, and cationic species. Finally, the drug controlled release properties of the three hydrogels were evaluated and results indicated that three hydrogels could control drug release by external surroundings stimuli. The drug controlled release properties of KPAsp/PVA IPN hydrogel are the most outstanding, and the correlative measured release profiles of salicylic acid at 37°C were 32.6 wt% at pH = 1.2 (simulated gastric fluid and 62.5 wt% at pH = 7.4 (simulated intestinal fluid, respectively. These results indicated that KPAsp/PVA IPN hydrogels are a promising carrier system for controlled drug delivery.

  19. Confocal fluorescence microscopy: An ultra-sensitive tool used to evaluate intracellular antiretroviral nano-drug delivery in HeLa cells

    Science.gov (United States)

    Mandal, Subhra; Zhou, You; Shibata, Annemarie; Destache, Christopher J.

    2015-08-01

    In the last decade, confocal fluorescence microscopy has emerged as an ultra-sensitive tool for real-time study of nanoparticles (NPs) fate at the cellular-level. According to WHO 2007 report, Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) is still one of the world's major health threats by claiming approximately 7,000 new infections daily worldwide. Although combination antiretroviral drugs (cARV) therapy has improved the life-expectancy of HIV-infected patients, routine use of high doses of cARV has serious health consequences and requires complete adherence to the regimen for success. Thus, our research goal is to fabricate long-acting novel cARV loaded poly(lactide-co-glycolic acid) (PLGA) nanoparticles (cARV-NPs) as drug delivery system. However, important aspects of cARV-NPs that require special emphasis are their cellular-uptake, potency, and sustained drug release efficiency over-time. In this article, ultra-sensitive confocal microscopy is been used to evaluate the uptake and sustained drug release kinetics of cARV-NPs in HeLa cells. To evaluate with the above goal, instead of cARV-drug, Rhodamine6G dye (fluorescent dye) loaded NPs (Rho6G NPs) have been formulated. To correlate the Rhodamin6G release kinetics with the ARV release from NPs, a parallel HPLC study was also performed. The results obtained indicate that Rho6G NPs were efficiently taken up at low concentration (delivery with the potential to reduce drug dosage as well as the number of drug administrations per month.

  20. Comparative proteomic analysis of sequential isolates of Mycobacterium tuberculosis from a patient with pulmonary tuberculosis turning from drug sensitive to multidrug resistant

    Directory of Open Access Journals (Sweden)

    Amit Singh

    2015-01-01

    Full Text Available Background & objectives: Tuberculosis is a major health problem in India, and the emergence of multidrug resistant (MDR and extensively drug resistant (XDR strains of Mycobacterium tuberculosis (Mtb has further complicated the situation. Though several studies characterizing drug sensitive and drug resistant strains are available in literature, almost all studies are done on unrelated strains. Therefore, the objective of this study was to compare the proteomic data of four sequential isolates of Mtb from a single patient who developed MDR-TB during the course of anti-tuberculosis therapy (ATT. Methods: In this study, using two-dimensional (2D gel electrophoresis and MALDI-TOF mass spectrometry, we compared and analyzed the cell lysate proteins of Mtb sequential clinical isolates from a patient undergoing anti-TB treatment. The mRNA expression levels of selected identified proteins were determined by quantitative real-time polymerase chain reaction (qRT-PCR. Results: The genotypes of all four isolates remained homologous, indicating no re-infection. The initial isolate (before treatment was sensitive to all first-line drugs, but the consecutive isolates were found to be resistant to isoniazid (INH and rifampicin (RIF and developed mutations in the katG, inhA and rpoB. the intensities of 27 protein spots were found to be consistently overexpressed in INH and RIF resistant isolates. The most prominent and overexpressed proteins found during the development of drug resistance were GarA (Rv1827, wag31 (Rv2145c, Rv1437 and Rv2970c. Interpretation & conclusions: This preliminary proteomic study provides an insight about the proteins that are upregulated during drug resistance development. These upregulated proteins, identified here, could prove useful as immunodiagnostic and possibly drug resistant markers in future. However, more studies are required to confirm these findings.

  1. A Mathematical Model for the Transmission and Spread of Drug Sensitive and Resistant Malaria Strains within a Human Population

    OpenAIRE

    Tumwiine, Julius; Hove-Musekwa, Senelani D.; Nyabadza, Farai

    2014-01-01

    Malaria remains by far the world's most important tropical disease, killing more people than any other communicable disease. A number of preventive and control measures have been put in place and most importantly drug treatment. The emergence of drug resistance against the most common and affordable antimalarials is widespread and poses a key obstacle to malaria control. A mathematical model that incorporates evolution of drug resistance and treatment as a preventive strategy is formulated an...

  2. Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

    Directory of Open Access Journals (Sweden)

    Menard Sandie

    2012-04-01

    Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a

  3. Ex vivo cultures of glioblastoma in three-dimensional hydrogel maintain the original tumor growth behavior and are suitable for preclinical drug and radiation sensitivity screening

    Energy Technology Data Exchange (ETDEWEB)

    Jiguet Jiglaire, Carine, E-mail: carine.jiguet-jiglaire@univ-amu.fr [Aix Marseille Université, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille (France); CRO2, UMR 911, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille Cedex (France); INSERM, U911, 13005 Marseille (France); Baeza-Kallee, Nathalie; Denicolaï, Emilie; Barets, Doriane [Aix Marseille Université, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille (France); CRO2, UMR 911, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille Cedex (France); INSERM, U911, 13005 Marseille (France); Metellus, Philippe [Aix Marseille Université, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille (France); CRO2, UMR 911, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille Cedex (France); INSERM, U911, 13005 Marseille (France); APHM, Timone Hospital, Department of Neurosurgery, 13005 Marseille (France); Timone Hospital, 264 Rue Saint Pierre, 13385 Marseille Cedex 5 (France); and others

    2014-02-15

    Identification of new drugs and predicting drug response are major challenges in oncology, especially for brain tumors, because total surgical resection is difficult and radiation therapy or chemotherapy is often ineffective. With the aim of developing a culture system close to in vivo conditions for testing new drugs, we characterized an ex vivo three-dimensional culture system based on a hyaluronic acid-rich hydrogel and compared it with classical two-dimensional culture conditions. U87-MG glioblastoma cells and seven primary cell cultures of human glioblastomas were subjected to radiation therapy and chemotherapy drugs. It appears that 3D hydrogel preserves the original cancer growth behavior and enables assessment of the sensitivity of malignant gliomas to radiation and drugs with regard to inter-tumoral heterogeneity of therapeutic response. It could be used for preclinical assessment of new therapies. - Highlights: • We have compared primary glioblastoma cell culture in a 2D versus 3D-matrix system. • In 3D morphology, organization and markers better recapitulate the original tumor. • 3D-matrix culture might represent a relevant system for more accurate drug screening.

  4. Drug release behavior of a pH/temperature sensitive calcium alginate/poly(N-acryloylglycine bead with core-shelled structure

    Directory of Open Access Journals (Sweden)

    2010-12-01

    Full Text Available In this study, a novel pH/temperature sensitive hydrogel bead with core-shelled structure, composed of calcium alginate (Ca-alginate and poly((N-acryloylglycine (PAG, was prepared using as a drug delivery system. The equilibrium swelling has indicated the distinct sensitivities of the beads to pH value and temperature. In pH = 7.4 phosphate buffer solution (PBS, the cumulative release amount of indomethacin loaded in the core of the beads was about 83.5% within 650 min, whereas this value only reached 16.6% in pH = 2.1 PBS. In addition, the release rate of indomethacin was much faster at 37°C than that at 24°C. The experimental results have showed that the Ca-alginate/PAG beads have a potential application for the pH/temperature-controlled drug release carrier in the biomedical field.

  5. Comparision of the Cytotoxic Effects of Birch Bark Extract, Betulin and Betulinic Acid Towards Human Gastric Carcinoma and Pancreatic Carcinoma Drug-sensitive and Drug-Resistant Cell Lines

    Directory of Open Access Journals (Sweden)

    Hermann Lage

    2009-04-01

    Full Text Available Betulin and betulinic acid are naturally occurring pentacyclic triterpenes showing cytotoxicity towards a number of cancer cell lines. These compounds can be found in the bark of the many plants. In this report we have compared the cytotoxic activity of crude birch bark extract and purified betulin and betulinic acid towards human gastric carcinoma (EPG85-257 and human pancreatic carcinoma (EPP85-181 drug-sensitive and drug-resistant (daunorubicin and mitoxantrone cell lines. Our results show significant differences in sensitivity between cell lines depending on the compound used, and suggest that both betulin and betulinic acid can be considered as a promising leads in the treatment of cancer.

  6. Pharmacokinetic interactions between artesunate-mefloquine and ritonavir-boosted lopinavir in healthy Thai adults

    OpenAIRE

    Rattanapunya, Siwalee; Cressey, Tim R.; Rueangweerayut, Ronnatrai; Tawon, Yardpiroon; Kongjam, Panida; Na-Bangchang, Kesara

    2015-01-01

    Background Concomitant use of anti-malarial and antiretroviral drugs is increasingly frequent in malaria and HIV endemic regions. The aim of the study was to investigate the pharmacokinetic interaction between the anti-malarial drugs, artesunate-mefloquine and the antiretroviral drug, lopinavir boosted with ritonavir (LPV/r). Methods The study was an open-label, three-way, sequential, cross-over, pharmacokinetic study in healthy Thai adults. Subjects received the following treatments: Period ...

  7. In vitro interaction of lumefantrine and piperaquine by atorvastatin against Plasmodium falciparum

    OpenAIRE

    Dormoi, Jérome; Savini, Hélène; Amalvict, Rémy; Baret, Eric; Pradines, Bruno

    2014-01-01

    Background There is an urgent need for the discovery of new anti-malarial drugs and combination therapy. A combinatorial approach protects each drug from the development of resistance and reduces generally the overall transmission rate of malaria. Statins, the inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and a family of lipid-lowering drugs, have in vitro anti-malarial properties, and more specially atorvastatin. However, atorvastatin has a short elimination half-life (14 hou...

  8. In silico analysis of Plasmodium species specific UvrD helicase

    OpenAIRE

    Tuteja, Renu

    2013-01-01

    Malaria is still a devastating disease caused by the mosquito-transmitted parasite Plasmodium, particularly Plasmodium falciparum. During the last few years the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several anti-malarial drugs. Thus there is an urgent need to find alternate ways to control malaria and therefore it is necessary to identify new drug targets and new classes of anti-malarial drugs. A malaria vaccine would be the u...

  9. CS/PAA@TPGS/PLGA nanoparticles with intracellular pH-sensitive sequential release for delivering drug to the nucleus of MDR cells.

    Science.gov (United States)

    Wang, Ying-Ying; Zhang, Dan-Dan; Kong, Yan-Yan; Shao, Luan-Luan; Zhang, Fen-Yi; Gao, Yu; Mu, Xu; Wang, Jie; Li, Hao-Fan; Yu, Shu-Qin; Xu, Qian

    2016-09-01

    Development of novel nano-drug delivery systems (NDDS) that can transport anticancer drugs into cell nuclei is still a highly desirable strategy for reversing multi-drug resistance (MDR) in cancer therapy. Herein, we designed and prepared a novel NDDS, designated S@L NPs, in which several smaller nanoparticles are contained within a larger nanoparticle. Our S@L NPs (CS/PAA/VP-16@TPGS/PLGA NPs) possess a structure in which smaller nanoparticles (Chitosan-Poly(acrylic acid) nanoparticles, CS/PAA NPs) containing the drug etoposide (VP-16) are loaded within a larger nanoparticle (Vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles, TPGS/PLGA NPs). The system utilizes intracellular pH gradients to achieve pH-sensitive sequential release within different intracellular domains of MDR cells. S@L NPs could be triggered to degrade and release CS/PAA/VP-16 NPs in the acid environment of the cytosol, endosomes or lysosomes, and CS/PAA/VP-16 NPs were capable of entering the nucleus through nucleopores. It is significant that CS/PAA/VP-16 NPs exhibit disaggregation in the alkaline environment of the nucleus and thereby release the contained anticancer drug. Further mechanistic studies showed that CS/PAA/VP-16 NPs escaped retention and degradation within lysosomes and protected the drug from P-glycoprotein-induced efflux. Simultaneously, S@L NPs enhanced the anticancer effect of the loaded drug by inducing autophagy and apoptosis of MDR cells. This novel NDDS may provide a promising platform for nuclear drug delivery for reversing MDR. PMID:27289313

  10. 肝癌化疗药敏试验与应用研究%Research and exploratory of chemotherapy drugs sensitivity tests in liver cancer

    Institute of Scientific and Technical Information of China (English)

    傅颖媛; 梅钧; 饶荣生; 张学敏; 徐江霞; 曾小平; 许静

    2008-01-01

    Objective To investigate the feasibility of the drug sensitivity tests of clinical liver cancer in vitro in order to prgvide a significant experimental basis to formulate a reasonable"individualizied"treatment plan.Methods 3H-thymidine incorporation assay(3H-TdR method)and MTS colorimetric assay(MTS method)were used to test the sensitivities of SMMC-7721 and NKM-45 cell lines to nine species of anticancer drugs[Hydroxyeamptothecin(HCPT),vinorelbine(NVB),adriamycin(ADM),5-fluomuracil(5-Fu),cisplatin(DDP),Pingyangmyein(PYM),mitomycin(MMC),Etopeside(VP-16),methotrexate(MTX)],and the other drug sensitivity test was carried on 53 eases of clinical tumor specimen(including 32 eases of liver cancer,13 cases of colorectal cancer,and 8 eases of gastric cancer)by MTS method.Results There Was no significant difference between MTS method and 3H-TdR method for the drug sensitivity tests(P>0.05).The total effective rates of these 9 drugs to 32 cases of clinical fiver ceancer cells samples were significantly different.Of which,the highest one was HCPT (90.63%)and the second NVB(78.10%).The sensitivities of the three species of clinical tumors to 9 drugs were different or partially different.Conclusion Both MTS method and 3H-TdR method are reliable and stable method for the drug sensitivity tests.It is necessary that the drug sensitivity test be carried on the patients before chemotherspy.HCPT and NVB can be priority for liver cancer patients if there is no other choice.%目的 探讨临床肝癌组织细胞体外药敏试验的可行性,为临床制定合理的肿瘤"个体化"治疗方案提供依据.方法 采用MTS比色法和3H-TdR掺入法测定肝癌SMMC-7721及胃癌NKM45细胞株对临床常用9种抗癌药物[羟基喜树碱(HCPT)、盖诺(NVB)、阿霉素(ADM)、5-氟尿嘧啶(5-FU)、顺铂(DDP)、平阳霉素(PYM)、丝裂霉素(MMC)、足叶乙甙(VP-16)、甲氨蝶呤(MTX)]的敏感性,并用MTS比色法对53例临床肿瘤标本(其中肝癌32例、结直肠癌13

  11. Mitoxantrone Loaded Superparamagnetic Nanoparticles for Drug Targeting: A Versatile and Sensitive Method for Quantification of Drug Enrichment in Rabbit Tissues Using HPLC-UV

    Directory of Open Access Journals (Sweden)

    Rainer Tietze

    2010-01-01

    Full Text Available In medicine, superparamagnetic nanoparticles bound to chemotherapeutics are currently investigated for their feasibility in local tumor therapy. After intraarterial application, these particles can be accumulated in the targeted area by an external magnetic field to increase the drug concentration in the region of interest (Magnetic-Drug-Targeting. We here present an analytical method (HPLC-UV, to detect pure or ferrofluid-bound mitoxantrone in a complex matrix even in trace amounts in order to perform biodistribution studies. Mitoxantrone could be extracted in high yields from different tissues. Recovery of mitoxantrone in liver tissue (5000 ng/g was 76±2%. The limit of quantification of mitoxantrone standard was 10 ng/mL ±12%. Validation criteria such as linearity, precision, and stability were evaluated in ranges achieving the FDA requirements. As shown for pilot samples, biodistribution studies can easily be performed after application of pure or ferrofluid-bound mitoxantrone.

  12. pH-sensitive micellar systems for controlled drug delivery: synthesis and structural characterization by small-angle neutron scattering

    OpenAIRE

    Joset, Arnaud; Jérôme, Christine; Brulet, Annie; Leyh, Bernard

    2009-01-01

    The aim of the project is the preparation of micellar nanocarriers made of biocompatibles copolymers and their structural analysis by Small Angle Neutron Scattering (SANS). These micelles could be used in drug delivery applications to fight cancer1. The hydrophobic polycaprolactone (PCL) core is intended to incorporate the drug. The corona of hydrophilic polyethylene oxide (PEO) stabilizes the nanocarriers with respect to the plasma proteins. The pH in the neighborhood of the tumoral cells is...

  13. A comprehensive and sensitive method for hair analysis in drug-facilitated crimes and incorporation of zolazepam and tiletamine into hair after a single exposure.

    Science.gov (United States)

    Kim, Jihyun; Yum, Hyesun; Jang, Moonhee; Shin, Ilchung; Yang, Wonkyung; Baeck, Seungkyung; Suh, Joon Hyuk; Lee, Sooyeun; Han, Sang Beom

    2016-01-01

    Hair is a highly relevant specimen that is used to verify drug exposure in victims of drug-facilitated crime (DFC) cases. In the present study, a new analytical method involving ultrahigh-performance liquid chromatography-tandem mass spectrometry was developed for determining the presence of model drugs, including zolazepam and tiletamine and their metabolites in hair specimens from DFCs. The incorporation of zolazepam and tiletamine into hair after a single exposure was investigated in Long-Evans rats with the ratio of the hair concentration to the area under the curve. For rapid and simple sample preparation, methanol extraction and protein precipitation were performed for hair and plasma, respectively. No interference was observed in drug-free hair or plasma, except for hair-derived diphenhydramine in blank hair. The coefficients of variance of the matrix effects were below 12%, and the recoveries of the analytes exceeded 70% in all of the matrices. The precision and accuracy results were satisfactory. The limits of quantification ranged from 20 to 50 pg in 10 mg of hair. The drug incorporation rates were 0.03 ± 0.01% for zolazepam and 2.09 ± 0.51% for tiletamine in pigmented hair. We applied the present method to real hair samples in order to determine the drug that was used in seven cases. These results suggest that this comprehensive and sensitive hair analysis method can successfully verify a drug after a single exposure in crimes and can be applied in forensic and clinical toxicology laboratories. PMID:26454443

  14. Overexpression of miR-34c regulates the sensitivity to doxorubicin in drug-resistant breast cancer cell lines MCF-7/DOX

    Institute of Scientific and Technical Information of China (English)

    Han Li; Tong Li; Li-Hong Zhang

    2016-01-01

    Objective:To study the regulating effect of overexpressing miR-34c on the sensitivity to doxorubicin in drug-resistant breast cancer cell line MCF-7/DOX. Methods:Breast cancer cell lines MCF-7 and drug-resistant breast cancer cell lines MCF-7/DOX were cultured, transfected with miR-34c and negative control fragments and treated with different doses of doxorubicin;treated cells were taken, CCK-8 kits were used to detect cell viability, and RNA detection kits were used to detect mRNA contents of drug resistance-related genes. Results: miR-34a, 34b and 34c expression levels in MCF-7/DOX cell lines were lower than those in MCF-7 cell lines and the reduction of miR-34c expression level was the most significant, and mRNA contents of MDR1, BCRP, UCP2, Twist and c-Src were significantly higher than those in MCF-7 cell lines;after transfection of miR-34c, the inhibitory effect of doxorubicin on the viability of MCF-7/DOX cell lines was stronger than that of MCF-7/DOX cell lines transfected with negative control, and mRNA contents of MDR1, BCRP, UCP2, Twist and c-Src were significantly lower than those in MCF-7 cell lines transfected with negative control. Conclusions:Overexpression of miR-34c in drug-resistant breast cancer cell lines MCF-7/DOX can increase the sensitivity to doxorubicin and inhibit the expression levels of drug resistance-related genes MDR1, BCRP, UCP2, Twist and c-Src .

  15. Towards rapid genotyping of resistant malaria parasites: could loop-mediated isothermal amplification be the solution?

    OpenAIRE

    Abdul-Ghani, Rashad

    2014-01-01

    Loop-mediated isothermal amplification (LAMP) is an innovative molecular technique that has been validated for point-of-care testing to diagnose malaria. Molecular detection and tracking of anti-malarial drug resistance is mainly based on highly sophisticated, costly and time-consuming techniques. With the validation of resistance-associated gene mutations in malaria parasites, there is a need to develop rapid, easy-to-use molecular tests for anti-malarial drug resistance genotyping. LAMP cou...

  16. Chitosan-based intelligent theragnosis nanocomposites enable pH-sensitive drug release with MR-guided imaging for cancer therapy

    Science.gov (United States)

    Lim, Eun-Kyung; Sajomsang, Warayuth; Choi, Yuna; Jang, Eunji; Lee, Hwunjae; Kang, Byunghoon; Kim, Eunjung; Haam, Seungjoo; Suh, Jin-Suck; Chung, Sang Jeon; Huh, Yong-Min

    2013-11-01

    Smart drug delivery systems that are triggered by environmental conditions have been developed to enhance cancer therapeutic efficacy while limiting unwanted effects. Because cancer exhibits abnormally high local acidities compared to normal tissues (pH 7.4) due to Warburg effects, pH-sensitive systems have been researched for effective cancer therapy. Chitosan-based intelligent theragnosis nanocomposites, N-naphthyl- O-dimethymaleoyl chitosan-based drug-loaded magnetic nanoparticles ( NChitosan-DMNPs), were developed in this study. NChitosan-DMNPs are capable of pH-sensitive drug release with MR-guided images because doxorubicin (DOX) and magnetic nanocrystals (MNCs) are encapsulated into the designed N-naphthyl- O-dimethymaleoyl chitosan ( N-nap- O-MalCS). This system exhibits rapid DOX release as acidity increases, high stability under high pH conditions, and sufficient capacity for diagnosing and monitoring therapeutic responses. These results demonstrate that NChitosan-DMNPs have potential as theragnosis nanocomposites for effective cancer therapy.

