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Sample records for evaluate anti-malarial drug

  1. Evaluation of bioluminescence-based assays of anti-malarial drug activity

    PubMed Central

    2013-01-01

    Background Transgenic Plasmodium falciparum expressing luciferase offers an attractive bioluminescence-based assay platform for the investigation of the pharmacological properties of anti-malarial drugs. Here a side-by-side comparison of bioluminescence and fluorescence-based assays, utilizing a luciferase reporter cassette that confers a strong temporal pattern of luciferase expression during the S-phase of intraerythrocytic development, is reported. Methods Key assay parameters for a range of commercially available luminogenic substrates are determined and compared to those measured using a Malaria Sybr Green I fluorescence assay. In addition, the short-term temporal effects of anti-malarial compounds are evaluated using both bioluminescent and fluorescent assay platforms. Results The Z’, % coefficient of variation and 50% inhibition concentrations are essentially the same for bioluminescent and fluorescent assays in transgenic parasites generated in both chloroquine-sensitive and -resistant genetic backgrounds. Bioluminescent assays, irrespective of the luminogenic agent employed, do, however, offer significantly enhanced signal-to-noise ratios. Moreover, the bioluminescent assay is more dynamic in terms of determining temporal effects immediately following drug perturbation. Conclusion This study suggests that opportunities for bioluminescence-based assays lie not in the measurement of 50% inhibition concentrations, where the cheaper fluorescence assay performs excellently and is not restricted by the need to genetically modify the parasite clone under investigation. Instead, assays that use the dynamic response of the luciferase reporter for semi-automated screening of additional pharmacological properties, such as relative rate-of-kill and lethal dose estimation, are a more attractive development opportunity. PMID:23394077

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

    PubMed Central

    Mukherjee, Avinaba; Sadhukhan, Gobinda Chandra

    2016-01-01

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

  3. Artemisinin anti-malarial drugs in China.

    PubMed

    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

  4. Artemisinin anti-malarial drugs in China

    PubMed Central

    Guo, Zongru

    2016-01-01

    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

  5. Evaluation of anti-malarial drugs’ use in Fitche Hospital, North Shoa, Oromia Region, Ethiopia

    PubMed Central

    Getachew, Rosa; Amelo, Wote; Bobasa, Eshetu Mulisa

    2016-01-01

    Objective: Retrospective evaluation of anti-malarial drugs’ use in Fitche Hospital, North Shoa, Oromia Region, Ethiopia. Methods: Retrospective cross-sectional study design was conducted using selected patients cards of 1-year (January 2012–January 2013 G.C) with anti-malarial agents from January 18 to 30, 2013. The sample size was calculated by using Joint Commission on the Accreditation of Health care Organization criteria and sampling was done by using a systematic random sampling technique. Results: One hundred and twenty-five patient cards with anti-malarial drugs were reviewed of which 32.8%, 21.6%, 15.2% belongs to age range of 20–29, 10–19, and 30–39, respectively. Chloroquine prescription accounts for 50.4% from total anti-malarial drugs. 71.2% and 78.4% of patients received antibiotics and analgesics, respectively, with anti-malarial drugs. 77.6% of drugs were prescribed by generic name while the brand name was 22.39%. Conclusions: The study done in Fitche Hospital revealed that the use of anti-malarial agent was not in complete agreement with the current guideline of Ethiopia despite good practice. PMID:26957867

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

    2010-01-01

    Background Interventions to reverse trends in malaria-related morbidity and mortality in Kenya focus on preventive strategies and drug efficacy. However, the pattern of use of anti-malarials in malaria-endemic populations, such as in western Kenya, is still poorly understood. It is critical to understand the patterns of anti-malarial drug use to ascertain that the currently applied new combination therapy to malaria treatment, will achieve sustained cure rates and protection against parasite resistance. Therefore, this cross-sectional study was designed to determine the patterns of use of anti-malarial drugs in households (n = 397) in peri-urban location of Manyatta-B sub-location in Kisumu in western Kenya. Methods Household factors, associated with the pattern of anti-malarials use, were evaluated. Using clusters, questionnaire was administered to a particular household member who had the most recent malaria episode (within <2 weeks) and used an anti-malarial for cure. Mothers/caretakers provided information for children aged <13 years. Results Stratification of the type of anti-malarial drugs taken revealed that 37.0% used sulphadoxine/pyrimethamine (SP), 32.0% artemisinin-based combined therapy (ACT), 11.1% anti-pyretics, 7.3% chloroquine (CQ), 7.1% quinine, 2.5% amodiaquine (AQ), while 3.0% used others which were perceived as anti-malarials (cough syrups and antibiotics). In a regression model, it was demonstrated that age (P = 0.050), household size (P = 0.047), household head (P = 0.049), household source of income (P = 0.015), monthly income (P = 0.020), duration of use (P = 0.029), dosage of drugs taken (P = 0.036), and source of drugs (P = 0.005) significantly influenced anti-malarial drug use. Overall, 38.8% of respondents used drugs as recommended by the Ministry of Health. Conclusion This study demonstrates that consumers require access to correct and comprehensible information associated with use of drugs, including self-prescription. There is

  8. Current issues for anti-malarial drugs to control P. falciparum malaria.

    PubMed

    Schellenberg, D; Abdulla, S; Roper, C

    2006-03-01

    Successful malaria control depends heavily on efficacious anti-malarial drugs for the treatment of malaria. Artesunate-containing Combination Treatments (ACT) are increasingly recommended as first line malaria treatment in endemic countries, but implementation of this recommendation is limited by the small number of available and affordable co-formulated anti-malarial drugs. In recent years Intermittent Preventive Treatment has been recommended for malaria control in pregnancy and has been shown to be of potential public health importance in the prevention of malaria and anaemia in children. The use of drugs for malaria treatment or prevention is associated with the development of resistance and recent advances in molecular biology facilitate the evaluation of the impact on drug resistance of new drug-based strategies. This review concentrates on the challenges surrounding the use of ACT, the current understanding of IPT in infants and the use of molecular approaches to enhance our understanding of the effects of interventions on the spread of drug resistance. PMID:16515515

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

    PubMed

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

    2015-01-01

    Standard anti-malarial drug efficacy and drug resistance assessments neglect the gametocyte parameters in their protocols. With the spread of drug resistance and the absence of clinically proven vaccines, the use of gametocytocidal drugs or drug combinations with transmission-blocking activity is a high priority for malaria control and elimination. However, the limited repertoire of gametocytocidal drugs and induction of gametocytogenesis after treatment with certain anti-malarial drugs necessitate both regular monitoring of gametocytocidal activities of anti-malarial drugs in clinical use and the effectiveness of candidate gametocytocidal agents. Therefore, updating current protocols of anti-malarial drug efficacy is needed to reflect the effects of anti-malarial drugs or drug combinations on gametocyte carriage and gametocyte density along with asexual parasite density. Developing protocols of anti-malarial drug efficacy that include gametocyte parameters related to both microscopic and submicroscopic gametocytaemias is important if drugs or drug combinations are to be strategically used in transmission-blocking interventions in the context of malaria elimination. The present piece of opinion highlights the challenges in gametocyte detection and follow-up and discuss the need for including the gametocyte parameter in anti-malarial efficacy studies. PMID:26481312

  10. CRIMALDDI: a prioritized research agenda to expedite the discovery of new anti-malarial drugs

    PubMed Central

    2013-01-01

    The CRIMALDDI Consortium has been a three-year project funded by the EU Framework Seven Programme. It aimed to develop a prioritized set of recommendations to speed up anti-malarial drug discovery research and contribute to the setting of the global research agenda. It has attempted to align thinking on the high priority issues and then to develop action plans and strategies to address these issues. Through a series of facilitated and interactive workshops, it has concluded that these priorities can be grouped under five key themes: attacking artemisinin resistance; creating and sharing community resources; delivering enabling technologies; exploiting high throughput screening hits quickly; and, identifying novel targets. Recommendations have been prioritized into one of four levels: quick wins; removing key roadblocks to future progress; speeding-up drug discovery; and, nice to have (but not essential). Use of this prioritization allows efforts and resources to be focused on the lines of work that will contribute most to expediting anti-malarial drug discovery. Estimates of the time and finances required to implement the recommendations have also been made, along with indications of when recommendations within each theme will make an impact. All of this has been collected into an indicative roadmap that, it is hoped, will guide decisions about the direction and focus of European anti-malarial drug discovery research and contribute to the setting of the global research agenda. PMID:24191947

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

    PubMed Central

    2011-01-01

    Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance. PMID:21609473

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    2010-01-01

    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. PMID:20626844

  14. Stated preferences for anti-malarial drug characteristics in Zomba, a malaria endemic area of Malawi

    PubMed Central

    2014-01-01

    Background The evidence on determinants of individuals’ choices for anti-malarial drug treatments is scarce. This study sought to measure the strength of preference for adult antimalarial drug treatment attributes of heads of urban, rural and peri-urban households in a resource-limited malaria-endemic area of sub-Saharan Africa. Methods Discrete choice experiments were conducted with 508 heads of household interviewed face-to-face for a household population survey of health-seeking behavior in Zomba District, Malawi. The interviews were held in Chichewa and the choice experiment questions were presented with cartoon aids. The anti-malarial drug attributes included in the stated preference experiment were: speed of fever resolution, side effects (pruritus) risk, protection (duration of prophylactic effect), price, duration of treatment course and recommendation by a health professional. Sixteen treatment profiles from a fractional factorial design by orthogonal array were paired into choice scenarios, and scenarios were randomly assigned to participants so that each participant was presented with a series of eight pairwise choice scenarios. Respondents had the option to state indifference between the two profiles or decline to choose. Data were analysed in a mixed logit model, with normally distributed coefficients for all six attributes. Results The sex ratio was balanced in urban areas, whereas 63% of participants in rural areas were male. The proportion of individuals with no education was considerably higher in the rural group (25%) than in the urban (5%) and peri-urban (6%) groups. All attributes investigated had the expected influence, and traded-off in most respondents’ choices. There were heterogeneous effects of price, pruritus risk, treatment recommendation by a professional, and duration of prophylaxis across respondents, only partly explained by their differences in education, household per capita expenditure, sex and age. Individuals´ demand

  15. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives.