  17. An in vitro drug sensitivity test using a higher 3H-TdR incorporation and a modified human tumor stem cell assay

    International Nuclear Information System (INIS)

    An in vitro drug sensitivity test was developed to evaluate the lethal effects of drugs on human pulmonary carcinoma cells (HPCC). This method was a variant and combination of Human Tumor Stem (HTSCA) and a short-term test using 3H-TdR incorporation. It consisted of a cell containing liquid top layer and a soft agar bottom layer in 24-well microplates. The medium was RPMI 1640 supplemented with 20% malignant pleural effusion, which could enhance 3H-TdR incorporation into malignant cells. When 50%, 40%, 30% and 30% of cell survival rate defined as sensitivity-threshold for VCR, MMC, DDP and ADM respectively, in the vitro effectiveness were close to those of clinical single-drug treatment in HPCC by Wright et al. This method was also compared with HTSCA in ten human lung cancer cell lines and four pulmonary carcinoma tissues. The agreement rates were 83% and 100% respectively. Thus we presume this system is more useful for oncological clinics than the others

  18. The Effectiveness and Safety of Fluoroquinolone-Containing Regimen as a First-Line Treatment for Drug-Sensitive Pulmonary Tuberculosis: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Lee, Hyun Woo; Lee, Jung Kyu; Kim, Eunyoung; Yim, Jae-Joon; Lee, Chang-Hoon

    2016-01-01

    Background Fluoroquinolone is recommended as a pivotal antituberculous agent for treating multi-drug-resistant pulmonary tuberculosis. However, its effectiveness as first-line treatment remains controversial. The present study was conducted to validate the fluoroquinolone-containing regimen for drug-sensitive pulmonary tuberculosis. Methods We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials until June 5, 2015. Randomized controlled trials (RCTs) that compared antituberculous regimens containing fluoroquinolone with the standard regimen were included. Results Eleven RCTs that included 6,334 patients were selected. Fluoroquinolone-containing regimens had a higher rate of sputum culture conversion at 2 months of treatment (M-H fixed odds ratio [OR], 1.36; 95% confidence interval [CI], 1.20–1.54). However, the outcomes were less favorable (M-H fixed OR, 0.69; 95% CI, 0.59–0.82) and the associated total adverse events were more frequent (M-H fixed OR, 1.84; 95% CI, 1.46–2.31) in the fluoroquinolone-containing regimen group, without a significant heterogeneity according to treatment duration. Treatment with the fluoroquinolone-containing regimen for 4 months showed a higher relapse rate. Conclusions Despite a higher culture conversion rate at 2 months of treatment, the fluoroquinolone-containing regimen had limitations, including less favorable outcomes and more adverse events, as the first-line therapy for drug-sensitive pulmonary tuberculosis. PMID:27455053

  19. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus

    DEFF Research Database (Denmark)

    de Evgrafov, Mari Cristina Rodriguez; Gumpert, Heidi; Munck, Christian;

    2015-01-01

    As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations......, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory...... concentration levels, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased...

  20. Impact of hydrogenation on physicochemical and biomedical properties of pH-sensitive PMAA-b-HTPB-b-PMAA triblock copolymer drug carriers.

    Science.gov (United States)

    Xu, Feng; Xu, Jing-Wen; Luo, Yan-Ling

    2016-05-01

    pH-Sensitive poly(methacrylic acid)-block-hydroxyl-terminated polybutadiene-block-poly(methacrylic acid) (PMAA-b-HTPB-b-PMAA) was synthesized and then hydrogenated in this work. The chain structure, phase behavior and thermal properties were characterized by(1)H NMR, FTIR, XRD, DSC, TGA, etc., and the physicochemical and biomedical properties were investigated via fluorescence spectroscopy, TEM, DLS, loading and release of drug and MTT, and so on. The experimental results indicated that the hydrogenation led to the change in the chain aggregate structure of hydrophobic HTPB blocks and the formation of more stable spherical core-shell micelle aggregates, and the critical micelle concentration decreased from 41.8 mg L(-1)before hydrogenation to 4.4 mg L(-1)after hydrogenation. The hydrogenated block copolymer micelle aggregates exhibited pH-triggered response, and could entrap twice as much hydrophobic drug as the unhydrided counterparts and the encapsulation efficiency was significantly improved, which makes them fine to meet the requirements for drug carriers. Therefore, the hydrogenated PMAA-b-HTPB-b-PMAA copolymer micelles as drug target release carriers can be well used in the field of prevention and treatment of cancers. PMID:26939939

  1. Using temperature-sensitive smart polymers to regulate DNA-mediated nanoassembly and encoded nanocarrier drug release.

    Science.gov (United States)

    Hamner, Kristen L; Alexander, Colleen M; Coopersmith, Kaitlin; Reishofer, David; Provenza, Christina; Maye, Mathew M

    2013-08-27

    In this paper we describe the use of a temperature-responsive polymer to regulate DNA interactions in both a DNA-mediated assembly system and a DNA-encoded drug delivery system. A thermoresponsive pNIPAAm-co-pAAm polymer, with a transition temperature (TC) of 51 °C, was synthesized with thiol modification and grafted onto gold nanoparticles (Au NPs) also containing single-stranded oligonucleotides (ssDNA). The thermoresponsive behavior of the polymer regulated the accessibility of the sequence-specific hybridization between complementary DNA-functionalized Au NPs. At T TC, the polymer shell undergoes a hydrophilic to -phobic phase transition and collapses, shrinking below the outer ssDNA, allowing for the sequence-specific hybridization to occur. The potential application of this dynamic interface for drug delivery is shown, in which the chemotherapy drug doxorubicin (DOX) is bound to double-stranded DNA (dsDNA)-functionalized Au NPs whose sequences are known to be high-affinity intercalation points for it. The presence of the polymer capping is shown to decrease drug release kinetics and equilibrium at T TC, thus improving the cytotoxicity of the encoded nanocarrier design. PMID:23899347

  2. Evaluation of pH-sensitive poly(2-hydroxyethyl methacrylate-co-2-(diisopropylaminoethyl methacrylate copolymers as drug delivery systems for potential applications in ophthalmic therapies/ocular delivery of drugs

    Directory of Open Access Journals (Sweden)

    P. A. Faccia

    2015-06-01

    Full Text Available Smart polymers like pH sensitive systems can improve different pharmacological treatment. In this work the behavior of copolymers containing 2-hydroxyethyl methacrylate (HEMA with different proportions of 2-(diisopropylamino ethyl methacrylate (DPA and different amounts of cross-linker agent, ethylene glycol dimethacrylate (EGDMA are evaluated as pH-sensitive drug delivery systems for potential application in ophthalmic therapies. A detailed characterization of the pH-responsive behavior was performed by swelling studies and scanning electron microscopy (SEM analysis. Drug loading and release studies at different pH values were evaluated using Rhodamine 6G (Rh6G as a model drug. The interaction between Rh6G and hydrogels was studied by Fourier Transform Infrared (FTIR spectroscopy and scanning electron microscopy (SEM. The results show that the presence of DPA in the copolymers confers pH-responsive properties to the polymer, as noted in swelling and SEM studies, when the pH decreases below 7.40 the swelling degree increases and a porous morphology is observed. The apparent pKa of copolymers was estimated between 6.80 and 7.17 depending on the composition. The amount of Rh6G loaded depends mainly on the medium pH and the interaction between the drug and the copolymers, observed by SEM and FTIR spectrum. The release of Rh6G of copolymers p(HEMA/DPA show a normal Fickian or anomalous diffusion behavior at different pH values, depending on the HEMA/DPA ratio.

  3. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  4. Effect of anticancer drugs on breast cancer cells sensitive and resistant to doxorubicin: expression of mRNAs of TGF-β and its receptors

    OpenAIRE

    Chorna I. V.; Fedorenko O. V.; Stoika R. S.

    2014-01-01

    Aim. Comparative study of the effect of chemotherapeutic drugs (doxorubicin, methotrexate and cisplatin) and TGF-β on the human breast carcinoma MCF-7 cells, sensitive (wt) and resistant (DOX/R) to the doxorubicin action. Methods. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the estimation of expression of mRNAs coding for the TGF-β isoforms (TGF-β1 and TGF-β2) and the TGF-β type I and II receptors (TRI and TRII). Trypan blue exclusion method was use...

  5. An analysis on drug sensitivity of 279 clinical Candida isolates%279株临床标本念珠菌药物敏感的分析

    Institute of Scientific and Technical Information of China (English)

    林建鹏; 龙淑珍; 潘莉明

    2011-01-01

    目的 分析279株临床念珠菌的药物敏感性,以指导临床合理用药治疗真菌感染.方法 沙保弱培养基培养标本,用APIAUX20C真菌板条进行鉴定分型,用ATB药敏板条进行药敏实验.结果 分离的菌株对两性霉素B敏感率100%、其次是5-氟胞嘧啶除了白色念珠菌敏感率88.2%,其它念珠菌在100%.依曲康唑,氟康唑,依立康唑敏感率很低,都在32%以上.结论 两性霉素B、5-氟胞嘧啶为治疗念珠菌感染的首选用药.%Objective To instruct reasonable use of medications for fungal infections by analyzing the drug sensitivity of 279 clinical Candida isolates. Methods The Candida isolates were cultured with Sobouraud's bouillon and were then typed with the API AUX 20C fungi ID panel. Susceptibility testing was performed with ATB strips. Results The sensitivity of all the isolates to amphotericin B was 100%, and that of all the isolates except Candida albicans to 5-fluorocytosine was 100%; 88.2% of Candida albicans isolates were sensitive to 5-fluorocytosine. The sensitivity to itraconazole, fluconazole, or uniconazole was very low ( approximately 32% ). Conclusions Amphotericin B and 5-fluorocytosine are the first drug of choice for treating Candida infections.

  6. Prenatal stress alters progestogens to mediate susceptibility to sex-typical, stress-sensitive disorders, such as drug abuse: a review

    Directory of Open Access Journals (Sweden)

    Cheryl A Frye

    2011-10-01

    Full Text Available Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well understood. Our hypothesis is that allopregnanolone, during gestation, plays a particularly vital role in mitigating effects of stress on the developing fetus and may mediate, in part, alterations apparent throughout the lifespan. Specifically, altered balance between glucocorticoids and progestogens during critical periods of development (stemming from psychological, immunological, and/or endocrinological stressors during gestation may permanently influence behavior, brain morphology, and/or neuroendocrine-sensitive processes. 5α-reduced progestogens are integral in the developmental programming of sex-typical, stress-sensitive, and/or disorder-relevant phenotypes. Prenatal stress may alter these responses and dysregulate allopregnanolone and its normative effects on stress axis function. As an example of a neurodevelopmental, neuropsychiatric and/or neurodegenerative process, this review focuses on responsiveness to drugs of abuse, which is sensitive to prenatal stress and progestogen milieu. This review explores the notion that allopregnanolone may effect, or be influenced by, prenatal stress, with consequences for neurodevelopmental-, neuropsychiatric- and/or neurodegenerative- relevant processes, such as addiction.

  7. Dielectrophoretic analysis of changes in cytoplasmic ion levels due to ion channel blocker action reveals underlying differences between drug-sensitive and multidrug-resistant leukaemic cells

    International Nuclear Information System (INIS)

    Dielectrophoresis (DEP)-the motion of particles in non-uniform AC fields-has been used in the investigation of cell electrophysiology. The technique offers the advantages of rapid determination of the conductance and capacitance of membrane and cytoplasm. However, it is unable to directly determine the ionic strengths of individual cytoplasmic ions, which has potentially limited its application in assessing cell composition. In this paper, we demonstrate how dielectrophoresis can be used to investigate the cytoplasmic ion composition by using ion channel blocking agents. By blocking key ion transporters individually, it is possible to determine their overall contribution to the free ions in the cytoplasm. We use this technique to evaluate the relative contributions of chloride, potassium and calcium ions to the cytoplasmic conductivities of drug sensitive and resistant myelogenous leukaemic (K562) cells in order to determine the contributions of individual ion channel activity in mediating multi-drug resistance in cancer. Results indicate that whilst K+ and Ca2+ levels were extremely similar between sensitive and resistant lines, levels of Cl- were elevated by three times to that in the resistant line, implying increased chloride channel activity. This result is in line with current theories of MDR, and validates the use of ion channel blockers with DEP to investigate ion channel function. (note)

  8. NOTE: Dielectrophoretic analysis of changes in cytoplasmic ion levels due to ion channel blocker action reveals underlying differences between drug-sensitive and multidrug-resistant leukaemic cells

    Science.gov (United States)

    Duncan, L.; Shelmerdine, H.; Hughes, M. P.; Coley, H. M.; Hübner, Y.; Labeed, F. H.

    2008-01-01

    Dielectrophoresis (DEP)—the motion of particles in non-uniform AC fields—has been used in the investigation of cell electrophysiology. The technique offers the advantages of rapid determination of the conductance and capacitance of membrane and cytoplasm. However, it is unable to directly determine the ionic strengths of individual cytoplasmic ions, which has potentially limited its application in assessing cell composition. In this paper, we demonstrate how dielectrophoresis can be used to investigate the cytoplasmic ion composition by using ion channel blocking agents. By blocking key ion transporters individually, it is possible to determine their overall contribution to the free ions in the cytoplasm. We use this technique to evaluate the relative contributions of chloride, potassium and calcium ions to the cytoplasmic conductivities of drug sensitive and resistant myelogenous leukaemic (K562) cells in order to determine the contributions of individual ion channel activity in mediating multi-drug resistance in cancer. Results indicate that whilst K+ and Ca2+ levels were extremely similar between sensitive and resistant lines, levels of Cl- were elevated by three times to that in the resistant line, implying increased chloride channel activity. This result is in line with current theories of MDR, and validates the use of ion channel blockers with DEP to investigate ion channel function.

  9. Dielectrophoretic analysis of changes in cytoplasmic ion levels due to ion channel blocker action reveals underlying differences between drug-sensitive and multidrug-resistant leukaemic cells

    Energy Technology Data Exchange (ETDEWEB)

    Duncan, L [Centre for Biomedical Engineering, School of Engineering (H5), University of Surrey, Guildford GU27XH (United Kingdom); Shelmerdine, H [Centre for Biomedical Engineering, School of Engineering (H5), University of Surrey, Guildford GU27XH (United Kingdom); Hughes, M P [Centre for Biomedical Engineering, School of Engineering (H5), University of Surrey, Guildford GU27XH (United Kingdom); Coley, H M [Postgraduate Medical School, University of Surrey, Guildford GU27XH (United Kingdom); Huebner, Y [Centre for Biomedical Engineering, School of Engineering (H5), University of Surrey, Guildford GU27XH (United Kingdom); Labeed, F H [Centre for Biomedical Engineering, School of Engineering (H5), University of Surrey, Guildford GU27XH (United Kingdom)

    2008-01-21

    Dielectrophoresis (DEP)-the motion of particles in non-uniform AC fields-has been used in the investigation of cell electrophysiology. The technique offers the advantages of rapid determination of the conductance and capacitance of membrane and cytoplasm. However, it is unable to directly determine the ionic strengths of individual cytoplasmic ions, which has potentially limited its application in assessing cell composition. In this paper, we demonstrate how dielectrophoresis can be used to investigate the cytoplasmic ion composition by using ion channel blocking agents. By blocking key ion transporters individually, it is possible to determine their overall contribution to the free ions in the cytoplasm. We use this technique to evaluate the relative contributions of chloride, potassium and calcium ions to the cytoplasmic conductivities of drug sensitive and resistant myelogenous leukaemic (K562) cells in order to determine the contributions of individual ion channel activity in mediating multi-drug resistance in cancer. Results indicate that whilst K{sup +} and Ca{sup 2+} levels were extremely similar between sensitive and resistant lines, levels of Cl{sup -} were elevated by three times to that in the resistant line, implying increased chloride channel activity. This result is in line with current theories of MDR, and validates the use of ion channel blockers with DEP to investigate ion channel function. (note)

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

    Directory of Open Access Journals (Sweden)

    Denis Zofou

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

  11. Influenza A virus infection in zebrafish recapitulates mammalian infection and sensitivity to anti-influenza drug treatment

    Directory of Open Access Journals (Sweden)

    Kristin A. Gabor

    2014-11-01

    Full Text Available Seasonal influenza virus infections cause annual epidemics and sporadic pandemics. These present a global health concern, resulting in substantial morbidity, mortality and economic burdens. Prevention and treatment of influenza illness is difficult due to the high mutation rate of the virus, the emergence of new virus strains and increasing antiviral resistance. Animal models of influenza infection are crucial to our gaining a better understanding of the pathogenesis of and host response to influenza infection, and for screening antiviral compounds. However, the current animal models used for influenza research are not amenable to visualization of host-pathogen interactions or high-throughput drug screening. The zebrafish is widely recognized as a valuable model system for infectious disease research and therapeutic drug testing. Here, we describe a zebrafish model for human influenza A virus (IAV infection and show that zebrafish embryos are susceptible to challenge with both influenza A strains APR8 and X-31 (Aichi. Influenza-infected zebrafish show an increase in viral burden and mortality over time. The expression of innate antiviral genes, the gross pathology and the histopathology in infected zebrafish recapitulate clinical symptoms of influenza infections in humans. This is the first time that zebrafish embryos have been infected with a fluorescent IAV in order to visualize infection in a live vertebrate host, revealing a pattern of vascular endothelial infection. Treatment of infected zebrafish with a known anti-influenza compound, Zanamivir, reduced mortality and the expression of a fluorescent viral gene product, demonstrating the validity of this model to screen for potential antiviral drugs. The zebrafish model system has provided invaluable insights into host-pathogen interactions for a range of infectious diseases. Here, we demonstrate a novel use of this species for IAV research. This model has great potential to advance our

  12. Influenza A virus infection in zebrafish recapitulates mammalian infection and sensitivity to anti-influenza drug treatment.

    Science.gov (United States)

    Gabor, Kristin A; Goody, Michelle F; Mowel, Walter K; Breitbach, Meghan E; Gratacap, Remi L; Witten, P Eckhard; Kim, Carol H

    2014-11-01

    Seasonal influenza virus infections cause annual epidemics and sporadic pandemics. These present a global health concern, resulting in substantial morbidity, mortality and economic burdens. Prevention and treatment of influenza illness is difficult due to the high mutation rate of the virus, the emergence of new virus strains and increasing antiviral resistance. Animal models of influenza infection are crucial to our gaining a better understanding of the pathogenesis of and host response to influenza infection, and for screening antiviral compounds. However, the current animal models used for influenza research are not amenable to visualization of host-pathogen interactions or high-throughput drug screening. The zebrafish is widely recognized as a valuable model system for infectious disease research and therapeutic drug testing. Here, we describe a zebrafish model for human influenza A virus (IAV) infection and show that zebrafish embryos are susceptible to challenge with both influenza A strains APR8 and X-31 (Aichi). Influenza-infected zebrafish show an increase in viral burden and mortality over time. The expression of innate antiviral genes, the gross pathology and the histopathology in infected zebrafish recapitulate clinical symptoms of influenza infections in humans. This is the first time that zebrafish embryos have been infected with a fluorescent IAV in order to visualize infection in a live vertebrate host, revealing a pattern of vascular endothelial infection. Treatment of infected zebrafish with a known anti-influenza compound, Zanamivir, reduced mortality and the expression of a fluorescent viral gene product, demonstrating the validity of this model to screen for potential antiviral drugs. The zebrafish model system has provided invaluable insights into host-pathogen interactions for a range of infectious diseases. Here, we demonstrate a novel use of this species for IAV research. This model has great potential to advance our understanding of

  13. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    OpenAIRE

    Kim, Jong Oh

    2015-01-01

    Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparti...

  14. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

    OpenAIRE

    Tran TH; Ramasamy T; Choi JY; Nguyen HT; Pham TT; Jeong JH; SK Ku; Choi HG; Yong CS; Kim JO

    2015-01-01

    Tuan Hiep Tran,1 Thiruganesh Ramasamy,1 Ju Yeon Choi,1 Hanh Thuy Nguyen,1 Thanh Tung Pham,1 Jee-Heon Jeong,1 Sae Kwang Ku,2 Han-Gon Choi,3 Chul Soon Yong,1 Jong Oh Kim11College of Pharmacy, Yeungnam University, Dae-Dong, 2College of Korean Medicine, Daegu Haany University, Gyeongsan, 3College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South KoreaAbstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles...

  15. ZEB1 knockdown mediated using polypeptide cationic micelles inhibits metastasis and effects sensitization to a chemotherapeutic drug for cancer therapy

    Science.gov (United States)

    Fang, Shengtao; Wu, Lei; Li, Mingxing; Yi, Huqiang; Gao, Guanhui; Sheng, Zonghai; Gong, Ping; Ma, Yifan; Cai, Lintao

    2014-08-01

    Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced metastasis in the lung. When DOX and siRNA were co-delivered by the nanocarriers (siRNA-DOX-NP), a synergistic therapeutic effect was observed, resulting in dramatic inhibition of tumor growth in a H460 xenograft model. These results demonstrated that the siRNA-NP or siRNA-DOX-NP complex targeting ZEB1 could be developed into a new therapeutic approach for non-small cell lung cancer (NSCLC) treatment.Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced

  16. Novel pH-sensitive nano-containers based on EUDRAGIT/Brij98 mixture for oral drug delivery

    Czech Academy of Sciences Publication Activity Database

    Kaberov, Leonid; Hrubý, Martin; Bogomolova, Anna; Pánek, Jiří; Štěpánek, Petr; Filippov, Sergey K.

    Dresden: Leibniz-Institut für Polymerforschung Dresden e.V. (IPF), 2015. 254 /SOFT-P-032/. ISBN 978-3-936028-89-8. [European Polymer Federation Congress 2015. 21.06.2015-26.06.2015, Dresden] R&D Projects: GA MŠk(CZ) LH14292; GA ČR(CZ) GC15-10527J Grant ostatní: AV ČR(CZ) M200501201 Institutional support: RVO:61389013 Keywords : eudragit * drug delivery Subject RIV: CD - Macromolecular Chemistry

  17. Cytotoxicity of Elaoephorbia drupifera and other Cameroonian medicinal plants against drug sensitive and multidrug resistant cancer cells

    OpenAIRE

    Kuete, Victor; Voukeng, Igor K; Tsobou, Roger; Mbaveng, Armelle T; Wiench, Benjamin; Beng, Veronique P; Efferth, Thomas

    2013-01-01

    Background Multidrug resistance (MDR) is a major hurdle for cancer treatment worldwide and accounts for chemotherapy failure in over 90% of patients with metastatic cancer. Evidence of the cytotoxicity of Cameroonian plants against cancer cell lines including MDR phenotypes is been intensively and progressively provided. The present work was therefore designed to evaluate the cytotoxicity of the methanol extracts of twenty-two Cameroonian medicinal plants against sensitive and MDR cancer cell...

  18. Enhanced sensitivity of A549 cells to the cytotoxic action of anticancer drugs via suppression of Nrf2 by procyanidins from Cinnamomi Cortex extract

    International Nuclear Information System (INIS)

    Highlights: → We found a novel inhibitor of Nrf2 known as a chemoresistance factor. → Overexpressed Nrf2 in lung cancer cells was suppressed by Cinnamomi Cortex extract. → Cytotoxic action of anticancer drugs in cells treated with the extract was enhanced. → Procyanidin tetramers and pentamers were active components in suppressing Nrf2. -- Abstract: Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor because Nrf2-regulated enzymes play a key role in antioxidant and detoxification processes. Recent studies have reported that lung cancer cells overexpressing Nrf2 exhibit increased resistance to chemotherapy. Suppression of overexpressed Nrf2 is needed for a new therapeutic approach against lung cancers. In the present study, we found that Cinnamomi Cortex extract (CCE) has an ability to suppress Nrf2-regulated enzyme activity and Nrf2 expression in human lung cancer A549 cells with high Nrf2 activity. Moreover, we demonstrated that CCE significantly enhances sensitivity of A549 cells to the cytotoxic action of doxorubicin and etoposide as well as increasing the intracellular accumulation of both drugs. These results suggest that CCE might be an effective concomitant agent to reduce anticancer drug resistance derived from Nrf2 overexpression. Bioactivity-guided fractionation revealed that procyanidin tetramers and pentamers contained in CCE were active components in suppressing Nrf2.

  19. Enhanced sensitivity of A549 cells to the cytotoxic action of anticancer drugs via suppression of Nrf2 by procyanidins from Cinnamomi Cortex extract

    Energy Technology Data Exchange (ETDEWEB)

    Ohnuma, Tomokazu; Matsumoto, Takashi; Itoi, Ayano; Kawana, Ayako; Nishiyama, Takahito; Ogura, Kenichiro [Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392 (Japan); Hiratsuka, Akira, E-mail: hiratuka@toyaku.ac.jp [Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392 (Japan)

    2011-10-07

    Highlights: {yields} We found a novel inhibitor of Nrf2 known as a chemoresistance factor. {yields} Overexpressed Nrf2 in lung cancer cells was suppressed by Cinnamomi Cortex extract. {yields} Cytotoxic action of anticancer drugs in cells treated with the extract was enhanced. {yields} Procyanidin tetramers and pentamers were active components in suppressing Nrf2. -- Abstract: Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor because Nrf2-regulated enzymes play a key role in antioxidant and detoxification processes. Recent studies have reported that lung cancer cells overexpressing Nrf2 exhibit increased resistance to chemotherapy. Suppression of overexpressed Nrf2 is needed for a new therapeutic approach against lung cancers. In the present study, we found that Cinnamomi Cortex extract (CCE) has an ability to suppress Nrf2-regulated enzyme activity and Nrf2 expression in human lung cancer A549 cells with high Nrf2 activity. Moreover, we demonstrated that CCE significantly enhances sensitivity of A549 cells to the cytotoxic action of doxorubicin and etoposide as well as increasing the intracellular accumulation of both drugs. These results suggest that CCE might be an effective concomitant agent to reduce anticancer drug resistance derived from Nrf2 overexpression. Bioactivity-guided fractionation revealed that procyanidin tetramers and pentamers contained in CCE were active components in suppressing Nrf2.

  20. Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

    Directory of Open Access Journals (Sweden)

    Zhang CY

    2014-10-01

    Full Text Available Can Yang Zhang, Di Xiong, Yao Sun, Bin Zhao, Wen Jing Lin, Li Juan Zhang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong Province, People’s Republic of China Abstract: A novel amphiphilic triblock pH-sensitive poly(ß-amino ester-g-poly(ethylene glycol methyl ether-cholesterol (PAE-g-MPEG-Chol was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation–deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy. Keywords: micelle, pH-sensitive, cholesterol, poly(ß-amino ester, drug delivery

  1. Preparation, characterization, and in vitro drug release behavior of glutathione-sensitive long-circulation micelles based on polyethylene glycol prodrug.

    Science.gov (United States)

    Shi, Liyan; Ding, Kaikai; Sun, Xin; Zhang, Ling; Zeng, Tian; Yin, Yihua; Zheng, Hua

    2016-04-01

    In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition-elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile - glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV-vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs. PMID:26764973

  2. In vitro Plasmodium falciparum drug sensitivity assay: inhibition of parasite growth by incorporation of stomatocytogenic amphiphiles into the erythrocyte membrane.

    Science.gov (United States)

    Ziegler, Hanne L; Staerk, Dan; Christensen, Jette; Hviid, Lars; Hägerstrand, Henry; Jaroszewski, Jerzy W

    2002-05-01

    Lupeol, which shows in vitro inhibitory activity against Plasmodium falciparum 3D7 strain with a 50% inhibitory concentration (IC50) of 27.7 +/- 0.5 microM, was shown to cause a transformation of the human erythrocyte shape toward that of stomatocytes. Good correlation between the IC50 value and the membrane curvature changes caused by lupeol was observed. Preincubation of erythrocytes with lupeol, followed by extensive washing, made the cells unsuitable for parasite growth, suggesting that the compound incorporates into erythrocyte membrane irreversibly. On the other hand, lupeol-treated parasite culture continued to grow well in untreated erythrocytes. Thus, the antiplasmodial activity of lupeol appears to be indirect, being due to stomatocytic transformation of the host cell membrane and not to toxic effects via action on a drug target within the parasite. A number of amphiphiles that cause stomatocyte formation, but not those causing echinocyte formation, were shown to inhibit growth of the parasites, apparently via a mechanism similar to that of lupeol. Since antiplasmodial agents that inhibit parasite growth through erythrocyte membrane modifications must be regarded as unsuitable as leads for development of new antimalarial drugs, care must be exercised in the interpretation of results of screening of plant extracts and natural product libraries by an in vitro Plasmodium toxicity assay. PMID:11959580

  3. Yolk-shell hybrid nanoparticles with magnetic and pH-sensitive properties for controlled anticancer drug delivery

    Science.gov (United States)

    Li, Shunxing; Zheng, Jianzhong; Chen, Dejian; Wu, Yijin; Zhang, Wuxiang; Zheng, Fengying; Cao, Jing; Ma, Heran; Liu, Yaling

    2013-11-01

    A facile and effective way for the preparation of nano-sized Fe3O4@graphene yolk-shell nanoparticles via a hydrothermal method is developed. Moreover, the targeting properties of the materials for anticancer drug (doxorubicin hydrochloride) delivery are investigated. Excitingly, these hybrid materials possess favorable dispersibility, good superparamagnetism (the magnetic saturation value is 45.740 emu g-1), high saturated loading capacity (2.65 mg mg-1), and effective loading (88.3%). More importantly, the composites exhibit strong pH-triggered drug release response (at the pH value of 5.6 and 7.4, the release rate was 24.86% and 10.28%, respectively) and good biocompatibility over a broad concentration range of 0.25-100 μg mL-1 (the cell viability was 98.52% even at a high concentration of 100 μg mL-1) which sheds light on their potentially bright future for bio-related applications.

  4. Radiation sensitizers

    International Nuclear Information System (INIS)

    The following classes of radiosensitizers are discussed: electron affinic compounds, pyrimidine analogs, and antibiotics. Metronidazole and nitroimidazole are discussed as examples of electron-affinic compounds. Studies on the enhancement ratio for sensitization of x-irradiated hamster cells showed that these drugs sensitize at concentrations much lower than the toxic concentrations. Criteria for a clinically useful hypoxic cell sensitizer are listed and mechanisms of electron-affinic sensitizers are discussed. The radiosensitizing effects of the pyrimidine analogs, BUDR, BCDR, IUDR, CUDR, and FUDR, are examined and the enhancement of radiation effects by the chemotherapeutic agent, 5-fluorouracil, is discussed. Other agents discussed are methotrexate, actinomycin D, bleomycin, and adriamycin

  5. Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery.

    Science.gov (United States)

    Zhang, Can Yang; Xiong, Di; Sun, Yao; Zhao, Bin; Lin, Wen Jing; Zhang, Li Juan

    2014-01-01

    A novel amphiphilic triblock pH-sensitive poly(β-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation-deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy. PMID:25364250

  6. Quantitative evaluation of cellular uptake, DNA incorporation and adduct formation in cisplatin sensitive and resistant cell lines: Comparison of different Pt-containing drugs.

    Science.gov (United States)

    Corte-Rodríguez, M; Espina, M; Sierra, L M; Blanco, E; Ames, T; Montes-Bayón, M; Sanz-Medel, A

    2015-11-01

    The use of Pt-containing compounds as chemotherapeutic agents facilitates drug monitoring by using highly sensitive elemental techniques like inductively coupled plasma mass spectrometry (ICP-MS). However, methodological problems arise when trying to compare different experiments due to the high variability of biological parameters. In this work we have attempted to identify and correct such variations in order to compare the biological behavior of cisplatin, oxaliplatin and pyrodach-2 (a novel platinum-containing agent). A detailed study to address differential cellular uptake has been conducted in three different cell lines: lung adenocarcinoma (A549); cisplatin-sensitive ovarian carcinoma (A2780); and cisplatin-resistant ovarian carcinoma (A2780cis). The normalization of Pt results to cell mass, after freeze-drying, has been used to minimize the errors associated with cell counting. Similarly, Pt accumulation in DNA has been evaluated by referencing the Pt results to the DNA concentration, as measured by (31)P monitoring using flow-injection and ICP-MS detection. These strategies have permitted to address significantly lower Pt levels in the resistant cells when treated with cisplatin or oxaliplatin as well as an independent behaviour from the cell type (sensitive or resistant) for pyrodach-2. Similarly, different levels of incorporation in DNA have been found for the three drugs depending on the cell model revealing a different behavior regarding cell cisplatin resistance. Further speciation experiments (by using complementary HPLC-ICP-MS and HPLC-ESI-Q-TOF MS) have shown that the main target in DNA is still the N7 of the guanine but with different kinetics of the ligand exchange mechanism for each of the compounds under evaluation. PMID:26352094

  7. Monitoring the drug-sensitivity of Plasmodium falciparum in coastal towns in Madagascar by use of in vitro chemosensitivity and mutation detection tests

    Directory of Open Access Journals (Sweden)

    Rason M.A.

    2002-09-01

    Full Text Available The dissemination of mutant and resistant strains of Plasmodium falciparum makes a considerable contribution to the spread of drug-resistant malaria. Populations around harbours and airports could be particularly exposed to Plasmodium isolates introduced with imported cases of malaria. The use of chloroquine as well as the use of and sulfadoxine/pyrimethamine is currently an effective method for treating uncomplicated cases of malaria in Madagascar. As part of a monitoring programme, in vitro methods were used to assess the sensitivity of P. falciparum isolates in two coastal towns in Madagascar: Mahajanga on the west coast and Toamasina on the east coast. All of the isolates from both sites were sensitive to amodiaquine, quinine, pyrimethamine and cycloguanil. All of the isolates from Mahajanga were sensitive to chloroquine (n = 25; mean IC50 = 22.6 nM, 95 % confidence interval: 16.8-28.7 nM, whereas three of the isolates from Toamasina were resistant to chloroquine (n = 18; mean IC50 = 66.3 nM; 95 % confidence interval : 42.6-90 nM, The frequency of the Pfcrt Thr-76 and the dhfr Asn- 108 mutations was estimated by PCR/RFLP. The 43 P. falciparum isolates examined, including the three in vitro chloroquine-resistant isolates from Toamasina were all wild-type (Lys-76. Phenotyping and genotyping studies suggested that the prevalence of chloroquine- and pyrimethamine-resistant isolates and of mutant strains of P. falciparum is very low. These results showed that in vitro test and genotyping of resistance markers approaches could be successfully used to monitor the emergence of drug-resistant malaria and to try to alleviate the lack of medical teams able to carry out in vivo test. The possible hazard/risk associated with imported cases of malaria is discussed.

  8. TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line

    DEFF Research Database (Denmark)

    Deng, Xiaohong; Fogh, Louise; Lademann, Ulrik Axel;

    2013-01-01

    affect sensitivity to the HER2-targeting drugs trastuzumab and lapatinib. SK-BR-3 human breast cancer cells were stably transfected with TIMP-1, characterized with regard to TIMP-1 protein expression, proliferation, and functionality of the secreted TIMP-1, and the sensitivity to trastuzumab and...... lapatinib was studied in five selected single-cell subclones expressing TIMP-1 protein at various levels plus the parental SK-BR-3 cell line. Both trastuzumab and lapatinib reduced cell viability, as determined by MTT assay, but the sensitivity to the drugs was not associated with the expression level of...

  9. Preparation of pH-sensitive zwitterionic nano micelles and drug controlled release for enhancing cellular uptake.

    Science.gov (United States)

    Wu, Luyan; Ni, Caihua; Zhang, Liping; Shi, Gang

    2016-05-01

    Zwitterionic copolymers have exhibited high resistance to nonspecific protein adsorption and have wide applications in drug delivery systems. Herein, a pH-responsive poly(Lysine-alt-N,N'-bis(acryloyl) diaminohexane) was synthesized through the Michael addition polymerization between N, N'-bis(acryloyl) diaminohexane and lysine. Subsequently, nano micelles (NMs) were formed by self-assembly of the copolymer in an aqueous solution. The NMs showed a slightly negative charge in blood environment, but a positively charged surface in extracellular pH of tumor. This feature could be used to enhance permeability and retention effect, and reinforce tumor cell uptake. Vitro release studies revealed that the release of DOX from the DOX-loaded NMs was evidently faster at pH 5.0 than at pH 7.4. MTT assays revealed that NMs were nontoxic. Thus, these smart NMs were feasible candidates and could be potentially used in cancer chemotherapy. PMID:26813767

  10. 肉鸡沙门氏菌的分离鉴定及药敏试验%Isolation, Identification and Drug Sensitive Assay of Salmonella From Broiler

    Institute of Scientific and Technical Information of China (English)

    王傲雪; 张凌云; 张桉潮; 李昆鹏; 张秀丽; 梁晚枫; 张林波

    2013-01-01

    为了解吉林省某地鸡源性沙门氏菌的感染及耐药情况,对该地7个肉鸡场150份病鸡组织样品进行细菌分离,并进行了血凝试验、致病性试验和药敏试验.分离得到26株沙门氏菌,经血凝鉴定有19株呈阳性,其中5株呈强阳性并均能使雏鸡致死.药敏试验结果显示,该5株沙门氏菌对头孢噻肟较为敏感;对氨苄西林、替米考星、林可霉素、阿奇霉素和头孢拉定表现出极高的耐药性,耐药率高达100%;诺氟沙星、恩诺沙星、环丙沙星、强力霉素和氯霉素5种临床用药与痢菌净不具有协同或累加作用.试验结果表明,沙门氏菌是危害该地肉鸡养殖场的主要病原菌之一,且耐药性十分严重.%To find out the situations about infection of Salmonella and its drug resistance somewhere in Jilin province,the bacteria were isolated from 150 tissue samples of sick broiler of 7 farms in this city,and hemagglutinin test,pathogenity test and drug sensitive test were carried out.26 strains were isolated,and 19 strains were identified positive by the HA,of which five were strongly positive and killed broiler,drug sensitive test results showed that the 5 strains of Salmonella were more sensitive to cefotaxime,and very high resistance to ampicillin,tilmicosin,lincomycin,azithromycin and cephradine,resistance rates as high as 100 %.Norfloxacin,enrofloxacin,ciprofloxacin,doxycycline and chloramphenicol didn't have synergistic or additive effect with mequindox which was used in clinical.These results suggested that Salmonella was one of the main pathogens harmful to the broiler of farms,and resistance was very serious.

  11. Sensitive spectrophotometric determination of ascorbic acid in drugs and foods using surface plasmon resonance band of silver nanoparticles

    Directory of Open Access Journals (Sweden)

    Kobra Zarei

    2015-12-01

    Full Text Available A simple and sensitive procedure was proposed for spectrophotometric determination of ascorbic acid. It was found that the reduction of Ag+ to silver nanoparticles (Ag-NPs by ascorbic acid in the presence of polyvinylpyrrolidone (PVP as a stabilizing agent produce very intense surface plasmon resonance peak of Ag-NPs. The plasmon absorbance of the Ag-NPs at λ = 440 nm allows the quantitative spectrophotometric detection of the ascorbic acid. The calibration curve was linear with concentration of ascorbic acid in the range of 0.5–60 μM. The detection limit was obtained as 0.08 μM. The influence of potential interfering substances on the determination of ascorbic acid was studied. The proposed method was successfully applied for the determination of ascorbic acid in some powdered drink mixtures, commercial orange juice, natural orange juice, vitamin C injection, effervescent tablet, and multivitamin tablet.

  12. Behavioral Sensitization and Underlying Mechanism in Drug Addiction%成瘾药物行为敏化及机制

    Institute of Scientific and Technical Information of China (English)

    刘胜; 周文华; 杨国栋

    2004-01-01

    反复、间断给予依赖性药物(如吗啡、苯丙胺、可卡因、尼古丁、酒精等)后,能增强实验动物的自发性活动反应(locomotor response),这种伴随着反复给药而出现的行为反应增强被称为行为敏化(behavioral sensitization)。行为敏化的形成和表达与药物成瘾有着重要的关系,目前已经证明成瘾药物诱导的行为敏化对觅药行为和复吸的发生和维持有着重要的影响。

  13. The reliability of sensitive information provided by injecting drug users in a clinical setting: clinician-administered versus audio computer-assisted self-interviewing (ACASI).