    PubMed

    Nevin, Remington L; Croft, Ashley M

    2016-01-01

    The modern medical literature implicates malaria, and particularly the potentially fatal form of cerebral malaria, with a risk of neurocognitive impairment. Yet historically, even milder forms of malaria were associated in the literature with a broad range of psychiatric effects, including disorders of personality, mood, memory, attention, thought, and behaviour. In this article, the history of psychiatric effects attributed to malaria and post-malaria syndromes is reviewed, and insights from the historical practice of malariotherapy in contributing to understanding of these effects are considered. This review concludes with a discussion of the potentially confounding role of the adverse effects of anti-malarial drugs, particularly of the quinoline class, in the unique attribution of certain psychiatric effects to malaria, and of the need for a critical reevaluation of the literature in light of emerging evidence of the chronic nature of these adverse drug effects. PMID:27335053

  16. Policy options for deploying anti-malarial drugs in endemic countries: a population genetics approach

    PubMed Central

    2012-01-01

    Background Anti-malarial drugs are constantly exposed to the threat of evolving drug resistance so good stewardship of existing therapy is an essential component of public health policy. However, the widespread availability of numerous different drugs through informal providers could undermine official drug deployment policies. A policy of multiple first-line therapy (MFT) is compared with the conventional policy of sequential drug deployment, i.e., where one drug is used until resistance evolves and then replaced by the next drug in the sequence. Methods Population genetic models of drug resistance are used to make the comparison; this methodology explicitly tracks the genetics of drug resistance (including, importantly, recombination in the sexual stage, intrahost dynamics, and direction of linkage disequilibrium). Results A policy of MFT outlasts sequential application providing drug usages are low to moderate, and appears not to drive widespread multi-drug resistance. Inadequate dosing is an even more potent driver of drug resistance than the MFT/sequential policy decision. Conclusions The provision of MFT as a deliberate policy can be encouraged provided overall treatment rates are low or moderate (less than around half of malaria infections are treated) and the ad hoc provision of MFT through the private sector may be tolerated. This must be fully supported by education to ensure people take adequate doses of each of the drugs. PMID:23244624

  17. A SYBR Green 1-based in vitro test of susceptibility of Ghanaian Plasmodium falciparum clinical isolates to a panel of anti-malarial drugs

    PubMed Central

    2013-01-01

    Background Based on report of declining efficacy of chloroquine, Ghana shifted to the use of artemisinin-based combination therapy (ACT) in 2005 as the first-line anti-malarial drug. Since then, there has not been any major evaluation of the efficacy of anti-malarial drugs in Ghana in vitro. The sensitivity of Ghanaian Plasmodium falciparum isolates to anti-malarial drugs was, therefore, assessed and the data compared with that obtained prior to the change in the malaria treatment policy. Methods A SYBR Green 1 fluorescent-based in vitro drug sensitivity assay was used to assess the susceptibility of clinical isolates of P. falciparum to a panel of 12 anti-malarial drugs in three distinct eco-epidemiological zones in Ghana. The isolates were obtained from children visiting health facilities in sentinel sites located in Hohoe, Navrongo and Cape Coast municipalities. The concentration of anti-malarial drug inhibiting parasite growth by 50% (IC50) for each drug was estimated using the online program, ICEstimator. Results Pooled results from all the sentinel sites indicated geometric mean IC50 values of 1.60, 3.80, 4.00, 4.56, 5.20, 6.11, 10.12, 28.32, 31.56, 93.60, 107.20, and 8952.50 nM for atovaquone, artesunate, dihydroartemisin, artemether, lumefantrine, amodiaquine, mefloquine, piperaquine, chloroquine, tafenoquine, quinine, and doxycycline, respectively. With reference to the literature threshold value indicative of resistance, the parasites showed resistance to all the test drugs except the artemisinin derivatives, atovaquone and to a lesser extent, lumefantrine. There was nearly a two-fold decrease in the IC50 value determined for chloroquine in this study compared to that determined in 2004 (57.56 nM). This observation is important, since it suggests a significant improvement in the efficacy of chloroquine, probably as a direct consequence of reduced drug pressure after cessation of its use. Compared to that measured prior to the change in treatment policy

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

    PubMed Central

    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 local isolates obtained from the Centre de santé Elizabeth Diouf (Médina, Dakar, Senegal). Methods The prevalence of genetic polymorphisms in genes associated with anti-malarial drug resistance, i.e., pfcrt, pfdhfr, pfdhps and pfmdr1, were evaluated for a panel of 165 isolates collected from patients recruited from 17 August 2010 to 6 January 2011. The malaria isolates were assessed for susceptibility to chloroquine (CQ); quinine (QN); monodesethylamodiaquine (MDAQ), the active metabolite of amodiaquine; mefloquine (MQ); lumefantrine (LMF); dihydroartemisinin (DHA), the active metabolite of artemisinin derivatives; and doxycycline (DOX) using the Plasmodium lactate dehydrogenase (pLDH) ELISA. Results The prevalence of the in vitro resistant isolates, or isolates with reduced susceptibility, was 62.1% for MQ, 24.2% for CQ, 10.3% for DOX, 11.8% MDAQ, 9.7% for QN, 2.9% for LMF and 0% for DHA. The Pfcrt 76T mutation was identified in 43.6% of the samples. The pfmdr1 86Y, 184F and 1246Y mutations were found in 16.2%, 50.0% and 1.6% of the samples, respectively. The pfdhfr 108N, 51I and 59R mutations were identified in 81.9%, 77.4% and 79.4% of the samples, respectively. The double mutant (108N and 51I) was detected in 75.5% of the isolates, and the triple mutant (108N, 51I and 59R) was detected in 73.6% of the isolates. The pfdhps 437G, 436A and 613S mutations were found in 54.4%, 38.6% and 1.2% of the samples, respectively. There was only one double mutant, 437G and 540E, and one

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

    PubMed Central

    2012-01-01

    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.e. the infection became

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

    PubMed Central

    2014-01-01

    Background The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Results Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia (‘Ejirin’) Diospyros monbuttensis (‘Egun eja’) and Morinda lucida (‘Oruwo’) was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2nM) while the lowest was obtained from M. lucida (IC50 =25nM). Conclusions Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs. PMID:24555525

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

    PubMed Central

    Onwujekwe, Obinna; Kaur, Harparkash; Dike, Nkem; Shu, Elvis; Uzochukwu, Benjamin; Hanson, Kara; Okoye, Viola; Okonkwo, Paul

    2009-01-01

    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. PMID:19208221

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

    2011-01-01

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

  4. The potential of anti-malarial compounds derived from African medicinal plants, part II: a pharmacological evaluation of non-alkaloids and non-terpenoids

    PubMed Central

    2014-01-01

    Malaria is currently a public health concern in many countries in the world due to various factors which are not yet under check. Drug discovery projects targeting malaria often resort to natural sources in the search for lead compounds. A survey of the literature has led to a summary of the major findings regarding plant-derived compounds from African flora, which have shown anti-malarial/antiplasmodial activities, tested by in vitro and in vivo assays. Considerations have been given to compounds with activities ranging from “very active” to “weakly active”, leading to >500 chemical structures, mainly alkaloids, terpenoids, flavonoids, coumarins, phenolics, polyacetylenes, xanthones, quinones, steroids and lignans. However, only the compounds that showed anti-malarial activity, from “very active” to “moderately active”, are discussed in this review. PMID:24602358

  5. The potential of anti-malarial compounds derived from African medicinal plants, part I: a pharmacological evaluation of alkaloids and terpenoids

    PubMed Central

    2013-01-01

    Traditional medicine caters for about 80% of the health care needs of many rural populations around the world, especially in developing countries. In addition, plant-derived compounds have played key roles in drug discovery. Malaria is currently a public health concern in many countries in the world due to factors such as chemotherapy faced by resistance, poor hygienic conditions, poorly managed vector control programmes and no approved vaccines. In this review, an attempt has been made to assess the value of African medicinal plants for drug discovery by discussing the anti-malarial virtue of the derived phytochemicals that have been tested by in vitro and in vivo assays. This survey was focused on pure compounds derived from African flora which have exhibited anti-malarial properties with activities ranging from “very active” to “weakly active”. However, only the compounds which showed anti-malarial activities from “very active” to “moderately active” are discussed in this review. The activity of 278 compounds, mainly alkaloids, terpenoids, flavonoids, coumarines, phenolics, polyacetylenes, xanthones, quinones, steroids, and lignans have been discussed. The first part of this review series covers the activity of 171 compounds belonging to the alkaloid and terpenoid classes. Data available in the literature indicated that African flora hold an enormous potential for the development of phytomedicines for malaria. PMID:24330395

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

    2011-01-01

    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. PMID:21535894

  9. Development and evaluation of anti-malarial bio-conjugates: artesunate-loaded nanoerythrosomes.

    PubMed

    Agnihotri, Jaya; Saraf, Shubhini; Singh, Sobhna; Bigoniya, Papiya

    2015-10-01

    Biodegradable cellular carrier has desired properties for achieving effective long-term controlled release of drugs having short half life. To reduce the undesired effects of drug, advanced drug delivery systems are needed which are based on specific cell targeting module. Artesunate (ART) conjugation on nanoerythrosomes (NE) can have controlled delivery to avoid drug leakage, increase the stability, and reduce cost and toxicities. In this study nanosized lipoprotein membrane vesicles bearing ART were prepared by extrusion method. Developed ART-NE conjugate formulations were optimized on the basis of vesicle morphology, size and size distribution, polydispersity index, integrity of membrane, loaded drug concentration, drug leakage, effect of temperature and viscosity, syringeability, in vitro release profile and in vivo plasma concentration estimation studies. Fourier transform infrared (FTIR) spectroscopy reveals that lipid chain order of RBCs are insignificantly affected in moderate conditions after ART loading. The formulated ART-NE carrier revealed non aggregated, uniformly sized particles with smooth surfaces. The maximum drug loading was found to be 25.20 ± 1.3 μg/ml. ART-NE formulation was best fit for zero order kinetics and was found to be capable of controlled release of drug for 8 hrs. ART-NE formulation showed good redispersibility with desirable properties for parenteral administration. Formulation was stable when subjected to stress by centrifugal force of 7500 rpm and could bear turbulence shock of 15 passes from hypodermic needle of size 23 gauges. The ART-NE formulation administered intravenously showed higher plasma concentration compared to free drug signifying not only controlled release but higher rate of in vivo release. The developed formulation exhibited zero order release profile as per kinetic study analysis suggesting the suitability of carrier for the sustained and targeted delivery of ART. The developed ART-NE drug delivery system

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

    PubMed Central

    2011-01-01

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

  11. The effect of E. coli STa enterotoxin on the absorption of weakly dissociable anti-malarial drugs from rat intestine in vivo.

    PubMed Central

    Rawlings, J. M.; Lynch, J.; Lucas, M. L.

    1991-01-01

    1. The effect of E. coli heat stable (STa) enterotoxin on the absorption of radiolabelled anti-malarial weak bases and their appearance in peripheral blood was assessed in vivo by a recirculation procedure in rat intestinal loops. 2. Enterotoxin increased the jejunal disappearance of quinine (P less than 0.05), trimethoprim (P less than 0.05), proguanil (P less than 0.05) and chloroquine (P less than 0.001) and left pyrimethamine disappearance unaltered. Peripheral blood levels of trimethoprim (P less than 0.02) and proguanil (P less than 0.05) were higher after STa exposure. 3. In the ileum, enterotoxin increased the luminal disappearance (P less than 0.05) and peripheral blood appearance (P less than 0.001) of chloroquine. The luminal disappearance rate of trimethoprim was reduced (P less than 0.05) and that of pyrimethamine unchanged. 4. The increased jejunal absorption of the anti-malarial drugs occurred despite STa causing a reduction in the amount of net fluid absorption. It seems likely that the enhanced absorption with STa exposure is related to the effect of STa on the microclimate pH. An elevation in the microclimate pH would increase the amount of undissociated weak base available for non-ionic diffusion. 5. The favourable elevation of microclimate pH by STa seemed to be outweighted by the reduced fluid absorption in the ileum. Only chloroquine still showed enhanced absorption in the ileum and this may have been because unlike the other antimalarial drugs, chloroquine has two dissociable groups likely to be affected by the mucosal surface pH changes. PMID:1878755

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

    PubMed Central

    2012-01-01

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

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

    PubMed Central

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

    2008-01-01

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

  14. Repositioning: the fast track to new anti-malarial medicines?

    PubMed Central

    2014-01-01

    Background Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. Methods Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [3H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4’,6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low μM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D70087/N9 huSCID ‘humanized’ mouse model. Results Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally

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

    PubMed Central

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

    2012-01-01

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

  16. Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis

    PubMed Central

    Lim, Sharon; Lee, Se Jeong; Lim, Joung Eun; Nam, Do-Hyun; Joo, Kyeung Min; Jeong, Byong Chang; Jeon, Seong Soo; Choi, Han Yong; Lee, Hye Won

    2015-01-01

    Despite advances in the development of molecularly targeted therapies, metastatic renal cell carcinoma (RCC) is still incurable. Artesunate (ART), a well-known anti-malarial drug with low toxicity, exhibits highly selective anti-tumor actions against various tumors through generation of cytotoxic carbon-centered free radical in the presence of free iron. However, the therapeutic efficacy of ART against metastatic RCC has not yet been fully elucidated. In the analysis on a dataset from The Cancer Genome Atlas (TCGA) (n = 469) and a tissue microarray set from Samsung Medical Center (n = 119) from a cohort of patients with clear cell RCC (ccRCC), up-regulation of transferrin receptor 1 (TfR1), which is a well-known predictive marker for ART, was correlated with the presence of distant metastasis and an unfavorable prognosis. Moreover, ART exerted potent selective cytotoxicity against human RCC cell lines (Caki-1, 786-O, and SN12C-GFP-SRLu2) and sensitized these cells to sorafenib in vitro, and the extent of ART cytotoxicity correlated with TfR1 expression. ART-mediated growth inhibition of human RCC cell lines was shown to result from the induction of cell cycle arrest at the G2/M phase and oncosis-like cell death. Furthermore, ART inhibited cell clonogenicity and invasion of human RCC cells and anti-angiogenic effects in vitro in a dose-dependent manner. Consistent with these in vitro data, anti-tumor, anti-metastatic and anti-angiogenic effects of ART were also validated in human 786-O xenografts. Taken together, ART is a promising novel candidate for treating human RCC, either alone or in combination with other therapies. PMID:26426994

  17. Ex vivo anti-malarial drugs sensitivity profile of Plasmodium falciparum field isolates from Burkina Faso five years after the national policy change

    PubMed Central

    2014-01-01

    Background The recent reports on the decreasing susceptibility of Plasmodium falciparum to artemisinin derivatives along the Thailand and Myanmar border are worrying. Indeed it may spread to India and then Africa, repeating the same pattern observed for chloroquine resistance. Therefore, it is essential to start monitoring P. falciparum sensitivity to artemisinin derivatives and its partner drugs in Africa. Efficacy of AL and ASAQ were tested by carrying out an in vivo drug efficacy test, with an ex vivo study against six anti-malarial drugs nested into it. Results of the latter are reported here. Methods Plasmodium falciparum ex-vivo susceptibility to chloroquine (CQ), quinine (Q), lumefantrine (Lum), monodesethylamodiaquine (MDA), piperaquine (PPQ) and dihydroartemisinin (DHA) was investigated in children (6 months – 15 years) with a parasitaemia of at least ≥4,000/μl. The modified isotopic microtest technique was used. The results of cellular proliferation were analysed using ICEstimator software to determine the 50% inhibitory concentration (IC50) values. Results DHA was the most potent among the 6 drugs tested, with IC50 values ranging from 0.8 nM to 0.9 nM (Geometric mean IC50 = 0.8 nM; 95% CI [0.8 - 0.9]). High IC50 values ranged between 0.8 nM to 166.1 nM were reported for lumefantrine (Geometric mean IC50 = 25.1 nM; 95% CI [22.4 - 28.2]). MDA and Q IC50s were significantly higher in CQ-resistant than in CQ-sensitive isolates (P = 0.0001). However, the opposite occurred for Lum and DHA (P < 0.001). No difference was observed for PPQ. Conclusion Artemisinin derivatives are still very efficacious in Burkina Faso and DHA-PPQ seems a valuable alternative ACT. The high lumefantrine IC50 found in this study is worrying as it may indicate a decreasing efficacy of one of the first-line treatments. This should be further investigated and monitored over time with large in vivo and ex vivo studies that will include also plasma drug measurements

  18. Anti-malarial property of steroidal alkaloid conessine isolated from the bark of Holarrhena antidysenterica

    PubMed Central

    2013-01-01

    Background In the face of chronic and emerging resistance of parasites to currently available drugs and constant need for new anti-malarials, natural plant products have been the bastion of anti-malarials for thousands of years. Moreover natural plant products and their derivatives have traditionally been a common source of drugs, and represent more than 30% of the current pharmaceutical market. The present study shows evaluation of anti-malarial effects of compound conessine isolated from plant Holarrhena antidysenterica frequently used against malaria in the Garhwal region of north-west Himalaya. Methods In vitro anti-plasmodial activity of compound was assessed using schizont maturation and parasite lactate dehydrogenase (pLDH) assay. Cytotoxic activities of the examined compound were determined on L-6 cells of rat skeletal muscle myoblast. The four-day test for anti-malarial activity against a chloroquine-sensitive Plasmodium berghei NK65 strain in BALB/c mice was used for monitoring in vivo activity of compound. In liver and kidney function test, the activity of alkaline phosphatase (ALP) was examined by p-NPP method, bilirubin by Jendrassik and Grof method. The urea percentage was determined by modified Berthelot method and creatinine by alkaline picrate method in serum of mice using ENZOPAK/CHEMPAK reagent kits. Results Compound conessine showed in vitro anti-plasmodial activity with its IC50 value 1.9 μg/ml and 1.3 μg/ml using schizont maturation and pLDH assay respectively. The compound showed cytotoxity IC50= 14 μg/ml against L6 cells of rat skeletal muscle myoblast. The isolated compound from plant H. antidysenterica significantly reduced parasitaemia (at 10 mg/kg exhibited 88.95% parasite inhibition) in P. berghei-infected mice. Due to slightly toxic nature (cytotoxicity = 14), biochemical analysis (liver and kidney function test) of the serum from mice after administration of conessine were also observed. Conclusion The present investigation

  19. Community management of anti-malarials in Africa and iatrogenic risk.

    PubMed

    Orostegui, Lupé; Balu, Laurent; Chevret, Laurent; Habes, Dalila; Pussard, Eric

    2011-06-01

    Distribution of anti-malarials at the community level is one of the interventions recommended to reduce mortality from febrile illnesses. Inappropriate treatment of fever with anti-malarials may result in missed diagnosis and delays in appropriate treatments including consideration of other illnesses than malaria. We report the case of an 8-year-old black girl receiving prophylaxis with sulfadoxine-pyrimethamine from the caretaker of the community during her holidays in Ivory Coast. A persistent fever suspected to be due to malaria was treated inappropriately with atovaquone-proguanil and then with sulfadoxine-pyrimethamine again. Cumulative toxicity of anti-malarials leads to irreversible hepatic damages requiring hepatic transplantation. Community caretakers must be aware of the potential side effects and the contraindications of anti-malarials. Early identification of drug-induced toxicity and immediate discontinuation of the drug are the more effective tools to limit the progression of tissue damage. PMID:20807830

  20. 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

    PubMed Central

    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 demographic surveillance systems. Methods Active and passive surveillance methods were used to identify ADR from sulphadoxine-pyrimethamine (SP) and artemisinin (AS) use. ADR were identified by trained clinicians at health facilities (passive surveillance) and through cross-sectional household surveys (active surveillance). Potential cases were followed up at home, where a complete history and physical examination was undertaken, and household cost data collected. Patients were classified as having ‘possible’ or ‘probable’ ADR by a physician. Results A total of 95 suspected ADR were identified during a two-year period, of which 79 were traced, and 67 reported use of SP and/or AS prior to ADR onset. Thirty-four cases were classified as ‘probable’ and 33 as ‘possible’ ADRs. Most (53) cases were associated with SP monotherapy, 13 with the AS/SP combination (available in one of the two areas only), and one with AS monotherapy. Annual ADR incidence per 100,000 exposures was estimated based on ‘probable’ ADR only at 5.6 for AS/SP in combination, and 25.0 and 11.6 for SP monotherapy. Median ADR treatment costs per episode ranged from US$2.23 for those making a single provider visit to US$146.93 for patients with four visits. Seventy-three per cent of patients used out-of-pocket funds or sold part of their farm harvests to pay for treatment, and 19% borrowed money. Conclusion Both passive and active surveillance methods proved feasible methods for anti-malarial ADR