    Science.gov (United States)

    Islam, M Mofizul; Topp, Libby; Conigrave, Katherine M; van Beek, Ingrid; Maher, Lisa; White, Ann; Rodgers, Craig; Day, Carolyn A

    2012-01-01

    Research with injecting drug users (IDUs) suggests greater willingness to report sensitive and stigmatised behaviour via audio computer-assisted self-interviewing (ACASI) methods than during face-to-face interviews (FFIs); however, previous studies were limited in verifying this within the same individuals at the same time point. This study examines the relative willingness of IDUs to report sensitive information via ACASI and during a face-to-face clinical assessment administered in health services for IDUs. During recruitment for a randomised controlled trial undertaken at two IDU-targeted health services, assessments were undertaken as per clinical protocols, followed by referral of eligible clients to the trial, in which baseline self-report data were collected via ACASI. Five questions about sensitive injecting and sexual risk behaviours were administered to participants during both clinical interviews and baseline research data collection. "Percentage agreement" determined the magnitude of concordance/discordance in responses across interview methods, while tests appropriate to data format assessed the statistical significance of this variation. Results for all five variables suggest that, relative to ACASI, FFI elicited responses that may be perceived as more socially desirable. Discordance was statistically significant for four of the five variables examined. Participants who reported a history of sex work were more likely to provide discordant responses to at least one socially sensitive item. In health services for IDUs, information collection via ACASI may elicit more reliable and valid responses than FFI. Adoption of a universal precautionary approach to complement individually tailored assessment of and advice regarding health risk behaviours for IDUs may address this issue. PMID:22452446

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

    Science.gov (United States)

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

    2015-09-01

    Caseinolytic chaperones and proteases (Clp) belong to the AAA+ protein superfamily and are part of the protein quality control machinery in cells. The eukaryotic parasite Plasmodium falciparum, the causative agent of malaria, has evolved an elaborate network of Clp proteins including two distinct ClpB ATPases. ClpB1 and ClpB2 are involved in different aspects of parasitic proteostasis. ClpB1 is present in the apicoplast, a parasite-specific and plastid-like organelle hosting various metabolic pathways necessary for parasite growth. ClpB2 localizes to the parasitophorous vacuole membrane where it drives protein export as core subunit of a parasite-derived protein secretion complex, the Plasmodium Translocon of Exported proteins (PTEX); this process is central to parasite virulence and survival in the human host. The functional associations of these two chaperones with parasite-specific metabolism and protein secretion make them prime drug targets. ClpB proteins function as unfoldases and disaggregases and share a common architecture consisting of four domains-a variable N-terminal domain that binds different protein substrates, followed by two highly conserved catalytic ATPase domains, and a C-terminal domain. Here, we report and compare the first crystal structures of the N terminal domains of ClpB1 and ClpB2 from Plasmodium and analyze their molecular surfaces. Solution scattering analysis of the N domain of ClpB2 shows that the average solution conformation is similar to the crystalline structure. These structures represent the first step towards the characterization of these two malarial chaperones and the reconstitution of the entire PTEX to aid structure-based design of novel anti-malarial drugs. PMID:26130467

  15. A novel application of maleimide for advanced drug delivery: in vitro and in vivo evaluation of maleimide-modified pH-sensitive liposomes

    Directory of Open Access Journals (Sweden)

    Li T

    2013-10-01

    Full Text Available Tianshu Li, Shinji TakeokaDepartment of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns, Shinjuku-ku, Tokyo, JapanAbstract: Maleimide is a stable and easy-to-handle moiety that rapidly and covalently conjugates thiol groups of cysteine residues in proteins or peptides. Herein, we use maleimide to modify the surface of liposomes in order to obtain an advanced drug delivery system. Employing a small amount (0.3 mol% of maleimide-polyethylene glycol (PEG to modify the surface of the liposomes M-GGLG-liposomes, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (GGLG/cholesterol/poly(ethylene glycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG5000-DSPE/maleimide-PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03, drug delivery efficiency was remarkably improved both in vitro and in vivo compared to unmodified liposomes (GGLG-liposomes, composed of GGLG/cholesterol/PEG5000-DSPE/PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03. Moreover, this modification did not elicit any detectable increase in cytotoxicity. The maleimide-modification did not alter the physical characteristics of the liposomes such as size, zeta potential, pH sensitivity, dispersibility and drug encapsulation efficiency. However, M-GGLG-liposomes were more rapidly (≥2-fold internalized into HeLa, HCC1954, and MDA-MB-468 cells compared to GGLG-liposomes. In vivo, M-GGLG-liposomes encapsulating doxorubicin (M-GGLG-DOX-liposomes also showed a more potent antitumor effect than GGLG-DOX-liposomes and the widely used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC-DOX-liposomes after two subcutaneous injections around breast cancer tissue in mice. The biodistribution of liposomes in this model was observed using an in vivo imaging system, which showed that M-GGLG-liposomes were present for significantly longer at the injection site compared to GGLG-liposomes. The outstanding biological functions of

  16. pH-sensitive interpenetrating polymer network microspheres of poly(vinyl alcohol) and carboxymethyl cellulose for controlled release of the nonsteroidal anti-inflammatory drug ketorolac tromethamine.

    Science.gov (United States)

    Kondolot Solak, Ebru; Er, Akın

    2016-05-01

    In this study, we aimed to produce pH-sensitive microspheres for the controlled release of the nonsteroidal anti-inflammatory drug, ketorolac tromethamine (KT). For this purpose, an interpenetrating polymer network (IPN) of microspheres of poly(vinyl alcohol) (PVA)/sodium carboxymethyl cellulose (NaCMC) were prepared, based on different formulations using glutaraldehyde (GA) (0.66 M) and hydrochloric acid (HCl) (3%, v/v). The preparation conditions of the microspheres were optimized by considering the percentage of entrapment efficiency and swelling capacity of the microspheres, and their release data. The effects of PVA and NaCMC ratio on the release of KT for over a period of 6 h, at three pH values (1.2, 6.8, and 7.4), have been discussed. PMID:25619756

  17. In vitro study of drug sensitivity of Plasmodium falciparum: assessment of semi-microtest by /sup 3/H-hypoxanthine incorporation

    Energy Technology Data Exchange (ETDEWEB)

    Le Bras, J.; Andrieu, B.; Hatin, I.; Savel, J.; Coulaud, J.P. (Hopital Claude-Bernard, 75 - Paris (France))

    1984-05-01

    Recent advances in cultivation methods and knowledge of in vitro response of Plasmodium falciparum to antimalarials have led to improved chemosensitivity tests. The semi-microtest is a useful tool for screening presumptive antimalarials, and also for the testing sensitivity of strains recovered from patients in hospital and field studies to currently used drugs. Microscopic parasite counts on thin blood films can be replaced by measurement of /sup 3/H-hypoxanthine by the uptake parasite. Conditions which ensure optimal parasite growth and high radioisotope incorporation are described. Wells containing less than 3.10/sup 4/ asexualparasites can be studied with this method. Results of the semi-microtest are closely correlated with those of microscopic parasite count. Advantages of both methods are discussed.

  18. Optimization of a low cost and broadly sensitive genotyping assay for HIV-1 drug resistance surveillance and monitoring in resource-limited settings.

    Directory of Open Access Journals (Sweden)

    Zhiyong Zhou

    Full Text Available Commercially available HIV-1 drug resistance (HIVDR genotyping assays are expensive and have limitations in detecting non-B subtypes and circulating recombinant forms that are co-circulating in resource-limited settings (RLS. This study aimed to optimize a low cost and broadly sensitive in-house assay in detecting HIVDR mutations in the protease (PR and reverse transcriptase (RT regions of pol gene. The overall plasma genotyping sensitivity was 95.8% (N = 96. Compared to the original in-house assay and two commercially available genotyping systems, TRUGENE® and ViroSeq®, the optimized in-house assay showed a nucleotide sequence concordance of 99.3%, 99.6% and 99.1%, respectively. The optimized in-house assay was more sensitive in detecting mixture bases than the original in-house (N = 87, P<0.001 and TRUGENE® and ViroSeq® assays. When the optimized in-house assay was applied to genotype samples collected for HIVDR surveys (N = 230, all 72 (100% plasma and 69 (95.8% of the matched dried blood spots (DBS in the Vietnam transmitted HIVDR survey were genotyped and nucleotide sequence concordance was 98.8%; Testing of treatment-experienced patient plasmas with viral load (VL ≥ and <3 log10 copies/ml from the Nigeria and Malawi surveys yielded 100% (N = 46 and 78.6% (N = 14 genotyping rates, respectively. Furthermore, all 18 matched DBS stored at room temperature from the Nigeria survey were genotyped. Phylogenetic analysis of the 236 sequences revealed that 43.6% were CRF01_AE, 25.9% subtype C, 13.1% CRF02_AG, 5.1% subtype G, 4.2% subtype B, 2.5% subtype A, 2.1% each subtype F and unclassifiable, 0.4% each CRF06_CPX, CRF07_BC and CRF09_CPX.The optimized in-house assay is broadly sensitive in genotyping HIV-1 group M viral strains and more sensitive than the original in-house, TRUGENE® and ViroSeq® in detecting mixed viral populations. The broad sensitivity and substantial reagent cost saving make this assay more accessible

  19. Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Eric W Fish

    Full Text Available Fragile X syndrome (FXS is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y mice with intracranial self-stimulation (ICSS and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynylpyridine (MPEP, was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.

  20. Effect of anticancer drugs on breast cancer cells sensitive and resistant to doxorubicin: expression of mRNAs of TGF-β and its receptors

    Directory of Open Access Journals (Sweden)

    Chorna I. V.

    2014-01-01

    Full Text Available Aim. Comparative study of the effect of chemotherapeutic drugs (doxorubicin, methotrexate and cisplatin and TGF-β on the human breast carcinoma MCF-7 cells, sensitive (wt and resistant (DOX/R to the doxorubicin action. Methods. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR was used for the estimation of expression of mRNAs coding for the TGF-β isoforms (TGF-β1 and TGF-β2 and the TGF-β type I and II receptors (TRI and TRII. Trypan blue exclusion method was used for measuring cell number and cell viability. Results. The MCF-7(DOX/R cells were more refractory to the TGF1-dependent growth inhibition than the MCF-7(wt cells. The level of mRNAs coding for TGF and its receptors was higher in the untreated MCF-7 (DOX/R cells comparing to the MCF-7(wt cells. The expression of mRNA coding for TRII was decreased in both cell lines treated with doxorubicin, methotrexate and cisplatin, while the down-regulation of mRNA coding for TRI was revealed only in the MCF-7(DOX/R cells upon the treatment with doxorubicin and methotrexate. Conclusions. The differential effects of studied anticancer drugs and TGF-β on the doxorubicin-sensitive and -resistant cells have been demonstrated. The elucidation of the molecular mechanisms of escape of the MCF-7 (DOX/R cells from the growth inhibition by TGF-β requires further investigation.

  1. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer.

    Science.gov (United States)

    Park, Hansoo; Cho, Sung-Yup; Kim, Hyerim; Na, Deukchae; Han, Jee Yun; Chae, Jeesoo; Park, Changho; Park, Ok-Kyoung; Min, Seoyeon; Kang, Jinjoo; Choi, Boram; Min, Jimin; Kwon, Jee Young; Suh, Yun-Suhk; Kong, Seong-Ho; Lee, Hyuk-Joon; Liu, Edison T; Kim, Jong-Il; Kim, Sunghoon; Yang, Han-Kwang; Lee, Charles

    2015-10-01

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases. PMID:26401016

  2. The molecular epidemiological study of colistin-only-sensitive strains in multi-drug resistant Acinetobacter baumannii

    Institute of Scientific and Technical Information of China (English)

    YANG Li; HAN Lizhong; SUN Jingyong; YU Yunsong; NI Yuxing

    2007-01-01

    This paper reported the epidemiology of the colistin-only-sensitive Acinetobacter baumannii(COS-AB)in a tertiary teaching hospital in China.We analyzed the clinical data of 136 COS-AB isolates from June 2004 to May 2005 and collected 66 A.baumannii isolates in which 33 strains were COS-AB,and the rest were non-COS-AB.Random amplified polymorphic DNA(RAPD)analysis (primer ERIC2 and 272)showed that all COS-AB were identical,while pulsed-field gel electrophotesis(PFGE)analysis showed two separate genotypes of these COS-ABwhich were distinctly different from that of non-COS-AB.The COS-AB from burn wards showed the identical PFGE pattern which was distinguished from the genotype of COS-AB in other departments,mainly surgical systems.The cross-infection was severe and strict methods of disinfection and sterilization should be implemented.Meanwhile,the epidemiology of COS-AB in environment and patients should be closely monitored.The PFGE analysis is a reliable method of A.baumannii typing.

  3. pH-sensitive micelles based on acid-labile pluronic F68-curcumin conjugates for improved tumor intracellular drug delivery.

    Science.gov (United States)

    Fang, Xiao-Bin; Zhang, Jin-Ming; Xie, Xi; Liu, Di; He, Cheng-Wei; Wan, Jian-Bo; Chen, Mei-Wan

    2016-04-11

    Curcumin (Cur) is a highly pleiotropic anticancer agent that inhibits cell proliferation and induces apoptosis in cancer cells. A variety of nano-systems constituted by polymer-drug conjugates have been designed to overcome its shortages on water solubility, chemical instability, and poor bioavailability. However, most of them suffer from ineffective release of Cur in cancer cells in vivo. This work developed a novel flexible acid-responsive micelle formulation by covalently conjugating Cur on the hydrophilic terminals of pluronic F68 chains via cis-aconitic anhydride linkers. The synthesized F68-Cis-Cur conjugates can readily precipitate to form homogeneous micelles with average size about 100nm in aqueous solution. In acid environments, F68-Cis-Cur conjugates would break down and subsequently release Cur rapidly, for the reason of pH-sensitive cleavage of cis-aconitic anhydride linkers. In vitro anticancer activity tests demonstrated that F68-Cis-Cur micelles induced higher cytotoxicity against both A2780 and SMMC 7721 cells than free Cur. It provided a larger decrease of mitochondrion membrane potential and induced cellular apoptosis. F68-Cis-Cur micelles remarkably increased cellular uptake of Cur than free Cur through caveolae-mediated endocytosis in an energy-dependent manner. This study demonstrates F68-Cis-Cur conjugation as a promising tool for improving intracellular drug delivery in cancer therapy. PMID:26784981

  4. Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

    Directory of Open Access Journals (Sweden)

    Zantl Niko

    2010-06-01

    Full Text Available Abstract Background Human renal cell carcinoma (RCC is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

  5. Optimizing the HRP-2 in vitro malaria drug susceptibility assay using a reference clone to improve comparisons of Plasmodium falciparum field isolates

    Directory of Open Access Journals (Sweden)

    Rutvisuttinunt Wiriya

    2012-09-01

    Full Text Available Abstract Background Apparent emerging artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia requires development of practical tools to monitor for resistant parasites. Although in vitro anti-malarial susceptibility tests are widely used, uncertainties remain regarding interpretation of P. falciparum field isolate values. Methods Performance parameters of the W2 P. falciparum clone (considered artemisinin “sensitive” were evaluated as a reference for the HRP-2 immediate ex vivo assay. Variability in W2 IC50s was assessed, including intra- and inter-assay variability among and between technicians in multiple experiments, over five freeze-thaw cycles, over five months of continuous culture, and before and after transport of drug-coated plates to remote field sites. Nominal drug plate concentrations of artesunate (AS and dihydroartemisinin (DHA were verified by LC-MS analysis. Plasmodium falciparum field isolate IC50s for DHA from subjects in an artemisinin-resistant area in Cambodia were compared with W2 susceptibility. Results Plate drug concentrations and day-to-day technical assay performance among technicians were important sources of variability for W2 IC50s within and between assays. Freeze-thaw cycles, long-term continuous culture, and transport to and from remote sites had less influence. Despite variability in W2 susceptibility, the median IC50s for DHA for Cambodian field isolates were higher (p Conclusion The W2 reference clone improved the interpretability of field isolate susceptibility from the immediate ex vivo HRP-2 assay from areas of artemisinin resistance. Methods to increase the reproducibility of plate coating may improve overall assay interpretability and utility.

  6. Drug mules” as a radiological challenge: Sensitivity and specificity in identifying internal cocaine in body packers, body pushers and body stuffers by computed tomography, plain radiography and Lodox

    International Nuclear Information System (INIS)

    Purpose: The purpose of our study was to retrospectively evaluate the specificity, sensitivity and accuracy of computed tomography (CT), digital radiography (DR) and low-dose linear slit digital radiography (LSDR, Lodox®) in the detection of internal cocaine containers. Methods: Institutional review board approval was obtained. The study collectively consisted of 83 patients (76 males, 7 females, 16–45 years) suspected of having incorporated cocaine drug containers. All underwent radiological imaging; a total of 135 exams were performed: nCT = 35, nDR = 70, nLSDR = 30. An overall calculation of all “drug mules” and a specific evaluation of body packers, pushers and stuffers were performed. The gold standard was stool examination in a dedicated holding cell equipped with a drug toilet. Results: There were 54 drug mules identified in this study. CT of all drug carriers showed the highest diagnostic accuracy 97.1%, sensitivity 100% and specificity 94.1%. DR in all cases was 71.4% accurate, 58.3% sensitive and 85.3% specific. LSDR of all patients with internal cocaine was 60% accurate, 57.9% sensitive and 63.4% specific. Conclusions: CT was the most accurate test studied. Therefore, the detection of internal cocaine drug packs should be performed by CT, rather than by conventional X-ray, in order to apply the most sensitive exam in the medico-legal investigation of suspected drug carriers. Nevertheless, the higher radiation applied by CT than by DR or LSDR needs to be considered. Future studies should include evaluation of low dose CT protocols in order to address germane issues and to reduce dosage

  7. Drug mules” as a radiological challenge: Sensitivity and specificity in identifying internal cocaine in body packers, body pushers and body stuffers by computed tomography, plain radiography and Lodox

    Energy Technology Data Exchange (ETDEWEB)

    Flach, Patricia M., E-mail: patricia.flach@irm.uzh.ch [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Department of Neuroradiology, Inselspital Bern, University of Bern, 3010 Bern (Switzerland); Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich (Switzerland); Department of Radiology, University Hospital USZ, University of Zurich, Raemistrasse 100, 8091 Zurich (Switzerland); Ross, Steffen G. [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Ampanozi, Garyfalia; Ebert, Lars [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich (Switzerland); Germerott, Tanja; Hatch, Gary M. [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Thali, Michael J. [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich (Switzerland); Patak, Michael A. [Department of Radiology, Inselspital Bern, University of Bern, 3010 Bern (Switzerland); Department of Radiology, University Hospital USZ, University of Zurich, Raemistrasse 100, 8091 Zurich (Switzerland)

    2012-10-15

    Purpose: The purpose of our study was to retrospectively evaluate the specificity, sensitivity and accuracy of computed tomography (CT), digital radiography (DR) and low-dose linear slit digital radiography (LSDR, Lodox{sup ®}) in the detection of internal cocaine containers. Methods: Institutional review board approval was obtained. The study collectively consisted of 83 patients (76 males, 7 females, 16–45 years) suspected of having incorporated cocaine drug containers. All underwent radiological imaging; a total of 135 exams were performed: nCT = 35, nDR = 70, nLSDR = 30. An overall calculation of all “drug mules” and a specific evaluation of body packers, pushers and stuffers were performed. The gold standard was stool examination in a dedicated holding cell equipped with a drug toilet. Results: There were 54 drug mules identified in this study. CT of all drug carriers showed the highest diagnostic accuracy 97.1%, sensitivity 100% and specificity 94.1%. DR in all cases was 71.4% accurate, 58.3% sensitive and 85.3% specific. LSDR of all patients with internal cocaine was 60% accurate, 57.9% sensitive and 63.4% specific. Conclusions: CT was the most accurate test studied. Therefore, the detection of internal cocaine drug packs should be performed by CT, rather than by conventional X-ray, in order to apply the most sensitive exam in the medico-legal investigation of suspected drug carriers. Nevertheless, the higher radiation applied by CT than by DR or LSDR needs to be considered. Future studies should include evaluation of low dose CT protocols in order to address germane issues and to reduce dosage.

  8. The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya

    Directory of Open Access Journals (Sweden)

    Otieno Dorothy N

    2007-05-01

    Full Text Available Abstract Backgound Sulphadoxine/sulphalene-pyrimethamine (SP was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT in Africa are less well documented. Methods A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy. Results Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data

  9. 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

  10. EXPERIMENTAL RESEARCH OF EFFECTIVENESS OF siRNA-Her-2/neu ON DRUG SENSITIVITY OF Her-2/neu-OVER-EXPRESSING LUNG ADENOCARCINOMA CELL LINE

    Institute of Scientific and Technical Information of China (English)

    REN Shu-hua; WANG Jing-wei; QU Ping; LIU Yi; ZHANG Wei; ZHANG Lin

    2006-01-01

    Objective: Her-2/neu protein overexpression has been demonstrated in lung adenocarcinoma. Its overexpression often indicates a poor prognosis and resistance to chemotherapeutic agents. The objectives of this paper is to explore the effectiveness of double-stranded short inhibitory RNAs (siRNA) targeting Her-2/neu oncogene on the drug sensitivity of Her-2/neu-overexpressing lung adenocarcinoma cells. Methods: Lung adenocarcinoma cell line calu-3 was transfected with siRNAs formulated LipofectAMINE 2000, and Her-2/neu protein and P-gp were determined by flow cytometry (FCM). The chemosensitivity of transfected cells to cisplatin (CDDP) was measured by MTT. Cell apoptosis detection kit (Annexin V method) was used to examine the drug induced apoptosis rate. Results: siRNA targeting Her-2/neu greatly reduced the cell surface expression of Her-2/neu protein and had no effect on P-gp. Consequently the inhibitory rate of CDDP in combination with siRNA targeting Her-2/neu was (67.1(2.3)%, while the inhibitory rates were (48.1(3.5)%, (46.3(5.9)% and (50.2(2.9)% in untreated control, empty vector and unrelated siRNA groups, respectively. The FCM results showed that the apoptosis rate of cells treated with CDDP combined with siRNAs-Her-2/neu was elevated when compared with unrelated siRNA group and empty vector group. Conclusion: Sequence specific siRNA targeting Her-2/neu was capable of enhancing the chemosensitivity of calu-3 cell to cisplatin.

  11. A Cluster Randomised Trial Introducing Rapid Diagnostic Tests into Registered Drug Shops in Uganda: Impact on Appropriate Treatment of Malaria.

    Directory of Open Access Journals (Sweden)

    Anthony K Mbonye

    Full Text Available Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT in patients seeking treatment for fever in drug shops.A cluster-randomized trial of introducing mRDTs in registered drug shops was implemented in 20 geographical clusters of drug shops in Mukono district, central Uganda. Ten clusters were randomly allocated to the intervention (diagnostic confirmation of malaria by mRDT followed by ACT and ten clusters to the control arm (presumptive treatment of fevers with ACT. Treatment decisions by providers were validated by microscopy on a reference blood slide collected at the time of consultation. The primary outcome was the proportion of febrile patients receiving appropriate treatment with ACT defined as: malaria patients with microscopically-confirmed presence of parasites in a peripheral blood smear receiving ACT or rectal artesunate, and patients with no malaria parasites not given ACT.A total of 15,517 eligible patients (8672 intervention and 6845 control received treatment for fever between January-December 2011. The proportion of febrile patients who received appropriate ACT treatment was 72·9% versus 33·7% in the control arm; a difference of 36·1% (95% CI: 21·3 - 50·9, p<0·001. The majority of patients with fever in the intervention arm accepted to purchase an mRDT (97·8%, of whom 58·5% tested mRDT-positive. Drug shop vendors adhered to the mRDT results, reducing over-treatment of malaria by 72·6% (95% CI: 46·7- 98·4, p<0·001 compared to drug shop vendors using presumptive diagnosis (control arm

  12. Isolation, Identification and Drug-Sensitivity Test of P.aeruginosa%雏鸡绿脓杆菌的分离鉴定及药敏试验

    Institute of Scientific and Technical Information of China (English)

    靳双星; 陈理盾; 段继永

    2011-01-01

    对河南省中牟县某养殖户送检的病鸡进行病理剖检及细菌分离鉴定,根据发病临床症状,病理变化及病原分离鉴定,确诊为绿脓杆菌感染.药敏试验结果显示,所分离的绿脓杆菌对庆大霉素、氧氟沙星高度敏感;对丁胺卡那、多黏菌素中度敏感;对阿莫西林、氨苄西林及强力霉素耐药.%Diseased chicken collected in the Zhongmu country chicken house were examined. The investigation showed that P. Aeruginosa was main reason that caused chicken to death. P. Aeruginosa was isolated from diseased chickens. The result of drug-sensitivity suggested that isolated P. Aeruginosa was highly susceptible to Gentamicin,Ofloxacin. The isolated P. Aeruginosa was susceptible to Amikacin,Colistin. The isolated P. Aeruginosa showed resistance to Amoxicillin, Ampicillin.Doxycyc-line.