  1. Biological activities of nitidine, a potential anti-malarial lead compound

    PubMed Central

    2012-01-01

    Background Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action. Methods In this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated. Results Nitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine. Conclusion Nitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase

  2. Formulation, characterization and anti-malarial activity of homolipid-based artemether microparticles.

    PubMed

    Agubata, Chukwuma O; Nzekwe, Ifeanyi T; Attama, Anthony A; Mueller-Goymann, Christel C; Onunkwo, Godswill C

    2015-01-15

    The anti-malarial activity of artemether is dependent on its bioavailability. The purpose of the research is to improve the solubility, bioavailability and therapeutic efficacy of lipophilic artemether using homolipid-based microparticles. Irvingia fat was extracted from Irvingia gabonensis var. excelsa (Irvingia wombolu), and its lipid matrices (LM) with Phospholipon(®) 90G (P90G) were characterized by differential scanning calorimetry (DSC) and wide angle X-ray diffraction (WAXD). Solid lipid microparticles were formulated, characterized, filled and compressed into capsules and tablets, respectively, and drug release studied. In vivo anti-plasmodial activity of artemether SLMs was evaluated in mice. The crystallinity of the phyto-lipid reduced in the presence of P90G, which was integrated into the irvingia fat crystal lattice. SLM dispersions with 3:1 irvingia fat/P90G composition showed higher diffusion and permeability through dialysis membrane while lower proportion of P90G (9:1 LM) favored increased dissolution rate of artemether from capsules (p<0.05). Significant increase (p<0.05) in % plasmodial growth inhibition and reduced parasitemia were observed in mice administered with the SLM dispersions compared with the controls. Therefore, SLMs prepared with composite mixtures of a homolipid and P90G could be used to improve the solubility, dissolution, permeability, bioavailability and anti-malarial efficacy of artemether. PMID:25448583

  3. Do ethnobotanical and laboratory data predict clinical safety and efficacy of anti-malarial plants?

    PubMed Central

    2011-01-01

    Background Over 1200 plant species are reported in ethnobotanical studies for the treatment of malaria and fevers, so it is important to prioritize plants for further development of anti-malarials. Methods The “RITAM score” was designed to combine information from systematic literature searches of published ethnobotanical studies and laboratory pharmacological studies of efficacy and safety, in order to prioritize plants for further research. It was evaluated by correlating it with the results of clinical trials. Results and discussion The laboratory efficacy score correlated with clinical parasite clearance (rs=0.7). The ethnobotanical component correlated weakly with clinical symptom clearance but not with parasite clearance. The safety component was difficult to validate as all plants entering clinical trials were generally considered safe, so there was no clinical data on toxic plants. Conclusion The RITAM score (especially the efficacy and safety components) can be used as part of the selection process for prioritising plants for further research as anti-malarial drug candidates. The validation in this study was limited by the very small number of available clinical studies, and the heterogeneity of patients included. PMID:21411018

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

    PubMed

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

    2016-01-01

    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

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

    PubMed Central

    2011-01-01

    used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

    2011-01-01

    A “reverse pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “reverse pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered. PMID:21411019

  9. Two series of new semisynthetic triterpene derivatives: differences in anti-malarial activity, cytotoxicity and mechanism of action

    PubMed Central

    2013-01-01

    Background The discovery and development of anti-malarial compounds of plant origin and semisynthetic derivatives thereof, such as quinine (QN) and chloroquine (CQ), has highlighted the importance of these compounds in the treatment of malaria. Ursolic acid analogues bearing an acetyl group at C-3 have demonstrated significant anti-malarial activity. With this in mind, two new series of betulinic acid (BA) and ursolic acid (UA) derivatives with ester groups at C-3 were synthesized in an attempt to improve anti-malarial activity, reduce cytotoxicity, and search for new targets. In vitro activity against CQ-sensitive Plasmodium falciparum 3D7 and an evaluation of cytotoxicity in a mammalian cell line (HEK293T) are reported. Furthermore, two possible mechanisms of action of anti-malarial compounds have been evaluated: effects on mitochondrial membrane potential (ΔΨm) and inhibition of β-haematin formation. Results Among the 18 derivatives synthesized, those having shorter side chains were most effective against CQ-sensitive P. falciparum 3D7, and were non-cytotoxic. These derivatives were three to five times more active than BA and UA. A DiOC6(3) ΔΨm assay showed that mitochondria are not involved in their mechanism of action. Inhibition of β-haematin formation by the active derivatives was weaker than with CQ. Compounds of the BA series were generally more active against P. falciparum 3D7 than those of the UA series. Conclusions Three new anti-malarial prototypes were obtained from natural sources through an easy and relatively inexpensive synthesis. They represent an alternative for new lead compounds for anti-malarial chemotherapy. PMID:23497003

  10. Anticancer Effect of AntiMalarial Artemisinin Compounds

    PubMed Central

    Das, AK

    2015-01-01

    The anti-malarial drug artemisinin has shown anticancer activity in vitro and animal experiments, but experience in human cancer is scarce. However, the ability of artemisinins to kill cancer cells through a variety of molecular mechanisms has been explored. A PubMed search of about 127 papers on anti-cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. Experimental evidences suggest that artemisinin compounds may be a therapeutic alternative in highly aggressive cancers with rapid dissemination, without developing drug resistance. They also exhibit synergism with other anticancer drugs with no increased toxicity toward normal cells. It has been found that semisynthetic artemisinin derivatives have much higher antitumor activity than their monomeric counterparts via mechanisms like apoptosis, arrest of cell cycle at G0/G1, and oxidative stress. The exact mechanism of activation and molecular basis of these anticancer effects are not fully elucidated. Artemisinins seem to regulate key factors such as nuclear factor-kappa B, survivin, NOXA, hypoxia-inducible factor-1α, and BMI-1, involving multiple pathways that may affect drug response, drug interactions, drug resistance, and associated parameters upon normal cells. Newer synthetic artemisinins have been developed showing substantial antineoplastic activity, but there is still limited information regarding the mode of action of these synthetic compounds. In view of the emerging data, specific interactions with established chemotherapy need to be further investigated in different cancer cells and their phenotypes and validated further using different semisynthetic and synthetic artemisinin derivatives. PMID:25861527

  11. Synthesis and biological screening of some pyridine derivatives as anti-malarial agents.

    PubMed

    Bekhit, Adnan A; Hymete, Ariaya; Damtew, Ashenafi; Mohamed, Abdel Maaboud I; Bekhit, Alaa El-Din A

    2012-02-01

    Two series of pyridine derivatives were synthesised and evaluated for their in vivo anti-malarial activity against Plasmodium berghei. The anti-malarial activity was determined in vivo by applying 4-day standard suppressive test using chloroquine (CQ)-sensitive P. berghei ANKA strain-infected mice. Compounds 2a, 2g and 2h showed inhibition of the parasite multiplication by 90, 91 and 80%, respectively, at a dose level of 50 µmol/kg. Moreover, The most active compounds (2a, 2g and 2h) were tested in vitro against CQ-resistant Plasmodium falciparum RKL9 strains where compound 2g showed promising activity with IC(50) = 0.0402 µM. The compounds were non-toxic at 300 and 100 mg/kg through the oral and parenteral routes, respectively. The docking pose of the most active compounds (2a, 2g and 2h) in the active site of dihydrofolate reductase enzyme revealed several hydrogen and hydrophobic interactions that contribute to the observed anti-malarial activities. PMID:21612373

  12. Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-stage Anti-Malarial Compounds

    PubMed Central

    Caron, Joachim; Blundell, Scott; Liu, Feng; Chen, Xin; Srimongkolpithak, Nitipol; Jin, Jian; Charman, Susan A.; Scherf, Artur; Fuchter, Matthew J.

    2014-01-01

    Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of BIX01294 (1), a known human G9a inhibitor, together with its dose-dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimize the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for the antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and the human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as anti-malarial leads. PMID:25044750

  13. Anti-malarial activity of Holarrhena antidysenterica and Viola canescens, plants traditionally used against malaria in the Garhwal region of north-west Himalaya

    PubMed Central

    2011-01-01

    Background The increasing number of multidrug-resistant Plasmodium strains warrants exploration of new anti-malarials. Medicinal plant research has become more important, particularly after the development of Chinese anti-malarial drug artemisnin from Artemisia annua. The present study shows evaluation of anti-malarial effects of two plants commonly used against malaria in the Garhwal region of north-west Himalaya, in order to discover the herbal-based medicine. Methods In vitro anti-plasmodial sensitivity of plant extracts was assessed using schizont maturation and parasite lactate dehydrogenase (pLDH) assay. Cytotoxic activities of the examined extracts were determined on L-6 cells of rat skeletal muscle myoblast. The 4-day test for anti-malarial activity against a chloroquine sensitive Plasmodium berghei NK65 strain in Swiss albino mice was used for monitoring in vivo activity of plant extracts. Results Chloroform extract of H. antidysenterica (HA-2) and petroleum ether extract of V. canescens (VC-1) plants significantly reduced parasitaemia in P. berghei infected mice. The extract HA-2 showed in vitro anti-plasmodial activity with its IC50 value 5.5 μg/ml using pLDH assay and ED50 value 18.29 mg/kg in P. berghei infected Swiss albino mice. Similarly petroleum ether extract of V. canescens (VC-1) showed in vitro anti-plasmodial activity with its IC50 value 2.76 μg/ml using pLDH assay and ED50 15.8 mg/kg in P. berghei infected mice. The extracts coded as HA-2 at 30 mg/kg and VC-1 at 20 mg/kg exhibited parasite inhibition in mice: 73.2% and 63.0% respectively. Of these two plant extracts, petroleum ether extract of V. canescens was found slightly cytotoxic. Conclusion The present investigation reflects the use of these traditional medicinal plants against malaria and these plants may work as potential source in the development of variety of herbal formulations for the treatment of malaria. PMID:21288335

  14. Selective anti-malarial minor groove binders.

    PubMed

    Scott, Fraser J; Khalaf, Abedawn I; Duffy, Sandra; Avery, Vicky M; Suckling, Colin J

    2016-07-15

    A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30-500nM and therapeutic ratios in the range 10->500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia. PMID:27212070

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

    PubMed Central

    2010-01-01

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

  16. Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum

    PubMed Central

    Agarwal, Ankita; Paliwal, Sarvesh; Mishra, Ruchi; Sharma, Swapnil; Kumar Dwivedi, Anil; Tripathi, Renu; Gunjan, Sarika

    2015-01-01

    In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski’s violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation. PMID:26346444

  17. Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold.