  13. Drug-sensitive tuberculosis, multidrug-resistant tuberculosis, and nontuberculous mycobacterial pulmonary disease in nonAIDS adults: comparisons of thin-section CT findings

    International Nuclear Information System (INIS)

    The aim of this work was to compare thin-section CT (TSCT) findings of drug-sensitive (DS) tuberculosis (TB), multidrug-resistant (MDR) TB, and nontuberculous mycobacterial (NTM) pulmonary disease in nonAIDS adults. During 2003, 216 (113 DS TB, 35 MDR TB, and 68 NTM) patients with smear-positive sputum for acid-fast bacilli (AFB), and who were subsequently confirmed to have mycobacterial pulmonary disease, underwent thoracic TSCT. The frequency of lung lesion patterns on TSCT and patients' demographic data were compared. The commonest TSCT findings were tree-in-bud opacities and nodules. On a per-person basis, significant differences were found in the frequency of multiple cavities and bronchiectasis (P<0.001, chi-square test and multiple logistic regression analysis). Multiple cavities were more frequent in MDR TB than in the other two groups and extensive bronchiectasis in NTM disease (multiple logistic regression analysis). Patients with MDR TB were younger than those with DS TB or NTM disease (P<0.001, multiple logistic regression analysis). Previous tuberculosis treatment history was significantly more frequent in patients with MDR TB or NTM disease (P<0.001, chi-square test and multiple logistic regression analysis). In patients with positive sputum AFB, multiple cavities, young age, and previous tuberculosis treatment history imply MDR TB, whereas extensive bronchiectasis, old age, and previous tuberculosis treatment history NTM disease. (orig.)

  14. Pill characterization data streams for reducing exposure to inadequately identified anti-malarial medication in developing countries

    Directory of Open Access Journals (Sweden)

    Crandall Ian

    2010-07-01

    Full Text Available Abstract Background A large fraction of anti-malaria medicines (and indeed many other medicines classes used in developing countries are inadequately identified. Framing this problem as one of misidentification rather than the more common framing of criminal misrepresentation leads to new solutions sets not currently being considered. Method That reframing led to consideration and analysis of 4 new problems that informed design of a digital platform technology for delivering a distributed medicine characterization system: 1 problematic interests associated with a focus on preventing counterfeiting, 2 the complexity of the many ways that medicines can deviate from expected identities, 3 the challenge of choosing amongst a diversity of attribute characterization technologies, and 4 the need for a flexible and distributed data aggregation mechanism. Results Analysis of those new problems confirmed an initial insight that a previously described digital technology for tracking malaria tests results in infrastructure limited regions could be adapted for characterizing pill attributes. Feasibility is illustrated by describing how the platform design can be implemented using open-source software and commodity computational and communication technology readily available and supportable in developing countries. Discussion A system of this type would allow users to answer several questions. Is this medicine what it is supposed to be? Can it be used to treat locally encountered malaria? What has been the experience of others who have used pills having the same identity? Ubiquitous access to global digital telecommunication infrastructure allows the system to generate data streams from these distributed medicine characterization transactions that can be used to map global patterns of use of specifically identified medicines. This can provide feedback necessary to guide efforts to reduce the burden of malaria.

  15. Acyclic nucleoside bisphosphonates as inhibitors of hypoxanthine-guanine-(xanthine) phosphoribosyltransferases: Potential new anti-malarial compounds

    Czech Academy of Sciences Publication Activity Database

    Špaček, Petr; Hocková, Dana; Janeba, Zlatko; Vrbková, Silvie; Edstein, M.; de Jersey, J.; Keough, D. T.; Guddat, L. W.

    Amsterdam : Elsevier, 2012. P2.24-P2.24. [Tetrahedron Symposium: Challenges in Bioorganic & Organic Medicinal Chemistry /13./. 26.06.2012-29.06.2012, Amsterdam] Institutional research plan: CEZ:AV0Z40550506 Keywords : nucleoside phosphonates * biophosphonates Subject RIV: CC - Organic Chemistry

  16. Malaria Control Dynamics in Rural Tanzania: Evaluation of implementation of Artemisinin based Anti-malarial Combination Therapy

    OpenAIRE

    Khatib, Rashid Ali

    2010-01-01

    Malaria is the most important parasitic disease caused by protozoans of the genus plasmodia that are transmitted by female anophelene mosquitoes. Plasmodium falciparum is the most important species owing to its distribution, virulence and pathogenicity. World-wide some 500 million infections, 200-300 million episodes and about 1 million malaria-related deaths occur every year amounting to a burden of some 45 million DALYs (Disability Adjusted Life Years) [1]. At least 80% of this intolerable ...

  17. Malaria control dynamics in rural Tanzania : evaluation of implementation of artemisinin based anti-malarial combination therapy

    OpenAIRE

    Khatib, Rashid Ali

    2010-01-01

    Malaria is the most important parasitic disease caused by protozoans of the genus plasmodia that are transmitted by female anophelene mosquitoes. Plasmodium falciparum is the most important species owing to its distribution, virulence and pathogenicity. World-wide some 500 million infections, 200-300 million episodes and about 1 million malaria-related deaths occur every year amounting to a burden of some 45 million DALYs (Disability Adjusted Life Years) [1]. At least 80% of...

  18. Assessment of the effectiveness of the CD3+ tool to detect counterfeit and substandard anti-malarials

    OpenAIRE

    Batson, JaCinta S.; Bempong, Daniel K.; Lukulay, Patrick H.; Ranieri, Nicola; Satzger, R. Duane; Verbois, Leigh

    2016-01-01

    Background The US FDA recently developed CD3+, a counterfeit detection tool that is based on sample illumination at specific wavelengths of light and visual comparison of suspect sample and packaging materials to an authentic sample. To test performance of the CD3+ in field conditions, a study was conducted in Ghana which compared the CD3+ side-by-side with two existing medicine quality screening technologies—TruScan™ Portable Raman spectrometer and GPHF Minilab®. Methods A total of 84 anti-m...

  19. Estimating the Impact of Means-tested Subsidies under Treatment Externalities with Application to Anti-Malarial Bednets

    DEFF Research Database (Denmark)

    Bhattacharya, Debopam; Dupas, Pascaline; Kanaya, Shin

    Regular use of effective health-products such as insecticide-treated mosquito nets (ITN) by a household benefits its neighbors by (a) reducing chances of infection and (b) raising awareness about product-effectiveness, thereby increasing product-use. Due to their potential social benefits and high...... its neighbors. Using experimental data from Kenya where subsidies were randomized, coupled with GPS-based location information, we show how to estimate aggregate ITN use resulting from means-tested subsidies in the presence of such spatial spillovers. Accounting for spillovers introduces infinite......-dimensional estimated regressors corresponding to continuously distributed location coordinates and makes the inference problem novel. We show that even if individual ITN use unambiguously increases with increasing incidence of subsidy in the neighborhood, ignoring spillovers may over- or under-predict overall ITN use...

  20. Acyclic nucleoside phosphonates as inhibitors of hypoxanthine-guanine-(xanthine) phosphoribosyltransferase: new anti-malarial chemotherapy leads

    Czech Academy of Sciences Publication Activity Database

    Hocková, Dana; Holý, Antonín; Česnek, Michal; Baszczyňski, Ondřej; Tichý, Tomáš; Krečmerová, Marcela; Janeba, Zlatko; Skinner-Adams, T.; Naesens, L.; Keough, D. T.; de Jersey, J.; Guddat, L. W.

    Praha : ČSCH, 2011. s. 21-21. [Pokroky v organické, bioorganické a farmaceutické chemii - "Liblice 2011" /46./. 11.11.2011-13.11.2011, Lázně Bělohrad] R&D Projects: GA ČR GAP207/11/0108; GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : nucleotide analogues * antiviral activity * antiplasmodial activity * acyclic nucleoside phosphonates Subject RIV: CC - Organic Chemistry

  1. Factors Influencing Anti-Malarial Prophylaxis and Iron Supplementation Non-Compliance among Pregnant Women in Simiyu Region, Tanzania

    Science.gov (United States)

    Sambili, Benatus; Kimambo, Ronald; Peng, Yun; Ishunga, Elison; Matasha, Edna; Matumu, Godfrey; Noronha, Rita; Ngilangwa, David P.

    2016-01-01

    Malaria and iron-deficient anemia during pregnancy pose considerable risks for the mother and newborn. Intermittent Preventive Treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) and iron supplement to prevent anemia to all pregnant women receiving antenatal care (ANC) services is highly recommended. However, their compliance remains low. This study aimed at identifying factors influencing non-compliance of medications among pregnant women. A descriptive cross-sectional study was conducted in Simiyu region in northwest Tanzania using a structured questionnaire to collect data from 430 women who were pregnant or gave birth 12 months prior to data collection. Data were analyzed using non-parametric statistical analysis with STATA 10. Overall, 284 (66%) and 195 (45%) of interviewed women received IPTp-SP and iron supplementation during their ANC visits, respectively. The majority (85%) of women whom received medications were aware if they had received IPTp-SP or iron supplementation. Of those received IPTp-SP, only 11% took all the three doses, while the remaining 89% took only two doses or one dose. For women who received iron supplementation, 29% reported that they did not take any dose at all. Reasons given for not complying with regiments included not liking the medications and disapproval from male partners. Our findings suggest that IPTp-SP and iron supplement compliance among pregnant women in Simiyu region is low. Intensification of community education, further qualitative research and administration of medication through directly-observed therapy (DOT) are recommended to address the problem. PMID:27347981

  2. 三种不同方法检测结核分枝杆菌药物敏感性分析%Analyse of drug sensitivity of mycobacterium tuberculosis using three different methods

    Institute of Scientific and Technical Information of China (English)

    蔡杏珊; 张院良; 谭耀驹

    2010-01-01

    Objective To discuss the accordance of mycobacterium tuberculosis drug sensitivity test result with equipment liquid proportion method and L-J proportion method.Methods Detecting the four anti-mycobacterium drugs ( INH、 SM、 RFP, EMB ) susceptibility of 107 strains mycobacterium with BacT/ALERT 3D rapid drug sensitivity test 、MGIT 960 rapid drug sensitivity test and L-J proportion method. Results ( 1 ) The four drug ( INH、 SM、 RFP, EMB ) sensitivity ratio was 93%、 90%、 95% 、 90% respectively with BacT/ALERT 3D rapid drug sensitivity test、 MGIT 960 rapid drug sensitivity test and L-J proportion method.( 2 ) The resistance rate of INH、 SM、 RFP, EMB using BacT/ALERT 3D、 MGIT 960 and L-J proportion method was 27%、 28%、 24%; 12%、 13%、19%; 25%、 25%、 22%; 7%、 6%、 9% respectively.There was no significant difference among the drug resistance rate detected by the three methods.( 3 )The average drug sensitivity test time using BacT/ALERT 3D、 MGIT 960 and L-J proportion method was 10.5 days、 7.7 days、 28 days. There was significant difference through statistical analysis ( P < 0.001 ) Conclusions The four drug ( INH、 SM、 RFP,EMB )sensitivity test using BacT/ALEBT 3D、MGIT 960 and L-J proportion method had high comparability.The drug sensitivity test time was shortest using MGIT 960 method.%目的 探讨仪器液体比例法(BacT/ALERT 3D与MGIT 960系统)与L-J比例法测试结核分枝杆菌药物敏感性结果 的一致性.方法 用BacT/ALERT 3D快速药敏法、MGIT 960快速药敏法、L-J比例法同时对107株结核分枝杆菌进行INH、SM、RFP及EMB四种抗结核药物的耐药性测定.结果 (1)INH、SM、RFP及EMB用BacT/ALERT 3D法、MGIT960法、L-J比例法药敏测试结果 一致率分别为:93%、90%、95%、90%.(2)BacT/ALERT 3D法、MGIT 960法、L-J比例法对INH、SM、RFP、EMB的耐药率分别是:27%、28%、24%;12%、13%、19%;25%、25%、22%;7%、6%、9%.三种方法 四种药物的耐

  3. Fasciola hepatica: Histology of the Reproductive Organs and Differential Effects of Triclabendazole on Drug-Sensitive and Drug-Resistant Fluke Isolates and on Flukes from Selected Field Cases

    Directory of Open Access Journals (Sweden)

    Robert Hanna

    2015-06-01

    Full Text Available This review summarises the findings of a series of studies in which the histological changes, induced in the reproductive system of Fasciola hepatica following treatment of the ovine host with the anthelmintic triclabendazole (TCBZ, were examined. A detailed description of the normal macroscopic arrangement and histological features of the testes, ovary, vitelline tissue, Mehlis’ gland and uterus is provided to aid recognition of the drug-induced lesions, and to provide a basic model to inform similar toxicological studies on F. hepatica in the future. The production of spermatozoa and egg components represents the main energy consuming activity of the adult fluke. Thus the reproductive organs, with their high turnover of cells and secretory products, are uniquely sensitive to metabolic inhibition and sub-cellular disorganisation induced by extraneous toxic compounds. The flukes chosen for study were derived from TCBZ-sensitive (TCBZ-S and TCBZ-resistant (TCBZ-R isolates, the status of which had previously been proven in controlled clinical trials. For comparison, flukes collected from flocks where TCBZ resistance had been diagnosed by coprological methods, and from a dairy farm with no history of TCBZ use, were also examined. The macroscopic arrangement of the reproductive system in flukes was studied using catechol/carmine stained whole mounts, and the histology of the main organs was examined using conventional haematoxylin-eosin stained sections. Validation of apoptosis in the fluke sections was carried out using an in situ hybridisation method designed to label endonuclease-induced DNA strand breaks. In TCBZ-S flukes exposed to TCBZ metabolites for 24–96 h in vivo, but not in TCBZ-R flukes, those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles, were found to display progressive loss of cell content. This was due to apparent failure of cell division to keep pace with expulsion of the mature or

  4. Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis.

    Science.gov (United States)

    Zhang, Ruiguang; Li, Yan; Wang, Zhongliang; Chen, Lingjuan; Dong, Xiaorong; Nie, Xiu

    2015-11-01

    Non-small cell lung cancer is commonly seen with higher morbidity and mortality. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein, which is involved in multiple human diseases including cancers. However, the mechanisms of HMGB1 in non-small cell lung cancer remain unclear. The goal of the present study is to identify the relationship between HMGB1 and the progresssion of non-small cell lung cancer and investigate the molecular mechanism of HMGB1 in non-small lung cancer cell lines. Firstly, we detected the expression levels of HMGB1 by by real-time PCR and western blotting analysis, and the results demonstrated that HMGB1 was much higher expressed in non-small cell lung cancer cell lines, including A549, SPC-1-1, NCI-2170, SK-MES-1, and NCI-H1299, compared with that of WI-38. Next, 5 μM of adriamycin (AMD), 20 μM of cisplatin (DDP), and 50 μM of methotrexate (MTX) were used to treat A549 cells and SPC-A-1 cells for 48 h. The results showed that treatment with chemotherapy drugs significantly increased the levels of HMGB1 in A549 cells and SPC-A-1 cells. Moreover, the expression levels of HMGB1 increased in a time-dependent manner being treated with DDP. Then, the endogenous HMGB1 expression was successfully interferred with shRNA specific to HMGB1 in A549 and SPC-A-1 cells, which was detected by western blotting analysis. Then, the cisplatin-sensitive A549 cells and cisplatin-resistant A549/DDP cells were treated with increasing concentrations of cisplatin for 24, 48, and 72 h; cell viability were analyzed by MTT assay; and IC50 values were calculated. The results demonstrated that the expression level of HMGB1 in A549/DDP cells was much higher than that of A549 cells; moreover, transfection with HMGB1 shRNA in A549/DDP cells decreased the IC50 value of cisplatin in A549/DDP cells. The expression levels of autophagy-related proteins beclin-1 and LC3-II were significantly higher in A549/DDP cells or the A549 cells treated with

  5. A pivot mutation impedes reverse evolution across an adaptive landscape for drug resistance in Plasmodium vivax

    OpenAIRE

    Ogbunugafor, C. Brandon; Hartl, Daniel

    2016-01-01

    Background: The study of reverse evolution from resistant to susceptible phenotypes can reveal constraints on biological evolution, a topic for which evolutionary theory has relatively few general principles. The public health catastrophe of antimicrobial resistance in malaria has brought these constraints on evolution into a practical realm, with one proposed solution: withdrawing anti-malarial medication use in high resistance settings, built on the assumption that reverse evolution occurs ...

  6. In vivo evaluation of pH-sensitive polymeric microparticles for site specific drug delivery to the small intestine and colon

    OpenAIRE

    Kendall, R. A.; Murdan, S.; Basit, A. W.

    2006-01-01

    A novel emulsification/solvent evaporation process was developed to formulate prednisolone-loaded Eudragit L and S microparticles as drug delivery vehicles to target different regions of the gastrointestinal tract. Microparticles were characterised in vitro and in vivo. This is the first report of drug absorption form orally administered Eudragit L and S microparticles.

  7. Analysis of pathogens and drug sensitivity on 87 cases of chronic suppurative osteomyelitis%87例慢性化脓性骨髓炎病原菌构成及药敏分析

    Institute of Scientific and Technical Information of China (English)

    陈爱宝; 龚琦; 宋建辉; 曾国庆

    2012-01-01

    Objective To analyse constitutes strains of pathogenic bacteria and drug sensitivity test of 87 cases of chronic suppurative osteomyelitis. Methods Bacteria culture and drug sensitive test were performed by taking sinus secretions or tissue in deep focus of infection from patients with chronic suppurative osteomyelitis. Results A total of 120 strains of pathogenic bacteria were isolated. From high to low infection rate the top 3 bacteria as Staphylococcus aureus ( 30% ), Pseudomonas aeruginosa (25% ), Escherichia coli ( 14.2% ). Vancomycin, imipenem were the highest rate of sensitive drug. Conclusion The main pathogens of chronic suppurative osteomyelitis were composed with Staphylococcus aureus, Pseudomonas aeruginosa. Drug sensitive test is the important basis for selection of antibiotics.%目的 分析87 例慢性化脓性骨髓炎的病原菌菌种构成、药敏实验结果.方法 取慢性化脓性骨髓炎患者窦道深部分泌物或病灶组织做细菌培养及药敏试验.结果 共培养出病原菌120 株,感染率由高到低前三位菌为金黄色葡萄球菌(占30%)、铜绿假单胞菌(占25%)、大肠埃希菌(占14.2%).万古霉素、亚胺培南是敏感率最高药物.结论 慢性化脓性骨髓炎的病原菌构成以金黄色葡萄球菌、铜绿假单胞菌为主,药敏试验是选用抗菌药物的重要依据.