    PubMed

    Ciana, Claire-Lise; Siegrist, Romain; Aissaoui, Hamed; Marx, Léo; Racine, Sophie; Meyer, Solange; Binkert, Christoph; de Kanter, Ruben; Fischli, Christoph; Wittlin, Sergio; Boss, Christoph

    2013-02-01

    A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives. PMID:23260352

  18. Anti-malarial activity and HS-SPME-GC-MS chemical profiling of Plinia cerrocampanensis leaf essential oil

    PubMed Central

    2014-01-01

    Background Plinia cerrocampanensis is an endemic plant of Panama. The leaf essential oil of this plant has shown antibacterial activity. However, anti-malarial activity and chemical profiling by HS-SPME-GC-MS of this essential oil have not been reported before. Methods Anti-malarial activity of the essential oil (EO) was evaluated in vitro against chloroquine-sensitive HB3 and chloroquine-resistant W2 strains of Plasmodium falciparum. Synergistic effect of chloroquine and the EO on parasite growth was evaluated by calculating the combination index. A methodology involving headspace solid phase microextraction and gas chromatography-mass spectrometry (HS-SPME-GC-MS) was developed to investigate the composition of Plinia cerrocampanensis EO. Results Plinia cerrocampanensis EO showed a high anti-malarial activity and a synergistic interaction with chloroquine. The Plinia cerrocampanensis EO inhibited P. falciparum growth in vitro at an IC50 of 7.3 μg/mL. Chloroquine together with the EO decreased the IC50 of chloroquine from 0.1 μg/mL to 0.05 μg/mL, and of the EO from 7.3 μg/mL to 1.1 μg/mL. The measured combination index was 0.58, which clearly indicates that the EO acts synergistically with chloroquine. Since the EO maintained its inhibitory activity on the chloroquine-sensitive strain of the parasite, it could be acting by a different mechanism of action than chloroquine. The best HS-SPME-GC-MS analytical conditions were obtained when the temperature of extraction was 49°C, incubation time 14 min, and the time of extraction 10 min. This method allowed for the identification of 53 volatile constituents in the EO, including new compounds not reported earlier. Conclusions The anti-malarial activity exhibited by the Plinia cerrocampanensis EO may lend support for its possible use as an alternative for anti-malarial therapy. PMID:24410874

  19. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

    PubMed Central

    Ashton, Thomas M.; Fokas, Emmanouil; Kunz-Schughart, Leoni A.; Folkes, Lisa K.; Anbalagan, Selvakumar; Huether, Melanie; Kelly, Catherine J.; Pirovano, Giacomo; Buffa, Francesca M.; Hammond, Ester M.; Stratford, Michael; Muschel, Ruth J.; Higgins, Geoff S.; McKenna, William Gillies

    2016-01-01

    Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. PMID:27453292

  20. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia.

    PubMed

    Ashton, Thomas M; Fokas, Emmanouil; Kunz-Schughart, Leoni A; Folkes, Lisa K; Anbalagan, Selvakumar; Huether, Melanie; Kelly, Catherine J; Pirovano, Giacomo; Buffa, Francesca M; Hammond, Ester M; Stratford, Michael; Muschel, Ruth J; Higgins, Geoff S; McKenna, William Gillies

    2016-01-01

    Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. PMID:27453292

  1. Hypericum lanceolatum (Hypericaceae) as a potential source of new anti-malarial agents: a bioassay-guided fractionation of the stem bark

    PubMed Central

    2011-01-01

    Background Malaria is a major public health threat in Africa, and traditional medicine continues to play a key role in its control especially in rural areas. A bioassay-guided fractionation was carried out in order to evaluate the anti-malarial potential and the safety of the methanol extract of the Hypericum lanceolatum stem bark. Methods The anti-plasmodial activity was assayed by the lactate dehydrogenase method (pLDH) against the multidrug-resistant W2mef laboratory strain, and a field isolate (SHF4) of Plasmodium falciparum. Cytotoxicity tests were carried out using the LLC-MK2 monkey kidney epithelial cells. Results Five compounds were isolated from the most active and least cytotoxic ethylacetate sub-extract: betulinic acid (HLT1), 2,2',5,6'-tetrahydroxybenzophenone (HLT2), 5-hydroxy-3-methoxyxanthone (HLT3), 3-hydroxy-5-methoxyxanthone (HLT4) and HLT0 (yet to be identified). Three of the tested compounds presented significant anti-plasmodial activities (with 50% inhibitory concentration, IC50 < 5 μM), with 5-hydroxy-3-methoxyxanthone exerting the highest activity, followed by HLT0 and betulinic acid. All the compounds with significant anti-plasmodial activity were non-cytotoxic, except betulinic acid which showed a 50% cytotoxic concentration, CC50 of 25 μg/mL. Conclusions These findings justify the use of H. lanceolatum stem bark as anti-malarial by traditional healers of Western Cameroon, and could constitute a good basis for further studies towards development of new drug candidates or phytomedicines for malaria. PMID:21682873

  2. Development and Optimization of a Novel 384-Well Anti-Malarial Imaging Assay Validated for High-Throughput Screening

    PubMed Central

    Duffy, Sandra; Avery, Vicky M.

    2012-01-01

    With the increasing occurrence of drug resistance in the malaria parasite, Plasmodium falciparum, there is a great need for new and novel anti-malarial drugs. We have developed a 384-well, high-throughput imaging assay for the detection of new anti-malarial compounds, which was initially validated by screening a marine natural product library, and subsequently used to screen more than 3 million data points from a variety of compound sources. Founded on another fluorescence-based P. falciparum growth inhibition assay, the DNA-intercalating dye 4′,6-diamidino-2-phenylindole, was used to monitor changes in parasite number. Fluorescent images were acquired on the PerkinElmer Opera High Throughput confocal imaging system and analyzed with a spot detection algorithm using the Acapella data processing software. Further optimization of this assay sought to increase throughput, assay stability, and compatibility with our high-throughput screening equipment platforms. The assay typically yielded Z'-factor values of 0.5–0.6, with signal-to-noise ratios of 12. PMID:22232455

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

    PubMed Central

    Williams, Holly Ann; Vincent-Mark, Arlene; Herrera, Yenni; Chang, O Jaime

    2009-01-01

    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 change, utilized

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

    PubMed Central

    2013-01-01

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

  5. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy

    PubMed Central

    Phillips, Margaret A.; Rathod, Pradipsinh K.

    2010-01-01

    Malaria remains a globally prevalent infectious disease that leads to significant morbidity and mortality. While there are a number of drugs approved for its treatment, drug resistance has compromised most of them, making the development of new drugs for the treatment and prevention of malaria essential. The completion of the Plasmodium falciparum genome and a growing understanding of parasite biology are fueling the search for novel drug targets. Despite this, few targets have been chemically validated in vivo. The pyrimidine biosynthetic pathway illustrates one of the best examples of successful identification of anti-malarial drug targets. This review focuses on recent studies to exploit the fourth enzyme in the de novo pyrimidine biosynthetic pathway of P. falciparum, dihydroorotate dehydrogenase (PfDHODH), as a new target for drug discovery. Several chemical scaffolds have been identified by high throughput screening as potent inhibitors of PfDHODH and these show strong selectivity for the malarial enzyme over that from the human host. Potent activity against parasites in whole cell models with good correlation between activity on the enzyme and the parasite have also been observed for a number of the identified series. Lead optimization of a triazolopyrimidine-based series has identified an analog with prolonged plasma exposure, that is orally bioavailable, and which shows good efficacy against the in vivo mouse model of the disease. These data provide strong evidence that PfDHODH is a validated target for the identification of new antimalarial chemotherapy. The challenge remains to identify compounds with the necessary combination of potency and metabolic stability to allow identification of a clinical candidate. PMID:20334617

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

    PubMed Central

    2011-01-01

    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 speed at which ASAQ Winthrop

  7. Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats

    PubMed Central

    2011-01-01

    Background Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats. Methods A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC. Results For nominal doses increasing in a 1:2:4 proportion, the Cmax and AUC0-∞ values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the Cmax and the AUC0-t values for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10-5 cm/s) in permeability study. Conclusions The pharmacokinetic

  8. Anti-malarial and anti-inflammatory effects of Gleichenia truncata mediated through inhibition of GSK3β.

    PubMed

    Suhaini, S; Liew, S Z; Norhaniza, J; Lee, P C; Jualang, G; Embi, N; Hasidah, M S

    2015-09-01

    Gleichenia truncata is a highland fern from the Gleicheniaceae family known for its traditional use among indigenous communities in Asia to treat fever. The scientific basis of its effect has yet to be documented. A yeast-based kinase assay conducted in our laboratory revealed that crude methanolic extract (CME) of G. truncata exhibited glycogen synthase kinase-3 (GSK3)-inhibitory activity. GSK3β is now recognized to have a pivotal role in the regulation of inflammatory response during bacterial infections. We have also previously shown that lithium chloride (LiCl), a GSK3 inhibitor suppressed development of Plasmodium berghei in a murine model of malarial infection. The present study is aimed at evaluating G. truncata for its anti-malarial and anti-inflammatory effects using in vivo malarial and melioidosis infection models respectively. In a four-day suppressive test, intraperitoneal injections of up to 250 mg/kg body weight (bw) G. truncata CME into P.berghei-infected mice suppressed parasitaemia development by >60%. Intraperitoneal administration of 150 mg/kg bw G. truncata CME into Burkholderia pseudomallei-infected mice improved survivability by 44%. G. truncata CME lowered levels of pro-inflammatory cytokines (TNF-α, IFN-γ) in serum and organs of B. pseudomallei-infected mice. In both infections, increased phosphorylations (Ser9) of GSK3β were detected in organ samples of animals administered with G. truncata CME compared to controls. Taken together, results from this study strongly suggest that the anti-malarial and anti-inflammatory effects elicited by G. truncata in part were mediated through inhibition of GSK3β. The findings provide scientific basis for the ethnomedicinal use of this fern to treat inflammation-associated symptoms. PMID:26695202