  8. IN VITRO EFFECT OF VITAMIN C ON THE LABORATORY ISOLATES OF MYCOBACTERIUM TUBERCULOSIS WITH KNOWN SENSITIVITY AND RESISTANCE TO THE FIRST LINE ANTI TUBERCULAR DRUGS: AN EXPERIMENTAL PILOT STUDY

    Directory of Open Access Journals (Sweden)

    Talaulikar Nikita.S , Dsouza Delia.B , Rodrigues Savio , Kulkarni MS

    2015-04-01

    Full Text Available Background and Objectives: Globally, 3.5% of new cases of Tuberculosis (TB and 20.5% of previously treated cases are estimated to have multidrug- resistant tuberculosis, the corresponding estimates for India are 2.2%, and 15% respectively. Progress has been made in research and development of new drugs for TB over the last decade, thus fuelling the need for more innovative options. Recent in-vitro studies that claim Vitamin C to have an inhibitory effect on Mycobacterium tuberculosis could possibly prove to be a major breakthrough in Medicine. Hence this experimental study was conducted on a pilot basis with the objective of studying the in -vitro effect of the active ingredient of vitamin C on the laboratory isolates of Mycobacterium tuberculosis that were known to be sensitive and resistant to the first line anti tubercular drugs (Isoniazid, Rifampicin, Pyrazinamide and Ethambutol and to compare the dose related response of both sensitive and resistant strains of Mycobacterium tuberculosis to varying concentrations of Vitamin C. Materials and Methods: Using a Completely Randomized Design, a total of 17 viable Mycobacterium tuberculosis strains, 10 of which were sensitive to all first line anti-TB drugs (Isoniazid, Rifampicin, Pyrazinamide and Ethambutol and seven strains resistant to all first line Anti-TB drugs were experimented upon. Proportion method was used to determine drug susceptibility of Mycobacterium tuberculosis to Ascorbic acid. Data is presented in a summary table. Results: With 1mM (millimole concentration of Ascorbic acid, growth of Mycobacterium tuberculosis was observed on both drug containing as well as control media, but with higher concentration of Ascorbic acid (10 mM and 100mM, no growth was observed on Ascorbic acid containing Lowenstein Jenson media. Conclusion: Although the findings of this pilot study add to the supportive evidence of an in- vitro susceptibility of Mycobacterium tuberculosis to Vitamin C, the authors

  9. Pectin-HPMC E15LV Vs pH sensitive polymer coating films for delayed drug delivery to colon: a comparison of two dissolution models to assess colonic targeting performance in-vitro

    Directory of Open Access Journals (Sweden)

    A. Maria John Newton

    2012-08-01

    Full Text Available Summary.The study was designed to evaluate the in vitro dissolution characteristics comparatively between pH sensitive polymer coated tablets and natural polymer coated tablets in a various simulated fluids (pH values 1.2, 6, 6.8, 7.2, 5. The fabricated Mesalamine tablets were coated with pectin-HPMC(Hydroxy propyl methyl cellulose E15LV (FC1-FC5 in combination and with Eudragit L100 ( FC6-FC10separately. Different buffer conditions were chosen to mimic the pH changes of the terminal part of the ileum as well as the colon.  Two in vitro studies were conducted separately in all the formulations. The impact of the pH changes on the coated tablets in normal pH condition and reduced pH condition (which occurs during inflammation in the colon were compared. The results showed that the impact of pH changes on the release profile of Eudragit L100  coated tablets was significant in reduced pH condition. In pH sensitive polymer coated tablets, drug release characteristics and the rate were affected when compared to the pectin coated tablets.  This study indicates that poly methacrylate polymers could not release the drug in predetermined rate in a variety of pH conditions. The present treatment methods of inflammatory bowel disease (IBD mostly depend on pH sensitive polymers. These pH sensitive polymers based colonic devices may not serve the patient need successfully because the influence of colonic pH on pH sensitive polymers plays an important role in drug release. The lowered pH condition in diseased state could not trigger the drug release, as it was not the threshold pH of the particular coated polymer. Therefore, in such diseased conditions natural polymer (pectinbased devices serve better for the objective of the therapy. The study on the effect of pH changes on the drug release profile of natural polymer-based colonic devices revealed that there was no impact by pH changes on the devices since they release the drug by the effect of colonic

  10. METHYLPHENIDATE ENHANCES THE ABUSE-RELATED BEHAVIORAL EFFECTS OF NICOTINE IN RATS: INTRAVENOUS SELF-ADMINISTRATION, DRUG DISCRIMINATION AND LOCOMOTOR CROSS-SENSITIZATION

    OpenAIRE

    Wooters, Thomas E.; Neugebauer, Nichole M.; Rush, Craig R.; Bardo, Michael T.

    2007-01-01

    Stimulant drugs, including d-amphetamine, cocaine and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination and locomotor cross-se...

  11. Mangiferin enhances the sensitivity of human multiple myeloma cells to anticancer drugs through suppression of the nuclear factor κB pathway.

    Science.gov (United States)

    Takeda, Tomoya; Tsubaki, Masanobu; Kino, Toshiki; Kawamura, Ayako; Isoyama, Shota; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzoh; Muraoka, Osamu; Matsuda, Hideaki; Satou, Takao; Nishida, Shozo

    2016-06-01

    Multiple myeloma (MM) is still an incurable hematological malignancy with a 5-year survival rate of ~35%, despite the use of various treatment options. The nuclear factor κB (NF-κB) pathway plays a crucial role in the pathogenesis of MM. Thus, inhibition of the NF-κB pathway is a potential target for the treatment of MM. In a previous study, we showed that mangiferin suppressed the nuclear translocation of NF-κB. However, the treatment of MM involves a combination of two or three drugs. In this study, we examined the effect of the combination of mangiferin and conventional anticancer drugs in an MM cell line. We showed that the combination of mangiferin and an anticancer drug decreased the viability of MM cell lines in comparison with each drug used separately. The decrease in the combination of mangiferin and an anticancer drug induced cell viability was attributed to increase the expression of p53 and Noxa and decreases the expression of XIAP, survivin, and Bcl-xL proteins via inhibition of NF-κB pathway. In addition, the combination treatment caused the induction of apoptosis, activation of caspase-3 and the accumulation of the cells in the sub-G1 phase of the cell cycle. Our findings suggest that the combination of mangiferin and an anticancer drug could be used as a new regime for the treatment of MM. PMID:27035859

  12. Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [11C]methamphetamine in methamphetamine sensitized dog: Application of PET to drug pharmacokinetic study

    International Nuclear Information System (INIS)

    Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [11C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D2 receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [11C]MAP using positron emission tomography (PET). A significant increase of [11C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumulation may affect the development or expression of MAP-induced behavioral sensitization

  13. Dual fluorescent HPMA copolymers for passive tumor targeting with pH-sensitive drug release II: impact of release rate on biodistribution

    Czech Academy of Sciences Publication Activity Database

    Chytil, Petr; Hoffmann, S.; Schindler, Lucie; Kostka, Libor; Ulbrich, Karel; Caysa, H.; Mueller, T.; Mäder, K.; Etrych, Tomáš

    2013-01-01

    Roč. 172, č. 2 (2013), s. 504-512. ISSN 0168-3659. [International Symposium on Recent Advances in Drug Delivery Systems /16./. Salt Lake City, 03.02.2013-06.02.2013] R&D Projects: GA ČR GCP207/12/J030; GA MŠk EE2.3.30.0029 Institutional support: RVO:61389013 Keywords : HPMA copolymers * pH-responsive drug release * tumor accumulation Subject RIV: CD - Macromolecular Chemistry Impact factor: 7.261, year: 2013

  14. Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells

    OpenAIRE

    Sokolosky, Melissa; Chappell, William H.; Stadelman, Kristin; Abrams, Stephen L.; Davis, Nicole M.; Steelman, Linda S.; McCubrey, James A.

    2014-01-01

    The PI3K/Akt/mTORC1 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, and metastasis. One molecule regulated by this pathway is GSK-3β. GSK-3β is phosphorylated by Akt on S9, which leads to its inactivation; however, GSK-3β also can regulate the activity of the PI3K/Akt/mTORC1 pathway by phosphorylating molecules such as PTEN, TSC2, p70S6K, and 4E-BP1. To further elucidate the roles of GSK-3β in chemotherapeutic drug and hormonal resistance o...

  15. Drug sensitivity analysis of type 2 diabetes complicated with urinary tract infection in Handan City%邯郸市2型糖尿病伴尿路感染的药敏分析

    Institute of Scientific and Technical Information of China (English)

    高玉梅; 韩永霞; 冯采兰

    2013-01-01

    目的 分析2型糖尿病伴尿路感染病例药敏试验结果,以指导临床合理选择抗生素.方法 取糖尿病伴尿路感染患者的清洁中段尿进行培养,采用配套的药敏卡进行药敏试验;按糖尿病伴尿路感染和非糖尿病伴尿路感染分组进行分析.结果 糖尿病伴尿路感染组患者感染的菌种存在多样性,糖尿病伴尿路感染组比非糖尿病伴尿路感染组对亚胺培南(敏感率91.49%)、阿米卡星(敏感率53.19%)敏感率高,且两组比较,差异有统计学意义(P<0.05).两组对头孢哌酮/舒巴坦、哌拉西林/他唑巴坦敏感率均>60%,所有菌株均对亚胺培南、阿米卡星敏感;糖尿病伴尿路感染阳性组有4例合并肠球菌感染.结论 糖尿病伴尿路感染患者应根据药敏试验结果合理使用抗生素,亚胺培南、阿米卡星、头孢哌酮/舒巴坦、哌拉西林/他唑巴坦为敏感药物.%[Objective] To analyze the results of drug sensitive test of type 2 diabetes complicated with urinary tract infection cases, guide reasonable choice of antibiotics in clinic. [ Methods] The samples of clean midstream urine from patients with diabetes and u-rinary tract infection were cultured, and the drug sensitive test was conducted with targeted drug sensitivity cards. Two groups, which included the diabetes with urinary tract infection group and the non-diabetes with urinary tract infection group, were analyzed. [ Results] The patients in the diabetes with urinary tract infection group were infected with a variety of bacteria. The sensitivity to imipenem (91.49% ) and amikacin (53.19% ) of the diabetes with urinary tract infection group was higher than that of the non-diabetes with urinary tract infection group, and the differences were significant (P < 0. 05). The sensitivity to cefoperazone/ sulbactam and piperacillin/tazobactam of both two groups were higher than 60% , while all strains were sensitive to imipenem and amikacin. 4 cases were

  16. Localization of the ATP-binding cassette (ABC) transport proteins PfMRP1, PfMRP2, and PfMDR5 at the Plasmodium falciparum plasma membrane.

    NARCIS (Netherlands)

    Kavishe, R.A.; Heuvel, J.M.W. van den; Vegte-Bolmer, M. van de; Luty, A.J.; Russel, F.G.M.; Koenderink, J.B.

    2009-01-01

    BACKGROUND: The spread of drug resistance has been a major obstacle to the control of malaria. The mechanisms underlying drug resistance in malaria seem to be complex and multigenic. The current literature on multiple drug resistance against anti-malarials has documented PfMDR1, an ATP-binding casse

  17. Drug Facts

    Medline Plus

    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Abuse Hurts Other People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental ...

  18. On the absorption and emission properties of three new non-steroidal anti-inflammatory drugs-β-cyclodextrin host-guest inclusion complexes: differentiated sensitivity to the microenvironment upon light excitation

    OpenAIRE

    MONTI S; Salemi, M. G.; S. Giuffrida; De Fazio, S; Guidi, G.; Sortino, S.

    1999-01-01

    The effects of β-cyclodextrin (β-CD) complexation on the absorption and emission properties of the non-steroidal anti-inflammatory drugs tolmetin (TM), diflunisal (DF), and fenbufen (FB) have been investigated. The absorption spectra of all these compounds are only slightly affected by the addition of ��-CD. In contrast, the emission properties were markedly influenced by CD complexation and in a different manner for the three compounds due to a differentiated sensitivity of the exci...

  19. 生牛乳中金黄色葡萄球菌的分离鉴定与药物敏感性分析%Analysis on Isolation,Identification and Drug Sensitivity of Staphylococcus aureus in Raw Cow Milk

    Institute of Scientific and Technical Information of China (English)

    王文博; 谷晓红; 苑学霞; 李瑞菊; 梁京芸; 李鸳鸯

    2015-01-01

    采用金黄色葡萄球菌(Staphylococcus aureus)测试片快速筛选的方法,对采集于陕西省西安市和渭南市20份样品中 S.aureus 进行分离鉴定及药物敏感性研究,以了解此地区生牛乳中 S.aureus 的污染情况及对药物敏感性。结果表明:S.aureus 测试片可用于大量生牛乳样品中 S.aureus 的初筛工作,方便且省力;S.aureus 的检出率为10%;检出的两株 S.aureus 对青霉素都为耐药,其中一株对磺胺异恶唑也表现为耐药,两株 S.aureus 对复方新诺明、红霉素、万古霉素、氧氟沙星、克林霉素都表现为敏感。牛场应根据药物敏感性实时调整抗感染药物的使用方案。%With 20 samples from Xi’an and Weinan City,Shaanxi Province,as materials,the isolation, identification and drug sensitivity of Staphylococcus aureus in raw cow milk were studied using S.aureus detec-tive slips to know the pollution situation and drug sensitivity of S.aures in this area.The results showed that S. aureus detective slips could be used to screen the S.aureus preliminarily from a large number of raw cow milk samples.The method was convenient and labor -saving.The detection rate of S.aureus was 1 0%.Both the detected S.aureus isolates were resistant to penicillin,but sensitive to trimethoprim -sulfamethoxazole,eryth-romycin,vancomycin,ofloxacin and clindamycin.One of the isolates was resistant to sulfisoxazole.Cow farms should adjust their anti -infection drugs timely according to the drug sensitivity of pathogen.

  20. Drug Facts

    Medline Plus

    Full Text Available ... Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts ... and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free Talking to Kids ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What To Say if You Were ...

  2. The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study

    Directory of Open Access Journals (Sweden)

    Tom D. Bunney

    2015-03-01

    Full Text Available Fibroblast growth factor receptors (FGFRs are recognized therapeutic targets in cancer. We here describe insights underpinning the impact of mutations on FGFR1 and FGFR3 kinase activity and drug efficacy, using a combination of computational calculations and experimental approaches including cellular studies, X-ray crystallography and biophysical and biochemical measurements. Our findings reveal that some of the tested compounds, in particular TKI258, could provide therapeutic opportunity not only for patients with primary alterations in FGFR but also for acquired resistance due to the gatekeeper mutation. The accuracy of the computational methodologies applied here shows a potential for their wider application in studies of drug binding and in assessments of functional and mechanistic impacts of mutations, thus assisting efforts in precision medicine.

  3. In vitro Plasmodium falciparum drug sensitivity assay: inhibition of parasite growth by incorporation of stomatocytogenic amphiphiles into the erythrocyte membrane

    DEFF Research Database (Denmark)

    Ziegler, Hanne L; Staerk, Dan; Christensen, Jette;

    2002-01-01

    -treated parasite culture continued to grow well in untreated erythrocytes. Thus, the antiplasmodial activity of lupeol appears to be indirect, being due to stomatocytic transformation of the host cell membrane and not to toxic effects via action on a drug target within the parasite. A number of amphiphiles that...... cause stomatocyte formation, but not those causing echinocyte formation, were shown to inhibit growth of the parasites, apparently via a mechanism similar to that of lupeol. Since antiplasmodial agents that inhibit parasite growth through erythrocyte membrane modifications must be regarded as unsuitable...... as leads for development of new antimalarial drugs, care must be exercised in the interpretation of results of screening of plant extracts and natural product libraries by an in vitro Plasmodium toxicity assay....

  4. Highly fluorescent and morphology-controllable graphene quantum dots-chitosan hybrid xerogels for in vivo imaging and pH-sensitive drug carrier.

    Science.gov (United States)

    Lv, Ouyang; Tao, Yongxin; Qin, Yong; Chen, Chuanxiang; Pan, Yan; Deng, Linhong; Liu, Li; Kong, Yong

    2016-10-01

    Highly fluorescent graphene quantum dots (GQDs)-chitosan (CS) hybrid xerogels (GQDs-CS) were facilely synthesized, and the morphology of GQDs-CS was controllable by varying the content of GQDs in the xerogel. The GQDs-CS exhibited a porous and three-dimensional (3D) network structure when the content of GQDs reached 43% (wt%) in the xerogel, which was beneficial for drug loading and sustained release. The as-prepared GQDs-CS could also be applied for in vivo imaging since it showed strong blue, green and red luminescence under excitation of varying wavelengths. Moreover, the pH-induced protonation/deprotonation of the -NH2 groups on CS chains can result in a pH-dependent drug delivery behavior of the GQDs-CS hybrid xerogel. PMID:27287145

  5. Alteration of Drug Sensitivity in Human Colon Cancer Cells after Exposure to Heat: Implications for Liver Metastasis Therapy using RFA and Chemotherapy

    OpenAIRE

    Makizumi, Ryouji; Yang, Weng-Lang; Owen, Randall P.; Sharma, Rohit R.; Ravikumar, T S

    2008-01-01

    Radiofrequency ablation (RFA) is gaining popularity for treating colorectal liver metastases by inducing image guided tumor hyperthermia. In order to reduce tumor recurrence, adjuvant therapies have been administered post-RFA. We hypothesized that tumor cells escaping RFA cytotoxicity by being in the sublethal zones of tumor might develop differential behavior toward cytotoxic drugs. Here, we used cultured human colorectal cancer cells to evaluate the interaction between heat treatment and ch...

  6. Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug-resistant human hepatocellular carcinoma cells to 5-FU

    OpenAIRE

    Tang, Bo; Hu, Zhigao; Li, Yang; YUAN, SHENGGUANG; Wang, Zhenran; Yu, Shuiping; He, Songqing

    2015-01-01

    δ opioid receptor (DOR) was the first opioid receptor of the G protein-coupled receptor family to be cloned. Our previous studies demonstrated that DOR is involved in regulating the development and progression of human hepatocellular carcinoma (HCC), and is involved in the regulation of the processes of invasion and metastasis of HCC cells. However, whether DOR is involved in the development and progression of drug resistance in HCC has not been reported and requires further elucidation. The ...

  7. A sensitive and semi-quantitative method for determination of multi-drug residues in animal body fluids using multiplex dipstick immunoassay.

    Science.gov (United States)

    Han, Shuaijuan; Zhou, Tianjiao; Yin, Bingjie; He, Pingli

    2016-07-13

    The objective of this research was to develop a multiplex dipstick immunoassay method for the simultaneous determination of multi-veterinary drug residues, such as β-agonists, sulfonamides, and tetracyclines in milk, urine, and serum. The multiplex dipstick assay format was based on an indirect competitive approach: Three test lines (different antigens) and one control line (goat anti-mouse IgG) were located on the strip membrane. Labeled antibodies were freeze-dried in microwells. Samples did not require pretreatment and could be directly analyzed within 10 min. Threshold levels in different sample matrices were visually estimated at 0.3-0.45 ng mL(-1) for clenbuterol; 3-4 ng mL(-1) for sulfadiazine; and 4.5-6 ng mL(-1) for tetracycline, respectively. The linear relationship between the concentrations of veterinary drug residues and the Au nanoparticles plasmon absorbance allowed quantitative determination of these veterinary drug residues. The recoveries of clenbuterol, sulfadiazine and tetracycline in spiked samples ranged from 78.4% to 112.6%, and the relative standard deviations were below 11.2%. Analysis of animal samples suggested that the proposed multiplex dipstick assay method was consistent with the LC-MS/MS method. The percentage of false results was less than or equal to 5%. Thus, the proposed multiplex dipstick assay is inexpensive, easy-to-use, and suitable for the purposes of rapid and comprehensive screening of 3 families of β-agonists, sulfonamides and tetracyclines including 26 drugs in animal body fluids. PMID:27237838

  8. Analysis on drug sensitivity of ESBL-producing Escherichia coli%产超广谱β-内酰胺酶大肠埃希菌药敏情况分析

    Institute of Scientific and Technical Information of China (English)

    孙午; 熊莺

    2013-01-01

    目的 分析产ESBLs大肠埃希菌的临床分离和药敏情况,并与不产酶的大肠埃希菌的情况进行比较.方法 回顾性分析198株产ESBLs大肠埃希菌和287株不产ESBLs大肠埃希菌的耐药情况,采用x2检验分析耐药株和敏感株的来源差异和对常用抗菌药物的敏感性差异.结果 药敏实验证实产ESBLs大肠埃希菌和不产ESBLs大肠埃希菌除对亚胺培南、美洛培南和阿米卡星的敏感性差异无统计学意义外(P>0.05),对其他抗菌药物的敏感性差异都有统计学意义(P<0.05),产ESBLs大肠埃希菌对这些抗菌药物的耐药率相对于不产ESBLs大肠埃希菌都有不同程度的提高.结论 由于产ESBLs大肠埃希菌耐药机制的多样性和存在多重耐药情况,在临床确诊产ESBLs大肠埃希菌株感染时应根据药敏结果合理使用抗菌药物,同时应该珍惜使用对产ESBLs大肠埃希菌和不产ESBLs大肠埃希菌治疗无显著差异的碳青霉烯类以及阿米卡星等抗菌药物.%OBJECTIVE To analyze drug sensitivity of ESBL-producing Escherichia coli and compare with non-ESBL-produc-ing Escherichia coli. METHODS We got 198 ESBL-producing Escherichia coli and 287 non-ESBL-producing Escherichia coli. The results of ESBL-producing Escherichia coli and non-ESBL-producing Escherichia coli were analysed by χ2 test. RESULTS There were no significant differences in drug sensitivity of ESBL-producing Escherichia coli and Non-ESBL-producing Escherichia coli to imipenem, meropenem and amikacin (P> 0.05). Drug sensitive test discovered that there were significant differences in drug sensitivity of ESBL-producing Escherichia coli and non-ESBL-producing Escherichia coli to other antibiotics (P> 0.05), and drug sensitivity of ESBL-producing Escherichia coli was higher than non-ESBL-producing Escherichia coli. CONCLUSION We should use drug to treat patients in time and reasonably when the patient is diagnosed as infection by ESBL

  9. 儿童假丝酵母感染状况分析及药物敏感性研究%Analysis on the infection status of Candida in children and the drug sensitive test

    Institute of Scientific and Technical Information of China (English)

    王长嘉; 孙晓红; 贺丹; 李广泉; 高磊; 高嵩; 王丽

    2012-01-01

    目的:探讨儿童假丝酵母的感染情况,分析其对常用抗真菌药物的敏感性,为真菌感染的治疗和预防提供依据.方法:收集临床假丝酵母感染患儿标本77例,进行菌株的分离、鉴定.并从患儿年龄、基础疾病及标本来源、检出病原菌种类、菌株药物敏感性等方面进行分析.结果:真菌感染患儿的平均年龄为6岁.标本主要来源于咽拭子,白假丝酵母的分离率最高(63.6%),其次为光滑假丝酵母、热带假丝酵母、克柔假丝酵母和其他假丝酵母.药物敏感性实验结果表明,假丝酵母对两性霉素B (AmB)、5-氟胞嘧啶(5- FC)的敏感性较高.其中,白假丝酵母对AmB、5- FC、氟康唑(FCZ)及伊曲康唑(ICZ)的敏感率依次为100.0%、91.9%、83.7%、69.4%;对ICZ、FCZ、5- FC的耐药率依次为4.1%、2.0%、2.0%.结论:儿童真菌感染以白假丝酵母最多见,分离菌株对FCZ和ICZ的耐药性较高,临床医生应高度重视,并根据药物敏感性实验结果进行治疗和预防.%Objective: To explore the infection status of Candida in children, analyze its sensitivity to antibiotics commonly used in clinic, provide a basis for the treatment and prevention of fungal infection. Methods; A total of 77 specimens of clinical infection of Candida in children were collected, then isolation and identification of bacterial strains were conducted, then the results were analyzed from the aspects of age, basic diseases, source of specimens, types of pathogens detected , and drug sensitivity of bacterial strains. Results -. The average age of the children with fungal infection was six years. The specimens were mainly from nasopharyngeal swabs. The isolation rate of Candida albicans was the highest (63. 6% ) , followed by Candida glabrata, Candida tropicalis, Candida krusei, and other Candida. The results of drug sensitive test showed that the sensitivities of Candida to amphoteriein B and 5 - fluorouracil were high. The

  10. 4-IBP, a σ1 Receptor Agonist, Decreases the Migration of Human Cancer Cells, Including Glioblastoma Cells, In Vitro and Sensitizes Them In Vitro and In Vivo to Cytotoxic Insults of Proapoptotic and Proautophagic Drugs

    Directory of Open Access Journals (Sweden)

    Veronique Mégalizzi

    2007-05-01

    Full Text Available Although the molecular function of cr receptors has not been fully defined and the natural ligand(s is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-tibenzylpiperidin-4-yl-4iodobenzamide (4-IBP, a selective σ1, agonist, has been used to investigate whether this compound is able to modify: 1 in vitro the migration and proliferation of human cancer cells; 2 in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3 in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC models the survival of mice coadministered cytotoxic agents. 4-IBP has revealed weak anti proliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

  11. Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications

    Science.gov (United States)

    Liu, Xiaodong; Chen, Bizheng; Li, Xiaojun; Zhang, Lifen; Xu, Yujie; Liu, Zhuang; Cheng, Zhenping; Zhu, Xiulin

    2015-10-01

    Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (~7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells.Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR

  12. TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases

    Directory of Open Access Journals (Sweden)

    Kim Dong-Wan

    2010-07-01

    Full Text Available Abstract Background The development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp mediated multidrug resistance (MDR in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand down-regulates P-glycoprotein (P-gp through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs. Results MDR variants, CEM/VLB10-2, CEM/VLB55-8 and CEM/VLB100 cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB100 cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5. Conclusion This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by

  13. Effect of Skin Sensitizers on Inducible Nitric Oxide Synthase Expression and Nitric Oxide Production in Skin Dendritic Cells: Role of Different Immunosuppressive Drugs

    OpenAIRE

    Cruz, M. T.; Neves, B. M.; Gonçalo, M; Figueiredo, A; C. B. Duarte; Lopes, M C

    2007-01-01

    Nitric oxide (NO) is involved in the pathogenesis of acute and chronic inflammatory conditions, namely in allergic contact dermatitis (ACD). However, the mechanism by which NO acts in ACD remains elusive. The present study focuses on the effects of different contact sensitizers (2,4-dinitrofluorbenzene, 1,4-phenylenediamine, nickel sulfate), the inactive analogue of DNFB, 2,4-dichloronitrobenzene, and two irritants (sodium dodecyl sulphate and benzalkonium chloride) on the expression of the i...