  9. Thiamin supplementation does not reduce the frequency of adverse events after anti-malarial therapy among patients with falciparum malaria in southern Laos

    PubMed Central

    2014-01-01

    Background In a recent study one third of Lao patients presenting with uncomplicated Plasmodium falciparum malaria had biochemical evidence of thiamin deficiency, which was associated with a higher incidence of adverse events. Thiamin supplementation might, therefore, reduce adverse events in this population. Methods An exploratory, double-blind, parallel group, placebo-controlled, superiority trial of thiamin supplementation in patients of all ages with uncomplicated and severe falciparum malaria was conducted in Xepon District, Savannakhet Province, southern Laos. Patients were randomly assigned to either oral thiamin 10 mg/day for 7 days immediately after standard anti-malarial treatment then 5 mg daily until day 42, or identical oral placebo. Results After interim analyses when 630 patients (314 in thiamin and 316 in placebo groups) had been recruited, the trial was discontinued on the grounds of futility. On admission biochemical thiamin deficiency (alpha ≥ 25%) was present in 27% of patients and 9% had severe deficiency (alpha > 31%). After 42 days of treatment, the frequency of thiamin deficiency was lower in the thiamin (2%, 1% severe) compared to the placebo (11%, 3% severe) groups (p < 0.001 and p = 0.05), respectively. Except for diarrhoea, 7% in the placebo compared to 3% in the thiamin group (p = 0.04), and dizziness on day 1 (33% vs 25%, p = 0.045), all adverse events were not significantly different between the groups (p > 0.05). Clinical, haematological, and parasitological responses to treatment did not differ significantly between the two groups. Conclusion Thiamin supplementation reduced biochemical thiamin deficiency among Lao malaria patients following anti-malarial drug treatment, but it did not reduce the frequency of adverse events after anti-malarial therapy or have any detected clinical or parasitological impact. Trial registration ISRCTN 85411059 PMID:25027701

  10. Identification of a nucleoside/nucleobase transporter from Plasmodium falciparum, a novel target for anti-malarial chemotherapy.

    PubMed Central

    Parker, M D; Hyde, R J; Yao, S Y; McRobert, L; Cass, C E; Young, J D; McConkey, G A; Baldwin, S A

    2000-01-01

    Plasmodium, the aetiologic agent of malaria, cannot synthesize purines de novo, and hence depends upon salvage from the host. Here we describe the molecular cloning and functional expression in Xenopus oocytes of the first purine transporter to be identified in this parasite. This 422-residue protein, which we designate PfENT1, is predicted to contain 11 membrane-spanning segments and is a distantly related member of the widely distributed eukaryotic protein family the equilibrative nucleoside transporters (ENTs). However, it differs profoundly at the sequence and functional levels from its homologous counterparts in the human host. The parasite protein exhibits a broad substrate specificity for natural nucleosides, but transports the purine nucleoside adenosine with a considerably higher apparent affinity (K(m) 0.32+/-0.05 mM) than the pyrimidine nucleoside uridine (K(m) 3.5+/-1.1 mM). It also efficiently transports nucleobases such as adenine (K(m) 0.32+/-0.10 mM) and hypoxanthine (K(m) 0.41+/-0.1 mM), and anti-viral 3'-deoxynucleoside analogues. Moreover, it is not sensitive to classical inhibitors of mammalian ENTs, including NBMPR [6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine, or nitrobenzylthioinosine] and the coronary vasoactive drugs, dipyridamole, dilazep and draflazine. These unique properties suggest that PfENT1 might be a viable target for the development of novel anti-malarial drugs. PMID:10861212

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

    PubMed Central

    2012-01-01

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

  12. A Water-Soluble Polysaccharide from the Fruit Bodies of Bulgaria inquinans (Fries) and Its Anti-Malarial Activity

    PubMed Central

    Bi, Hongtao; Han, Han; Li, Zonghong; Ni, Weihua; Chen, Yan; Zhu, Jingjing; Gao, Tingting; Hao, Miao; Zhou, Yifa

    2011-01-01

    A water-soluble polysaccharide (BIWS-4b) was purified from the fruit bodies of Bulgaria inquinans (Fries). It is composed of mannose (27.2%), glucose (15.5%) and galactose (57.3%). Its molecular weight was estimated to be 7.4 kDa (polydispersity index, Mw/Mn: 1.35). Structural analyses indicated that BIWS-4b mainly contains (1 → 6)-linked, (1 → 5)-linked and (1 → 5,6)-linked β-Galf units; (1 → 4)-linked and non-reducing terminal β-Glcp units; and (1 → 2)-linked, (1 → 6)-linked, (1 → 2,6)-linked and non-reducing terminal α-Manp units. When examined by the 4-day method and in a prophylactic assay in mice, BIWS-4b exhibited markedly suppressive activity against malaria while enhancing the activity of artesunate. Immunological tests indicated that BIWS-4b significantly enhanced macrophage phagocytosis and splenic lymphocyte proliferation in malaria-bearing mice and normal mice. The anti-malarial activity of BIWS-4b might be intermediated by enhancing immune competence and restoring artesunate-suppressed immune function. Thus, BIWS-4b is a potential adjuvant of anti-malaria drugs. PMID:21785644

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

    PubMed Central

    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 non-malaria febrile illnesses is important. In this study, self-medication practice was assessed among community members and information on the habit of self-medication was gathered from health workers. Methods Twelve focus group discussions (FGD) with members of communities and 14 in-depth interviews (IDI) with health workers were conducted in Kilosa district, Tanzania. The transcripts were coded into different categories by MaxQDA software and then analysed through thematic content analysis. Results The study revealed that self-medication was a common practice among FGD participants. Anti-malarial drugs including sulphadoxine-pyrimethamine and quinine were frequently used by the participants for treatment of fever. Study participants reported that they visited health facilities following failure of self-medication or if there was no significant improvement after self-medication. The common reported reasons for self-medication were shortages of drugs at health facilities, long waiting time at health facilities, long distance to health facilities, inability to pay for health care charges and the freedom to choose the preferred drugs. Conclusion This study demonstrated that self-medication practice is common among rural communities in the study area. The need for community awareness is emphasized for correct and comprehensive information about drawbacks associated with self-medication practices. Deliberate efforts by the government and other stakeholders to improve health care

  14. Methods for implementing a medicine outlet survey: lessons from the anti-malarial market

    PubMed Central

    2013-01-01

    Background In recent years an increasing number of public investments and policy changes have been made to improve the availability, affordability and quality of medicines available to consumers in developing countries, including anti-malarials. It is important to monitor the extent to which these interventions are successful in achieving their aims using quantitative data on the supply side of the market. There are a number of challenges related to studying supply, including outlet sampling, gaining provider cooperation and collecting accurate data on medicines. This paper provides guidance on key steps to address these issues when conducting a medicine outlet survey in a developing country context. While the basic principles of good survey design and implementation are important for all surveys, there are a set of specific issues that should be considered when conducting a medicine outlet survey. Methods This paper draws on the authors’ experience of designing and implementing outlet surveys, including the lessons learnt from ACTwatch outlet surveys on anti-malarial retail supply, and other key studies in the field. Key lessons and points of debate are distilled around the following areas: selecting a sample of outlets; techniques for collecting and analysing data on medicine availability, price and sales volumes; and methods for ensuring high quality data in general. Results and conclusions The authors first consider the inclusion criteria for outlets, contrasting comprehensive versus more focused approaches. Methods for developing a reliable sampling frame of outlets are then presented, including use of existing lists, key informants and an outlet census. Specific issues in the collection of data on medicine prices and sales volumes are discussed; and approaches for generating comparable price and sales volume data across products using the adult equivalent treatment dose (AETD) are explored. The paper concludes with advice on practical considerations

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

    PubMed

    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

  16. Determination of metabolic profile of anti-malarial trioxane CDRI 99/411 in rat liver microsomes using HPLC.

    PubMed

    Mishra, Smriti; Manickavasagam, Lakshmi; Jain, Girish Kumar

    2012-01-01

    CDRI 99/411 is a potent 1,2,4-trioxane anti-malarial candidate compound of the Central Drug Research Institute, India. This study aimed to conduct comprehensive in vitro metabolic investigations of CDRI 99/411 to corroborate its preclinical investigations. Preliminary in vitro metabolic investigations were performed to assess the metabolic stability [in vitro half-life (t(1/2) ) and in vitro hepatic intrinsic clearance (Cl(int) )] of CDRI 99/411 in male Sprague-Dawley rat and human liver microsomes using validated high-performance liquid chromatography with photodiode array detector. The observed in vitro t(1/2) of the compound in rat and human liver microsomes was 13 min with in vitro Cl(int) 130.7±25.0 μL/min/mg and 19 min with in vitro Cl(int) 89.3 ± 17.40 μL/min/mg. These observations suggested moderate metabolic degradation and in vitro Cl(int) with insignificant difference (p>0.05) in the metabolic stability profile in rat and human. Hence, in vitro metabolic investigations were performed with rat liver microsomes. It was observed that CDRI 99/411 exhibited sigmoidal kinetics. At nonlinear regression (r ≥ 0.99) EC(50) and Hill slope values were 17 µm and 1.50, respectively. The metabolism of CDRI 99/411 was primarily mediated by CYP3A2 and was inferred by CYP reaction phenotyping with known potent inhibitors. Two metabolites of CDRI 99/411 were detected which were undetectable on incubation with 1-aminobenzotriazole and ketoconazole. PMID:21503937

  17. Chinese propriety medicines: an "alternative modernity?" The case of the anti-malarial substance artemisinin in East Africa.

    PubMed

    Hsu, Elisabeth

    2009-01-01

    This article discusses various modes of "modernizing" traditional Chinese medical drugs (zhongyao [image: see text]) and transforming them into so-called Chinese propriety medicines (zhongchengyao [image: see text]) that are flooding the current neoliberal wellness markets. This article argues that the chemical procedures used in the manufacture of Chinese propriety medicines are highly culture-specific and deserve being considered as instantiations of an "alternative modernity" (e.g., Knauft 2002), rather than of "Westernization." These Western-Chinese combinations, produced in strife toward fulfilling Mao Zedong's Communist-revolutionary vision, have a potential to represent a critical alterity to Western health policies, challenging rhetoric against such combinations. However, as is also noted in this article based on ethnographic fieldwork in East Africa, their potential alterity has been corroded for at least two reasons. First, the medical rationale for dispensing these medications has been shaped by commercial demands in ways that have worked toward transforming the formerly scholarly Chinese medical tradition (as outlined by Bates 1995) into a consumer-near and popular "folk medicine" (as defined by Farquhar 1994:212). Second, the repertoire of Chinese propriety medicines is impoverished as its efficacious "alternatively modern" drugs are being redefined as "modern" biomedical drugs. The article concludes that the potentially critical alterity of any formerly scholarly traditional medicine is more likely to be lost in those fields of health care that are both highly commercialized and polarized by the biomedical imperative to distinguish between "traditional" and "modern" medicines. As example for demonstrating how contentious the issue is, qinghaosu [image: see text] (artemisinin) is put center stage. It is an anti-malarial substance which in the 1970s Chinese scientists extracted from the Chinese medical drug qinghao [image: see text] (Herba Artemisiae

  18. Combinatorial pathway engineering for optimized production of the anti-malarial FR900098.

    PubMed

    Freestone, Todd S; Zhao, Huimin

    2016-02-01

    As resistance to current anti-malarial therapeutics spreads, new compounds to treat malaria are increasingly needed. One promising compound is FR900098, a naturally occurring phosphonate. Due to limitations in both chemical synthesis and biosynthetic methods for FR900098 production, this potential therapeutic has yet to see widespread implementation. Here we applied a combinatorial pathway engineering strategy to improve the production of FR900098 in Escherichia coli by modulating each of the pathway's nine genes with four promoters of different strengths. Due to the large size of the library and the low screening throughput, it was necessary to develop a novel screening strategy that significantly reduced the sample size needed to find an optimal strain. This was done by using biased libraries that localize searching around top hits and home in on high-producing strains. By incorporating this strategy, a significantly improved strain was found after screening less than 3% of the entire library. When coupled with culturing optimization, a strain was found to produce 96 mg/L, a 16-fold improvement over the original strain. We believe the enriched library method developed here can be used on other large pathways that may be difficult to engineer by combinatorial methods due to low screening throughput. PMID:26245694

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

    SciTech Connect

    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

    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.

  20. In vitro inhibition of Toxoplasma gondii by the anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol.

    PubMed

    Xin, Chun-Feng; Kim, Hye-Sook; Sato, Akira; Lee, Hak-Jae; Lee, You-Won; Pyo, Kyoung-Ho; Shin, Eun-Hee

    2016-10-01

    An anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251), was studied to characterize its potential as a novel anti-Toxoplasma gondii drug. In the present study, IC50 and LC50 of N-251 on host cells and T. gondii were compared to those of artemisinin and sulfadiazine. The IC50 on Huh-7 cells was 10.19μg/ml, 67.69μg/ml and 310.17μg/ml for N-251, artemisinin, and sulfadiazine, respectively. The LC50 for anti-T. gondii effect was shown to be 1.11μg/ml, 5.79μg/ml, and 5.45μg/ml for N-251, artemisinin and sulfadiazine, respectively. N-251 concentration causing complete parasiticidal effect with minimal cytotoxicity on host cells was determined to be 5μg/ml. Additionally, the anti-T. gondii effect of N-251 was confirmed by ultrastructural changes, loss of organelles, degenerated morphology and the increase of amylopectin as detected by transmission electron microscope (TEM). Accordingly, the present study suggests that the anti-malarial synthetic endoperoxide, N-251, is an emerging drug candidate more effective than artemisinin and sulfadiazine. PMID:27380994

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

    SciTech Connect

    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.

  2. A population genetic model for the initial spread of partially resistant malaria parasites under anti-malarial combination therapy and weak intrahost competition.

    PubMed

    Kim, Yuseob; Escalante, Ananias A; Schneider, Kristan A

    2014-01-01

    To develop public-health policies that extend the lifespan of affordable anti-malarial drugs as effective treatment options, it is necessary to understand the evolutionary processes leading to the origin and spread of mutations conferring drug resistance in malarial parasites. We built a population-genetic model for the emergence of resistance under combination drug therapy. Reproductive cycles of parasites are specified by their absolute fitness determined by clinical parameters, thus coupling the evolutionary-genetic with population-dynamic processes. Initial mutations confer only partial drug-resistance. Therefore, mutant parasites rarely survive combination therapy and within-host competition is very weak among parasites. The model focuses on the early phase of such unsuccessful recurrent mutations. This ends in the rare event of mutants enriching in an infected individual from which the successful spread of resistance over the entire population is initiated. By computer simulations, the waiting time until the establishment of resistant parasites is analysed. Resistance spreads quickly following the first appearance of a host infected predominantly by mutant parasites. This occurs either through a rare transmission of a resistant parasite to an uninfected host or through a rare failure of drugs in removing "transient" mutant alleles. The emergence of resistance is delayed with lower mutation rate, earlier treatment, higher metabolic cost of resistance, longer duration of high drug dose, and higher drug efficacy causing a stronger reduction in the sensitive and resistant parasites' fitnesses. Overall, contrary to other studies' proposition, the current model based on absolute fitness suggests that aggressive drug treatment delays the emergence of drug resistance. PMID:25007207

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

    PubMed

    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

  4. Evaluation of anti-malarial effects of mass chemoprophylaxis in the Republic of Korea army.

    PubMed

    Yeom, Joon-Sup; Ryu, Seung-Ho; Oh, Sejoong; Choi, Dong-Hyun; Song, Kyoung-Jun; Oh, Young-Ha; Lee, Jae-Hyun; Kim, Young-A; Ahn, Sun-Young; Yang, Hwa-Young; Cha, Je-Eun; Park, Jae-Won

    2005-10-01

    Vivax malaria was endemic on the Korean peninsula for many centuries until the late 1970's when the Republic of Korea (ROK) was declared "malaria free". Since its re-emergence in 1993, the number of malaria cases in the military increased exponentially through 2000 near the demilitarized zone. Chemoprophylaxis with chloroquine and primaquine has been used in the ROK Army since 1997 in an attempt to reduce the number of the malaria cases throughout the ROK. Data show that chemoprophylaxis contributed, in part, to the decrease in the number of malaria cases among military personnel. However, mass chemoprophylaxis on a large scale in the ROK Army is unprecedented and extensive supervision and monitoring is warranted to determine its effectiveness and to monitor the appearance of chloroquine tolerant/resistant strains of Plasmodium vivax. PMID:16224140

  5. The Plasmodium berghei sexual stage antigen PSOP12 induces anti-malarial transmission blocking immunity both in vivo and in vitro.

    PubMed

    Sala, K A; Nishiura, H; Upton, L M; Zakutansky, S E; Delves, M J; Iyori, M; Mizutani, M; Sinden, R E; Yoshida, S; Blagborough, A M

    2015-01-01

    Anti-malarial transmission-blocking vaccines (TBVs) aim to inhibit the transmission of Plasmodium from humans to mosquitoes by targeting the sexual/ookinete stages of the parasite. Successful use of such interventions will subsequently result in reduced cases of malarial infection within a human population, leading to local elimination. There are currently only five lead TBV candidates under examination. There is a consequent need to identify novel antigens to allow the formulation of new potent TBVs. Here we describe the design and evaluation of a potential TBV (BDES-PbPSOP12) targeting Plasmodium berghei PSOP12 based on the baculovirus dual expression system (BDES), enabling expression of antigens on the surface of viral particles and within infected mammalian cells. In silico studies have previously suggested that PSOP12 (Putative Secreted Ookinete Protein 12) is expressed within the sexual stages of the parasite (gametocytes, gametes and ookinetes), and is a member of the previously characterized 6-Cys family of plasmodial proteins. We demonstrate that PSOP12 is expressed within the sexual/ookinete forms of the parasite, and that sera obtained from mice immunized with BDES-PbPSOP12 can recognize the surface of the male and female gametes, and the ookinete stages of the parasite. Immunization of mice with BDES-PbPSOP12 confers modest but significant transmission-blocking activity in vivo by active immunization (53.1% reduction in oocyst intensity, 10.9% reduction in oocyst prevalence). Further assessment of transmission-blocking potency ex vivo shows a dose-dependent response, with up to a 76.4% reduction in intensity and a 47.2% reduction in prevalence observed. Our data indicates that PSOP12 in Plasmodium spp. could be a potential new TBV target candidate, and that further experimentation to examine the protein within human malaria parasites would be logical. PMID:25454088

  6. Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols

    PubMed Central

    2010-01-01

    Background The clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier. Methods A library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed. Results The most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs). The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability. Conclusions A drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified. PMID:20149249

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

    PubMed Central

    2013-01-01

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

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

    PubMed Central

    2014-01-01

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

  9. Improving malaria home treatment by training drug retailers in rural Kenya.

    PubMed

    Marsh, V M; Mutemi, W M; Willetts, A; Bayah, K; Were, S; Ross, A; Marsh, K

    2004-04-01

    Recent global malaria control initiatives highlight the potential role of drug retailers to improve access to early effective malaria treatment. We report on the findings and discuss the implications of an educational programme for rural drug retailers and communities in Kenya between 1998 and 2001 in a study population of 70,000. Impact was evaluated through annual household surveys of over-the-counter (OTC) drug use and simulated retail client surveys in an early (1999) and a late (2000) implementation area. The programme achieved major improvements in drug selling practices. The proportion of OTC anti-malarial drug users receiving an adequate dose rose from 8% (n = 98) to 33% (n = 121) between 1998 and 1999 in the early implementation area. By 2001, and with the introduction of sulphadoxine pyrimethamine group drugs in accordance with national policy, this proportion rose to 64% (n = 441) across the early and late implementation areas. Overall, the proportion of shop-treated childhood fevers receiving an adequate dose of a recommended anti-malarial drug within 24 h rose from 1% (n = 681) to 28% (n = 919) by 2001. These findings strongly support the inclusion of private drug retailers in control strategies aiming to improve prompt effective treatment of malaria. PMID:15078263

  10. Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity.