  14. Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

    OpenAIRE

    Zhang, LIJUAN; Zhang, Can Yang; Xiong, Di; Sun, Yao; Zhao, Bin; Lin, Wen Jing

    2014-01-01

    Can Yang Zhang, Di Xiong, Yao Sun, Bin Zhao, Wen Jing Lin, Li Juan Zhang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong Province, People’s Republic of China Abstract: A novel amphiphilic triblock pH-sensitive poly(ß-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthe...

  15. Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

    OpenAIRE

    Zhang CY; Xiong D; Sun Y; Zhao B; Lin WJ; Zhang LJ

    2014-01-01

    Can Yang Zhang, Di Xiong, Yao Sun, Bin Zhao, Wen Jing Lin, Li Juan Zhang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong Province, People’s Republic of China Abstract: A novel amphiphilic triblock pH-sensitive poly(ß-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized co...

  16. Prenatal Stress Alters Progestogens to Mediate Susceptibility to Sex-Typical, Stress-Sensitive Disorders, such as Drug Abuse: A Review

    OpenAIRE

    Frye, Cheryl A.; Paris, Jason J.; Osborne, Danielle M.; Campbell, Joannalee C.; Kippin, Tod E.

    2011-01-01

    Maternal–offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well underst...

  17. Prenatal stress alters progestogens to mediate susceptibility to sex-typical, stress-sensitive disorders, such as drug abuse: a review

    OpenAIRE

    Frye, Cheryl A.; Paris, Jason J.; Danielle eOsborne; Joanna eCampbell; Tod eKippin

    2011-01-01

    Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well unders...

  18. Investigation of drug polymorphism: Case of artemisinin

    International Nuclear Information System (INIS)

    Highlights: • The Artemisinin dimorphic system was found to be enantiotropic. • The Orthorhombic modification is the form stable at low-temperatures and the triclinic modification the form stable at high-temperatures. • The polymorphic phase transition occurs at ∼130 °C. - Abstract: The polymorphism of the anti-malarial compound artemisinin was examined. The phase behavior of solid artemisinin has experimentally been investigated using differential scanning calorimetry and temperature-resolved X-Ray powder diffraction. In addition, complementary solution studies and suspension experiments were performed. The results clearly confirm the existence of two modifications of artemisinin, which are related enantiotropically. The orthorhombic modification is the thermodynamically stable form at low temperatures, while the triclinic form is the stable one at higher temperatures with a transition temperature of ∼130 °C. Problems associated with analysis of the polymorphic phase behavior are comprehensively addressed

  19. Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.

    Science.gov (United States)

    Li, Wei-Ming; Chiang, Chih-Sheng; Huang, Wei-Chen; Su, Chia-Wei; Chiang, Min-Yu; Chen, Jian-Yi; Chen, San-Yuan

    2015-12-28

    We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers. PMID:26478017

  20. Acupoint-Specific, Frequency-Dependent, and Improved Insulin Sensitivity Hypoglycemic Effect of Electroacupuncture Applied to Drug-Combined Therapy Studied by a Randomized Control Clinical Trial

    Directory of Open Access Journals (Sweden)

    Rong-Tsung Lin

    2014-01-01

    Full Text Available The application of electroacupuncture (EA to specific acupoints can induce a hypoglycemic effect in streptozotocin-induced rats, normal rats, and rats with steroid-induced insulin resistance. EA combined with the oral insulin sensitizer rosiglitazone improved insulin sensitivity in rats and humans with type II diabetes mellitus (DM. There are different hypoglycemic mechanisms between Zhongwan and Zusanli acupoints by EA stimulation. On low-frequency (2 Hz stimulation at bilateral Zusanli acupoints, serotonin was involved in the hypoglycemic effect in normal rats. Moreover, after 15 Hz EA stimulation at the bilateral Zusanli acupoints, although enhanced insulin activity mainly acts on the insulin-sensitive target organs, the muscles must be considered. In addition, 15 Hz EA stimulation at the bilateral Zusanli acupoints has the combined effect of enhancing cholinergic nerve activity and increasing nitric oxide synthase (NOS activity to enhance insulin activity. Despite the well-documented effect of pain control by EA in many systemic diseases, there are few high-quality long-term clinical trials on the hypoglycemic effect of EA in DM. Combination treatment with EA and other medications seems to be an alternative treatment to achieve better therapeutic goals that merit future investigation.

  1. 暹罗斗鱼致病性嗜水气单胞菌的分离·鉴定及药敏试验%Isolation, Identification and Drug Sensitivity Test of Pathogenic Aeromonas hydrophila from Betta splendens Regan

    Institute of Scientific and Technical Information of China (English)

    杨宁; 黄海; 张希; 魏赟; 巫火连

    2012-01-01

    [Objective] The research aimed to discuss the disease cause of Betta splcnders Regan and the prevention and control methods of its diseases and pests. [Method] The pathogenic bacteria of B, splenders were isolated and identified by determining die physiological and biochemical indices and 16 S rDNA sequencing. And the drug sensitivity test was made. [Result] Strain DY001 was the pathogenic bacteria that caused Aeromonas hydrophila disease of B. splenders. Strain DY001 was identified as Aeromonas hydrophila. The median lethal dose (LD50) of this pathogeny to B. splenders was 0. 04 × 106 CFU/g. The results of drug sensitivity test showed that this pathogenic bacteria was sensitive to azithromycin, ofloxacin, norfloxacin, compound sinomin, ceftriaxone, trimethoprim, chloramphenicol and other antibiotics. [Conclusion] Aeromonas hydropkila was the pathogenic bacteria that caused the disease incidence of B. splenders. The results of drug sensitivity test could provide references for the disease prevention and control of B. splenders.%[目的]探讨暹罗斗鱼的发病原因和病害防治方法.[方法]对暹罗斗鱼的病原菌进行分离,并通过生理生化指标测定和16S rDNA测序对其鉴定,同时进行药敏试验.[结果]菌株DY001为暹罗斗鱼嗜水气单胞菌病的病原菌.经鉴定,确定菌株DY001为嗜水气单胞菌(Aeromonas hydrophila).该病原菌对暹罗斗鱼的半致死量(LD50)为0.04×106 CFU/g.药敏试验结果表明,病原菌对阿奇霉素、奥复星、氟哌酸、复方新诺明、菌必治、甲氧苄啶和氯霉素等抗生素敏感.[结论]嗜水气单胞菌是引起此次暹罗斗鱼发病的病原菌,而药敏试验结果将为其防治提供参考.

  2. CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells

    International Nuclear Information System (INIS)

    R5 HIV-1 strains resistant to the CCR5 antagonist Maraviroc (MVC) can use drug-bound CCR5. We demonstrate that MVC-resistant HIV-1 exhibits delayed kinetics of coreceptor engagement and fusion during drug-bound versus free CCR5 infection of cell lines. Antibodies directed against the second extracellular loop (ECL2) of CCR5 had greater antiviral activity against MVC-bound compared to MVC-free CCR5 infection. However, in PBMCs, only ECL2 CCR5 antibodies HGS004 and HGS101, but not 2D7, inhibited infection by MVC resistant HIV-1 more potently with MVC-bound than with free CCR5. In addition, HGS004 and HGS101, but not 2D7, restored the antiviral activity of MVC against resistant virus in PBMCs. In flow cytometric studies, CCR5 binding by the HGS mAbs, but not by 2D7, was increased when PBMCs were treated with MVC, suggesting MVC increases exposure of the relevant epitope. Thus, HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance.

  3. 比较盐敏感性与非盐敏感性高血压的联合药物治疗%Comparison of Combined Drug Salt Sensitivity and Non Salt Sensitive Hypertension Treatment

    Institute of Scientific and Technical Information of China (English)

    姚萍; 朱江红

    2014-01-01

    Objective To explore the value of transabdominal and transvaginal ultrasonography in diagnosis of pregnancy. Methods 120 cases in hospitalized patients with mild to moderate hypertension, after the salt load test tests to determine the 60 cases of salt-sensitive hypertension group (SS), another 60 patients as a non-salt-sensitive hypertension group (NSS) , and then the two groups were in groups of 30 cases were randomly divided into two groups, each with felodipine tablets combined perindopril and indapamide sustained release tablets tablets combined perindopril tablets for 12 weeks, measuring treatment change after 24 h of each index. Results SS group compared with the NSS group, dif erent levels of FPG and Cr were statistical y significant ( <0.01), the difference FINS, LVMI, MAU, BMI, HOMA-IR are also statistically significant ( <0.05 ); SS group of patients is the use of joint training indapamide perindopril treatment, and the detection of indicators are within the normal range, the difference was statistical y significant ( <0.05); NSS group of patients is the use of felodipine combined perindopril treatment, and its detection indicators are located within the normal range, the dif erence was statistical y significant ( <0.05).Conclusion Salt-sensitive hypertension obvious target organ damage, for indapamide and perindopril combination therapy, rather than salt-sensitive patients for felodipine combination therapy with perindopril.%目的探讨盐敏感性与非盐敏感性高血压对靶器官的损害和联合药物治疗的差异。方法在住院的轻中度高血压患者中选取120例,经过盐负荷试验测试,确定60例为盐敏感性高血压组(SS),另选择60例作为非盐敏感性高血压组(NSS),再将这两组分别以每组30例随机分为两小组,分别用非洛地平片联合培哚普利片和吲达帕胺缓释片联合培哚普利片治疗12w,测量治疗前后24 h各指标的变化。结果 SS组与NSS组相比,FPG和Cr水

  4. Silencing of the transcription factor STAT3 sensitizes lung cancer cells to DNA damaging drugs, but not to TNFα- and NK cytotoxicity

    International Nuclear Information System (INIS)

    Transcription factor STAT3 (Signal Transducers and Activators of Transcription 3) is persistently active in human tumors and may contribute to tumor progression. Inhibition of STAT3 expression/activity could be a good strategy to modulate tumor cell survival and responses to cancer chemotherapeutics or immune cytotoxicity. We silenced STAT3 expression in human A549 lung cancer cells to elucidate its role in cell survival and resistance to chemotherapeutics, TNFα and natural killer (NK)-mediated cytotoxicity. We demonstrate that STAT3 is not essential for basal survival and proliferation of A549 cancer cells. Stable silencing of STAT3 expression sensitized A549 cells to DNA damaging chemotherapeutics doxorubicin and cisplatin in a p53-independent manner. Sensitization to DNA damage-inducing chemotherapeutics could be due to down-regulation of the Bcl-xL expression in STAT3 depleted cells. In contrast, knockdown of STAT3 in cancer cells did not modulate responses to TNFα and NK-mediated cytotoxicity. We found that STAT3 depletion increased the NFκB activity likely providing the compensatory, pro-survival signal. The treatment with TNFα, but not doxorubicin, enhanced this effect. We conclude that STAT3 is not crucial for the control of basal cell proliferation and survival of lung carcinoma cells but modulates susceptibility to DNA damaging chemotherapeutics by regulation of intrinsic pro-survival pathways. - Highlights: ► STAT3 silencing is negligent for basal lung cancer cell viability and proliferation. ► STAT3 depletion sensitizes lung cancer cells to DNA damaging chemotherapeutics. ► STAT3 depletion has no effect on susceptibility to extrinsic apoptosis inducers. ► Increased pro-survival NFκB activity may compensate for STAT3 depletion

  5. Silencing of the transcription factor STAT3 sensitizes lung cancer cells to DNA damaging drugs, but not to TNFα- and NK cytotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Kulesza, Dorota W. [Laboratory of Transcription Regulation, Department of Cell Biology, The Nencki Institute of Experimental Biology, Warsaw (Poland); Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw (Poland); Carré, Thibault; Chouaib, Salem [Unité INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif Cedex (France); Kaminska, Bozena, E-mail: bozenakk@nencki.gov.pl [Laboratory of Transcription Regulation, Department of Cell Biology, The Nencki Institute of Experimental Biology, Warsaw (Poland)

    2013-02-15

    Transcription factor STAT3 (Signal Transducers and Activators of Transcription 3) is persistently active in human tumors and may contribute to tumor progression. Inhibition of STAT3 expression/activity could be a good strategy to modulate tumor cell survival and responses to cancer chemotherapeutics or immune cytotoxicity. We silenced STAT3 expression in human A549 lung cancer cells to elucidate its role in cell survival and resistance to chemotherapeutics, TNFα and natural killer (NK)-mediated cytotoxicity. We demonstrate that STAT3 is not essential for basal survival and proliferation of A549 cancer cells. Stable silencing of STAT3 expression sensitized A549 cells to DNA damaging chemotherapeutics doxorubicin and cisplatin in a p53-independent manner. Sensitization to DNA damage-inducing chemotherapeutics could be due to down-regulation of the Bcl-xL expression in STAT3 depleted cells. In contrast, knockdown of STAT3 in cancer cells did not modulate responses to TNFα and NK-mediated cytotoxicity. We found that STAT3 depletion increased the NFκB activity likely providing the compensatory, pro-survival signal. The treatment with TNFα, but not doxorubicin, enhanced this effect. We conclude that STAT3 is not crucial for the control of basal cell proliferation and survival of lung carcinoma cells but modulates susceptibility to DNA damaging chemotherapeutics by regulation of intrinsic pro-survival pathways. - Highlights: ► STAT3 silencing is negligent for basal lung cancer cell viability and proliferation. ► STAT3 depletion sensitizes lung cancer cells to DNA damaging chemotherapeutics. ► STAT3 depletion has no effect on susceptibility to extrinsic apoptosis inducers. ► Increased pro-survival NFκB activity may compensate for STAT3 depletion.

  6. A STUDY ON AETIOLOGICAL AGENTS OF LRTI WITH SPECIAL EMPHASIS ON DRUG SENSITIVITY PATTERN OF ISOLATED BACTERIA AND INCIDENCE OF PNEUMOCYSTIS CARINII PNEUMONIA

    Directory of Open Access Journals (Sweden)

    Manab Kumar

    2015-12-01

    Full Text Available Lower Respiratory Tract Infections (LRTIs are important causes of morbidity and mortality for all age groups both in the hospital as well as in the community. Though international guidelines are available for treating bacterial LRTI they have not been validated very much in the Indian scenario. Scarce local information is available regarding aetiological agents of LRTI and their antibiotic sensitivity pattern. Pneumocystis carinii (Jiroveci is a common pathogen in LRTI in immuno-compromised patients. It is rarely documented in our country. MATERIALS AND METHODS Two hundred adults suffering from LRTI of less than 2 weeks duration from both inpatient and outpatient departments in a Tertiary Care Hospital at Kolkata were included in the study after taking valid informed consent. Study period was one year (2014- 15. Sputum samples were collected as per criteria of Murray et al. 1975. After performing routine culture, diagnosis was made based on colony character and biochemical reactions. Antimicrobial sensitivity testing was then done according to CLSI guidelines. RESULTS This study reveals that, LRTI was common in all age groups, in both Human Immunodeficiency Virus Non-Reactive (HIVNR and Human Immunodeficiency Virus Reactive (HIVR groups. In both the groups, 75% showed growth of single organism in sputum. But in the HIVR group, a considerable number showed growth of multiple organisms. Both the groups (HIVNR and HIVR showed predominance of Gram positive bacteria. Antibiotic sensitivity was unremarkable, but one E.coli isolate was an Extended Spectrum Beta-Lactamase producer (ESBL. Pneumocystis Carinii (PC was found in Giemsa stained smear of induced sputum in one HIVR case, who developed Pneumo-mediastinum and surgical emphysema, but recovered due to early initiation of treatment, suggesting that Pneumocystis Carinii (Jiroveci pneumonia was not uncommon in HIVR patients and early diagnosis and treatment can save the life of the patient

  7. Hormone Resistance in Two MCF-7 Breast Cancer Cell Lines is Associated with Reduced mTOR Signaling, Decreased Glycolysis, and Increased Sensitivity to Cytotoxic Drugs

    OpenAIRE

    Leung, Euphemia Yee; Kim, Ji Eun; Askarian-Amiri, Marjan; Joseph, Wayne R.; McKeage, Mark J; Baguley, Bruce C.

    2014-01-01

    The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume, and resistance to mTOR inhibition. Here, we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, d...

  8. Hormone resistance in two MCF-7 breast cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis and increased sensitivity to cytotoxic drugs

    OpenAIRE

    Euphemia Yee Leung; Ji Eun eKim; Marjan eAskarian-Amiri; Joseph, Wayne R.; McKeage, Mark J; Bruce Charles Baguley

    2014-01-01

    The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume and resistance to mTOR inhibition. Here we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, doc...

  9. The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Clausen, Mathias Porsmose; Bennetzen, Martin;

    2009-01-01

    interacts strongly with lipid bilayers of different composition leading to increased permeability. This implies that chlorpromazine can change influx properties of membranes hence suggesting that chlorpromazine may be a promising chemosensitizing compound for enhancing the cytotoxic effect of tamoxifen...... compound is now also recognized as a multitargeting drug with diverse potential applications, for example, it has antiproliferative properties and it can reverse resistance toward antibiotics in bacteria. Furthermore, chlorpromazine can reverse multidrug resistance caused by overexpression of P......-glycoprotein in cancer cells. In this study, we have investigated the effect of chlorpromazine on tamoxifen response of human breast cancer cells. We found that chlorpromazine worked synergistically together with tamoxifen with respect to reduction of cell growth and metabolic activity, both in the antiestrogen...

  10. Drug Facts

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    Full Text Available ... Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between Drug ...

  11. Drug Facts

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    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Abuse Hurts Other People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn ...

  12. Evaluation of zwitterionic polymersomes spontaneously formed by pH-sensitive and biocompatible PEG based random copolymers as drug delivery systems.

    Science.gov (United States)

    Laskar, Partha; Dey, Joykrishna; Ghosh, Sudip kumar

    2016-03-01

    The development of stimuli-responsive biocompatible polymersomes is important for the improvement of drug delivery systems. Herein, we report the spontaneous formation of polymersomes by three random copolymers, l-cys-graft-poly[GMA-co-mPEG300], containing different ratios of l-cysteine (Cys) and methoxy poly(ethylene glycol) (mPEG) covalently linked to the polymer backbone. Cysteine was conjugated to the polymeric backbone through metal free thiol-epoxy 'click' chemistry at final step. The copolymers, without having any typical hydrophobe in the backbone, are sufficiently surface active. The self-assembly formation of the copolymers was studied in aqueous solution by steady-state fluorescence probe technique. Spontaneous polymersomes formation, without any help of stimuli and organic solvent, above a relatively low critical aggregation concentration was confirmed by dynamic light scattering and microscopic techniques. Polymersomes were shown to be able to encapsulate not only hydrophilic dye in their aqueous core but also hydrophobic guest molecules in the bilayer membrane constituted by the mPEG chains. The polymersomes are sufficiently stable under physiological condition. These nano-sized polymersomes exhibit pH-triggered release of encapsulated guest under acidic pH. All three copolymers were found to be completely cell viable and hemocompatible up to very high concentration. Their ability to cross cell membrane was demonstrated by use of a fluorescent dye-tagged polymer. Further, these copolymers did not show any denaturising effect on the secondary structure of the human serum albumin, a transport protein in the blood. Based on the results of this study it is concluded that these spontaneously formed stable and biocompatible polymersomes can have potential use as drug delivery systems. PMID:26704991

  13. The putative ABC transporter encoded by the orf19.4531 plays a role in the sensitivity of Candida albicans cells to azole antifungal drugs.

    Science.gov (United States)

    Jiang, Linghuo; Xu, Dayong; Chen, Zhen; Cao, Yongbing; Gao, Pinghui; Jiang, Yuanying

    2016-05-01

    ATP-binding cassette (ABC) transporters constitute a large superfamily of integral membrane proteins in prokaryotic and eukaryotic cells. In the human fungal pathogenCandida albicans, there are 28 genes encoding ABC transporters and many of them have not been characterized so far. The orf19.4531 (also known as IPF7530) encodes a putative ABC transporter. In this study, we have demonstrated that disruption of orf19.4531 causesC. albicanscells to become tolerant to azoles, but not to polyene antifungals and terbinafine. Therefore, the protein encoded by orf19.4531 is involved in azole sensitivity and we name it asROA1, the regulator of azole sensitivity 1 gene. Consistently, we show that the expression ofROA1is responsive to treatment of either fluconazole or ketoconazole inC. albicans In addition, through a GFP tagging approach, Roa1 is localized in a small punctuate compartment adjacent to the vacuolar membrane. However,ROA1is not essential for thein vitrofilamentation ofC. albicanscells. PMID:26975389

  14. Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells.

    Directory of Open Access Journals (Sweden)

    Thomas Efferth

    Full Text Available BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART, a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo. However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated. The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains. Another salient feature of these compounds is the lack of severe side effects in malaria patients. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we used T-cell leukemias as a model system to study the molecular mechanisms of ART-induced apoptosis. The most typical anticancer drugs are DNA intercalators such as Doxorubicin. To investigate drug sensitivity and resistance, we chose a Doxorubicin-resistant leukemia cell line and investigated the killing effect of ART on these cells. We show that ART induces apoptosis in leukemic T cells mainly through the mitochondrial pathway via generation of reactive oxygen species (ROS, a mechanism different from Doxorubicin. This is confirmed by the fact that the antioxidant N-Acetyle-Cysteine (NAC could completely block ROS generation and, consequently, inhibited ART-induced apoptosis. Therefore, ART can overcome the Doxorubicin-resistance and induce the Doxorubicin-resistant leukemia cells to undergo apoptosis. We also show that ART can synergize with Doxorubicin to enhance apoptotic cell death in leukemic T cells. This synergistic effect can be largely explained by the fact that ART and Doxorubicin use different killing mechanisms. CONCLUSIONS: Our studies raise the possibility to develop ART in

  15. 金鱼嗜水气单胞菌的分离鉴定及药敏试验%Identification and Drug Sensitivity Test of Pathogenic Aeromonas hydrophila from Goldfish Carassius auratus

    Institute of Scientific and Technical Information of China (English)

    周毅; 张培培; 徐晔; 曹洁; 孟学平; 段宏安

    2014-01-01

    自病死金鱼肝脏中分离到一株优势菌,对其进行感染试验、培养特性观察、生化特性鉴定及16S rRNA序列分析。试验结果表明,该分离菌株为嗜水气单胞菌,与已报道的嗜水气单胞菌的16S rRNA序列同源性>99.3%。用纸片扩散法进行药敏试验,试验结果显示,该分离株对四环素类、喹诺酮类、磺胺类、头孢呋新、头孢他啶、头孢吡肟等21种药物敏感,对青霉素G、氨苄西林、阿莫西林、头孢氨苄、林可霉素、麦迪霉素耐药。本次金鱼发病是由嗜水气单胞菌感染引起,可选用强力霉素、麦迪霉素、复方新诺明、磺胺甲基异恶唑、阿奇霉素、恩诺沙星、诺氟沙星等多种药物进行防治。%Aeromonas hydrophila is one of the main pathogen of freshwater fish bacterial septicemia .The bacterium was isolated and identified from dead gold fish and drug sensitive tests were performed in order to provide references for the bacterial disease prevention and control in ornamental fish .A dominant bacteria strain was isolated from hepatopancreas of dead Carassius auratus and identified by artificial infection experiment ,cultural characteristics ,physical and chemical characters ,and 16S rRNA sequence analysis .The results showed that the strain was A .hydrophila .Homology of 16S rRNA of the isolated strain and other several A .hydrophila was more than 99 .3% .Drug sensitive test revealed that the isolated strain was highly sensitive to 21 kinds of drugs , including tetracyclines ,quinolones , sulfonamides , cefuroxime ,ceftazidimeand cefepime ,and resistant to penicillin G ,ampicillin ,amoxicillin ,cefalexin , lincomycin and medemycin . Results in this study showed that many antibiotics (such as doxycycline , midecamycin ,co‐trimoxazole ,sulfamethoxazole ,azithromycin ,enrofloxacin ,and norfloxaci) can be used to control and prevent bacterial disease caused by A .hydrophila in gold fish .

  16. Decreased prevalence of Plasmodium falciparum resistance markers to amodiaquine despite its wide scale use as ACT partner drug in Zanzibar

    Directory of Open Access Journals (Sweden)

    Fröberg Gabrielle

    2012-09-01

    Full Text Available Abstract Background Zanzibar has recently undergone a rapid decline in Plasmodium falciparum transmission following combined malaria control interventions with artemisinin-based combination therapy (ACT and integrated vector control. Artesunate-amodiaquine (ASAQ was implemented as first-line treatment for uncomplicated P. falciparum malaria in Zanzibar in 2003. Resistance to amodiaquine has been associated with the single nucleotide polymorphism (SNP alleles pfcrt 76T, pfmdr1 86Y, 184Y and 1246Y. An accumulation of these SNP alleles in the parasite population over time might threaten ASAQ efficacy. The aim of this study was to assess whether prolonged use of ASAQ as first-line anti-malarial treatment selects for P. falciparum SNPs associated with resistance to the ACT partner drug amodiaquine. Methods The individual as well as the combined SNP allele prevalence were compared in pre-treatment blood samples from patients with uncomplicated P. falciparum malaria enrolled in clinical trials conducted just prior to the introduction of ASAQ in 2002–2003 (n = 208 and seven years after wide scale use of ASAQ in 2010 (n = 122. Results There was a statistically significant decrease of pfcrt 76T (96–63%, pfmdr1 86Y (75–52%, 184Y (83–72%, 1246Y (28–16% and the most common haplotypes pfcrt/pfmdr1 TYYD (46–26% and TYYY (17–8%, while an increase of pfcrt/pfmdr1 KNFD (0.4–14% and KNYD (1–12%. Conclusions This is the first observation of a decreased prevalence of pfcrt 76T, pfmdr1 86Y, 184Y and 1246Y in an African setting after several years of extensive ASAQ use as first-line treatment for uncomplicated malaria. This may support sustained efficacy of ASAQ on Zanzibar, although it was unexpected considering that all these SNPs have previously been associated with amodiaquine resistance. The underlying factors of these results are unclear. Genetic dilution by imported P. falciparum parasites from mainland Tanzania, a de-selection by

  17. 368例宫颈分泌物支原体检测及药敏研究%368 cases of mycoplasma detection and drug sensitivity of cervical secretion

    Institute of Scientific and Technical Information of China (English)

    蔡晓红

    2015-01-01

    目的:结合临床资料研究女性宫颈分泌物支原体检测及药敏情况。方法:选择某院2013-2014年收治的368例女性患者为研究对象,提取其宫颈分泌物做支原体检测与药敏试验,对比解脲、人型支原体单项阳性率,以及具体的药敏检测结果,总结结论。结果:368例患者中,支原体感染178例,解脲、人型支原体单项阳性率分别为32.22%,11.3%,敏感率最高的是交沙霉素和强力霉素,比例为97.44%,86.19%。结论:女性宫颈分泌物出现支原体感染的几率很高,在做支原体检测和药敏测试时,需选择有效的抗菌药物,方能避免感染。%Objective: Combined with clinical data to investigate cervical secretions mycoplasma detection and drug susceptibility. Methods To choose a hospital treated 368 cases of female patients in 2013-2014 as the research object, and extract its cervical secretions do mycoplasma detection and drug sensitive test, comparison of ureaplasma, one type of single positive rate of mycoplasma, and drug susceptibility test of concrete results, summarizes the conclusion. Results 368 cases of patients, mycoplasma infection of 178 cases of ureaplasma, humanoid mycoplasma single positive rate were 32.22%, 11.3%, and the sensitive rate is the highest josamycin and doxycycline, the proportion is 97.44%, 86.19%. Conclusion Women cervical secretions in the mycoplasma infection is very high, doing mycoplasma detection and drug susceptibility test, need to select effective antimicrobial agents, in order to avoid infection.

  18. Hormone resistance in two MCF-7 breast cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis and increased sensitivity to cytotoxic drugs

    Directory of Open Access Journals (Sweden)

    Euphemia Yee Leung

    2014-09-01

    Full Text Available The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume and resistance to mTOR inhibition. Here we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, docetaxel and hydrogen peroxide. The mechanisms underlying these changes have not yet been characterized but may include a shift from glycolysis to mitochondrial respiration. If this phenotype is found in clinical hormone-resistant breast cancers, conventional cytotoxic therapy may be a preferred option for treatment.

  19. Radiation sensitivity of microorganisms adhering to the crude drug ''Bezoar Bovis'' and stability of its main components for γ-ray irradiation

    International Nuclear Information System (INIS)

    The sterilization dose (SD) of γ rays required for the microbial-contaminated crude drug ''Bezoar Bovis'' and the residual rates of its characteristic and effective components, bilirubin and some kinds of cholic acid, were studied experimentally. Samples of Bezoar Bovis made in America were used. The contamination level of the samples was 2.2 x 108 cells of bacteria and 6.0 x 105 spores of fungi per g specimen. The survival rate of these microorganisms showed nearly an exponential dependence on radiation dose. The decimal reduction doses (D10) for the bacteria and fungi were found to be 1.5 kGy and 1.1 kGy respectively. From these values, the dose required for attaining the contamination level provided by the administrative guidance (Bacteria, 3 cells/g; Fungi, 2 spores/g) were estimated to be 7.5 kGy and 4.3 kGy, respectively. The G-values for bilirubin, cholic acid and deoxycholic acid were calculated to be 13, 6 and 8, respectively. If the sterilization treatment is carried out with a dose less than 10 kGy on the specimen in a dry powder state, the reduction of the main components such as bilirubin and cholic acids by γ-ray irradiation is considered to be negligible. (author)

  20. Condition of mycoplasma infection of genitourinary tract and drug sensitive tests%泌尿生殖道支原体感染情况及药敏分析

    Institute of Scientific and Technical Information of China (English)

    刘宏; 李静; 王艳新; 张欣

    2011-01-01

    目的 了解本地区支原体在人类泌尿生殖系统的感染及药敏情况,指导临床合理用药.方法 采用支原体培养及药敏试剂盒对420例泌尿生殖道感染患者进行支原体培养和鉴定,并进行了12种常用抗生素的药敏试验.结果 420例泌尿生殖道感染患者中,支原体阳性205例,阳性率为48.8%,其中女性感染率(66.5%)高于男性感染率(30.2%)(P<0.05).解脲支原体(Uu)、人型支原体(Mh)、混合(Uu+Mh)感染率分别为29.8%、0.7%、18.3%;药敏结果显示支原体对美满霉素和强力霉素敏感性较高.结论 美满霉素和强力霉素可作为目前本地区治疗泌尿生殖道感染的首选药物.%Objective To understand the conditions of genitourinary system mycoplasma infection and drug sensitivity and provide rational administration for clinical practice. Methods The mycoplasma was cultured and identified by mycoplasma culture and identification kits in 420 cases with urinary genital tract mycoplasma infection and the sensitivity of mycoplasma to 12 antibacterials were tested. Results In 420 suspected cases,positive rate of mycoplasma was 48. 8% (205 cases) ,and the female infection rate(66. 5% ) was significantly higher than that of male(30.2% )(P<0.05). The Ureaplasma urealytic-um( Uu) ,Mycoplasma homins( Mh) and Uu + Mh infection rates were 29. 8% ,0. 7% , 18. 3% respectively. The sensitive tests showed that the mycoplasma had higher sensitivity to minocycline and deoxycycline. Conclusion The minocycline and deoxycycline can be used as the first choice drug for treatment genitourinary tract mycoplasma infection.

  1. Drug Facts

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    Full Text Available ... Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between Drug Abuse and HIV/AIDS Recovery & Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? ...

  2. Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans.

    Science.gov (United States)

    Schumacher, Fabian; Chakraborty, Sudipta; Kleuser, Burkhard; Gulbins, Erich; Schwerdtle, Tanja; Aschner, Michael; Bornhorst, Julia

    2015-11-01

    Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C. elegans to the monoamine oxidase B (MAO-B) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C. elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and

  3. 泌尿生殖道支原体属感染及药敏结果分析%Urogenital tract infection caused by Mycoplasma and analysis of drug sensitivity

    Institute of Scientific and Technical Information of China (English)

    刘家芹; 储新民; 马筱玲; 蒋法兴

    2014-01-01

    OBJECTIVE To analyze the infection status and antimicrobial susceptibility of Ureaplsma urealyticum (Uu) and Mycoplasma hominis (Mh) in urogenital tract ,and provide a basis for clinical rational selection of drugs .METHODS Using culture ,identification ,drug sensitivity integration kit ,Mycoplasma culture and anti‐microbial susceptibility test were performed on the urogenital tract specimens of 5 972 patients with suspected My‐coplasma infection ,statistical analysis was performed with SPSS10 .0 statistical software .RESULTS In the total of 5972 inspected specimens ,1641 cases were positive with a positive rate of 27 .5% .The positive rate of Uu ,and Mh was 78 .3% ,and 1 .7% respectively and the positive rate of Uu and Mh mixed infection was 20 .0% .The results of drug sensitive tests showed the drug resistances of Uu ,Uu+ Mh ,Mh infections were different for 13 kinds of antibacterials .The Uu was most resistant to lincocin (98 .0% ) ,then ciprofloxacin (81 .2% ) and norflox‐acin (70 .6% ) .Drug resistance rates of Uu + Mh to lincomycin ,ciprofloxacin ,norfloxacin ,azithromycin ,rox‐ithromycin ,clarithromycin ,and sparfloxacin were all over 70 .0% .CONCLUSION Mycoplasma infection in uro‐genital tract is mainly caused by Uu with a serious drug resistance ,and rational clinical medication should be used based on antimicrobial susceptibility test results .%目的:分析解脲脲支原体(Uu)和人支原体(Mh)在泌尿生殖道的感染状况及药物敏感性,为临床合理选用抗菌药物提供依据。方法采用支原体属培养、鉴定、药敏一体化试剂盒对5972例临床疑似患者送检的泌尿生殖道标本进行支原体属计数培养、鉴定及药物敏感试验,采用SPSS10.0进行统计分析。结果5972份标本中支原体属培养阳性1641例,阳性率27.5%,Uu、Mh、Uu+Mh的分布分别占78.3%、1.7%、20.0%;Uu、Mh、Uu+M h三类感染对13种抗菌药物的耐药性不同,U u

  4. Low-cost, high-sensitivity SERS nano-bio-chip for kinase profiling, drug monitoring and environmental detection: a translational platform technology

    Science.gov (United States)

    Chen, Yi; Liu, Logan

    2014-03-01

    The interaction of biomolecules and solid-state nanomaterials at the nano-bio interfaces is a long-lasting research topic in nanotechnology. Historically, fundamental problems, such as the electron transfer, energy transfer, and plasmonic interaction at the bio-nano interfaces, have been intensively studied, and revolutionary technologies, such as molecular electronics, peptide chips, nanoplasmonic sensors, have been created. With the combined effort of molecular dynamics simulation and surface-enhanced Raman spectroscopy, we studied the external electric field-induced conformation changes of dodecapeptide probes tethered to a nanostructured metallic surface. Through this study, we demonstrated a reversible manipulation of the biomolecule conformations as well as an in situ eletro-optical detection of the subnanometer conformational changes at the bio-nano interfaces. Based on the proof-of-concept established in this study, we further propose a novel nanophotonic peptide phosphorylation sensor for high-sensitive peptide kinase profiling. We have also demonstrated the same SERS nano-bio-chip can be used for environmental monitoring applications, such as detection of contaminants in drinking water at ultralow concentrates. The fabrication of this nanosensor is based on a single step, lithography-less nanomanufacturing process, which can produce hundreds of these chips in several minutes with nearly 100% yield and uniformity. Therefore, the demonstrated research can be readily translated into industrial mass productions.

  5. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... vomiting to life-threatening anaphylaxis . A true drug allergy is caused by a series of chemical steps ...

  6. A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosylcytosine (TAS106, sensitizes cells to radiation by suppressing BRCA2 expression

    Directory of Open Access Journals (Sweden)

    Fukushima Masakazu

    2011-07-01

    Full Text Available Abstract Background A novel anticancer drug 1-(3-C-ethynyl-β-D-ribo-pentofuranosylcytosine (ECyd, TAS106 has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs in tumor cells. Methods Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD, which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of γ-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and semi-quantitative RT-PCR analysis. Results In clonogenic survival assays, pretreatment of TAS106 showed radiosensitizing effects in various cell lines. TAS106 inhibited SLD repair and delayed the disappearance of γ-H2AX and 53BP1 foci, suggesting that DSB repair occurred in A549 cells. Western blot analysis demonstrated that TAS106 down-regulated the expression of BRCA2 and Rad51, which are known as keys among DNA repair proteins in the homologous recombination (HR pathway. Although a significant radiosensitizing effect of TAS106 was observed in the parental V79 cells, pretreatment with TAS106 did not induce any radiosensitizing effects in BRCA2-deficient V-C8 cells. Conclusions Our results indicate that TAS106 induces the down-regulation of BRCA2 and the subsequent abrogation of the HR pathway, leading to a radiosensitizing effect. Therefore, this study suggests that inhibition of the HR pathway may be useful to improve the therapeutic efficiency of

  7. Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

    DEFF Research Database (Denmark)

    Kavishe, Reginald A; Paulo, Petro; Kaaya, Robert D;

    2014-01-01

    recommended first-line drug in treatment of uncomplicated malaria. This study surveyed the distribution of the Plasmodium falciparum multidrug resistance protein-1 single nucleotide polymorphisms (SNPs) associated with increased parasite tolerance to ALu, in Tanzania. METHODS: A total of 687 Plasmodium......BACKGROUND: Resistance to anti-malarials is a major public health problem worldwide. After deployment of artemisinin-based combination therapy (ACT) there have been reports of reduced sensitivity to ACT by malarial parasites in South-East Asia. In Tanzania, artemether-lumefantrine (ALu) is the...... in all regions, ranging from 17% - 26%. CONCLUSION: This is the first country-wide survey on Pfmdr1 mutations associated with ACT resistance. Distribution of individual Pfmdr1 mutations at codons 86, 184 and 1246 varies throughout Tanzanian regions. There is a general homogeneity in distribution of...

  8. Isolation and Identification of Swine Streptococcus suis Pathogeny and Its Drug Sensitive Test%猪链球菌病病原的分离鉴定及药敏试验

    Institute of Scientific and Technical Information of China (English)

    范国英; 杨雪峰; 刘俊伟; 陈俊杰

    2012-01-01

    Based on the clinical samples of suspected streptococcic pigs from a pig farm of Xinxiang, the pathogens were I-dentified after isolation and culture, and then were used to do biochemistry identification, animal test and drug sensitive test. The results showed that the isolated pathogens were a -hemolytic Streptococcus suis. And it was hypersensitive to Bawangjinzhen, rifampicin and saratiofur, and high sensitive to tilmicosin, cefazolin sodium, ampicillin sodium, zhu kang-II.%采集疑似猪链球菌病的病猪病料,经病原分离培养、生化鉴定、动物试验和药教试验,结果表明所分离的细菌为α溶血链球菌(α-hemolytic streptococci.),该菌对霸王金针、利福平、沙拉噻呋极敏,对替米考星、头孢唑啉钠、氨苄西林钠、猪康2号为高敏.

  9. Mycoplasma infection among patients with abnormal pregnancy and drug sensitivity analysis%不良妊娠患者支原体感染及药敏的分析

    Institute of Scientific and Technical Information of China (English)

    赵秋彦; 盘宗敏; 梁国泉; 陈笑娟

    2015-01-01

    Objective To analyze the infection of mycoplasma hominis (Mh) and ureaplasma urealytium (Uu) and drug sensitivity of abnormal pregnant patients from Nansha district in Guangzhou city, so as to offer reference for clinical rational drug use. Methods During January 2011 to December 2013, 750 cases, including 245 cases of sterility, 266 cases of habitual abortion and 239 cases of premature, were randomized sampling into case group. Another 750 normal pregnant women were pair matched into control group according to age, occupation, cultural degree and nutrition condition. Mh and Uu culture and drug sensitivity test were done among 526 samples. Results The dete