    PubMed

    Ortmann, Regina; Wiesner, Jochen; Reichenberg, Armin; Henschker, Dajana; Beck, Ewald; Jomaa, Hassan; Schlitzer, Martin

    2003-07-01

    FR900098 represents an improved derivative of the new antimalarial drug fosmidomycin and acts through inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield acyloxyalkyl esters. The most successful compound demonstrated 2-fold increased activity in mice infected with the rodent malaria parasite Plasmodium vinckei. PMID:12798327

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

    PubMed Central

    Simoes-Pires, Claudia; Hostettmann, Kurt; Haouala, Amina; Cuendet, Muriel; Falquet, Jacques; Graz, Bertrand; Christen, Philippe

    2014-01-01

    Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. 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 Plasmodiumfalciparum. 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. PMID:25516845

  12. Access to artemisinin-based anti-malarial treatment and its related factors in rural Tanzania

    PubMed Central

    2013-01-01

    Background Artemisinin-based combination treatment (ACT) has been widely adopted as one of the main malaria control strategies. However, its promise to save thousands of lives in sub-Saharan Africa depends on how effective the use of ACT is within the routine health system. The INESS platform evaluated effective coverage of ACT in several African countries. Timely access within 24 hours to an authorized ACT outlet is one of the determinants of effective coverage and was assessed for artemether-lumefantrine (Alu), in two district health systems in rural Tanzania. Methods From October 2009 to June 2011we conducted continuous rolling household surveys in the Kilombero-Ulanga and the Rufiji Health and Demographic Surveillance Sites (HDSS). Surveys were linked to the routine HDSS update rounds. Members of randomly pre-selected households that had experienced a fever episode in the previous two weeks were eligible for a structured interview. Data on individual treatment seeking, access to treatment, timing, source of treatment and household costs per episode were collected. Data are presented on timely access from a total of 2,112 interviews in relation to demographics, seasonality, and socio economic status. Results In Kilombero-Ulanga, 41.8% (CI: 36.6–45.1) and in Rufiji 36.8% (33.7–40.1) of fever cases had access to an authorized ACT provider within 24 hours of fever onset. In neither of the HDSS site was age, sex, socio-economic status or seasonality of malaria found to be significantly correlated with timely access. Conclusion Timely access to authorized ACT providers is below 50% despite interventions intended to improve access such as social marketing and accreditation of private dispensing outlets. To improve prompt diagnosis and treatment, access remains a major bottle neck and new more innovative interventions are needed to raise effective coverage of malaria treatment in Tanzania. PMID:23651521

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

    PubMed Central

    2012-01-01

    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-malarial antibodies and total IgE levels were measured by a standardized ELISA technique. Host DNA was extracted and used for genotyping of selected SNPs in known genes associated with malaria. The antibody levels were analysed in relation to the past history of malaria (during past 10 years), age, sex, the location of residence within Kataragama and selected host genetic markers. Results A significant increase in antibodies against Plasmodium falciparum antigens AMA1, MSP2, NANP and Plasmodium vivax antigen MSP1 in individuals with past history of malaria were observed when compared to those who did not. A marked increase of anti-MSP1(Pf) and anti-AMA1(Pv) was also evident in individuals between 45–59 years (when compared to other age groups). Allele frequencies for two SNPs in genes that code for IL-13 and TRIM-5 were found to be significantly different between those who have experienced one or more malaria attacks within past 10 years and those who did not. When antibody levels were classified into a low-high binary trait, significant associations were found with four SNPs for anti-AMA1(Pf); two SNPs for anti-MSP1(Pf); eight SNPs for anti-NANP(Pf); three SNPs for anti-AMA1(Pv); seven SNPs for anti-MSP1(Pv); and nine SNPs for total IgE. Eleven of these SNPs with significant associations with anti-malarial antibody levels were found to be non–synonymous. Conclusions Evidence is suggestive of an age–acquired immunity in this study population in spite of low malaria

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

    PubMed

    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

  15. Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum

    PubMed Central

    2014-01-01

    Background In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. Methods The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as ‘signposts’ in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay. Results This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series. Conclusion A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical

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

    PubMed Central

    2012-01-01

    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 and Pfdhps 437G and 540E

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

    PubMed Central

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

  18. The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes.

    PubMed

    Wang, Yue; Huang, Zhouqing; Wang, Liansheng; Meng, Shu; Fan, Yuqi; Chen, Ting; Cao, Jiatian; Jiang, Rujia; Wang, Changqian

    2011-02-01

    Several kinds of sesquiterpene lactones have been proven to inhibit NF-κB and to retard atherosclerosis by reducing lesion size and changing plaque composition. The anti-malarial artemisinin (Art) is a pure sesquiterpene lactone extracted from the Chinese herb Artemisia annua (qinghao, sweet wormwood). In the present study, we demonstrate that artemisinin inhibits the secretion and the mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in a dose-dependent manner in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 human monocytes. We also found that the NF-κB specific inhibitor, Bay 11-7082, inhibited the expression of these pro-inflammatory cytokines, suggesting that the NF-κB pathway may be involved in the decreased cytokine release. At all time-points (1-6 h), artemisinin impeded the phosphorylation of IKKα/ß, the phosphorylation and degradation of IκBα and the nuclear translocation of the NF-κB p65 subunit. Additionally, artemisinin inhibited the translocation of the NF-κB p65 subunit as demonstrated by confocal laser scanning microscopic analysis and by NF-κB binding assays. Our data indicate that artemisinin exerts an anti-inflammatory effect on PMA-induced THP-1 monocytes, suggesting the potential role of artemisinin in preventing the inflammatory progression of atherosclerosis. PMID:21165548

  19. 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

    PubMed Central

    2010-01-01

    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 observation period. The only in

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

    PubMed

    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

  1. Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds

    SciTech Connect

    Yedidi, Ravikiran S.; Liu, Zhigang; Wang, Yong; Brunzelle, Joseph S.; Kovari, Iulia A.; Woster, Patrick M.; Kovari, Ladislau C.; Gupta, Deepak

    2012-06-19

    Two potent inhibitors (compounds 1 and 2) of malarial aspartyl protease, plasmepsin-II, were evaluated against wild type (NL4-3) and multidrug-resistant clinical isolate 769 (MDR) variants of human immunodeficiency virus type-1 (HIV-1) aspartyl protease. Enzyme inhibition assays showed that both 1 and 2 have better potency against NL4-3 than against MDR protease. Crystal structures of MDR protease in complex with 1 and 2 were solved and analyzed. Crystallographic analysis revealed that the MDR protease exhibits a typical wide-open conformation of the flaps (Gly48 to Gly52) causing an overall expansion in the active site cavity, which, in turn caused unstable binding of the inhibitors. Due to the expansion of the active site cavity, both compounds showed loss of direct contacts with the MDR protease compared to the docking models of NL4-3. Multiple water molecules showed a rich network of hydrogen bonds contributing to the stability of the ligand binding in the distorted binding pockets of the MDR protease in both crystal structures. Docking analysis of 1 and 2 showed a decrease in the binding affinity for both compounds against MDR supporting our structure-function studies. Thus, compounds 1 and 2 show promising inhibitory activity against HIV-1 protease variants and hence are good candidates for further development to enhance their potency against NL4-3 as well as MDR HIV-1 protease variants.

  2. Genetic diversity and signatures of selection of drug resistance in Plasmodium populations from both human and mosquito hosts in continental Equatorial Guinea

    PubMed Central

    2013-01-01

    Background In Plasmodium, the high level of genetic diversity and the interactions established by co-infecting parasite populations within the same host may be a source of selection on pathogen virulence and drug resistance. As different patterns have already been described in humans and mosquitoes, parasite diversity and population structure should be studied in both hosts to properly assess their effects on infection and transmission dynamics. This study aimed to characterize the circulating populations of Plasmodium spp and Plasmodium falciparum from a combined set of human blood and mosquito samples gathered in mainland Equatorial Guinea. Further, the origin and evolution of anti-malarial resistance in this area, where malaria remains a major public health problem were traced. Methods Plasmodium species infecting humans and mosquitoes were identified by nested-PCR of chelex-extracted DNA from dried blood spot samples and mosquitoes. Analysis of Pfmsp2 gene, anti-malarial-resistance associated genes, Pfdhps, Pfdhfr, Pfcrt and Pfmdr1, neutral microsatellites (STR) loci and Pfdhfr and Pfdhps flanking STR was undertaken to evaluate P. falciparum diversity. Results Prevalence of infection remains high in mainland Equatorial Guinea. No differences in parasite formula or significant genetic differentiation were seen in the parasite populations in both human and mosquito samples. Point mutations in all genes associated with anti-malarial resistance were highly prevalent. A high prevalence was observed for the Pfdhfr triple mutant in particular, associated with pyrimethamine resistance. Analysis of Pfdhps and Pfdhfr flanking STR revealed a decrease in the genetic diversity. This finding along with multiple independent introductions of Pfdhps mutant haplotypes suggest a soft selective sweep and an increased differentiation at Pfdhfr flanking microsatellites hints a model of positive directional selection for this gene. Conclusions Chloroquine is no longer recommended for

  3. Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates

    PubMed Central

    2014-01-01

    Background Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. Methods In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. Results Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC50) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. Conclusions Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria. PMID:24916383

  4. Immunologic Evaluation of Drug Allergy

    PubMed Central

    Gómez, Enrique; Torres, Maria Jose; Mayorga, Cristobalina

    2012-01-01

    Hypersensitivity drug reactions (HDR) consist of an individual abnormal response with the involvement of the immunological system. In addition to specific immunological mechanisms where specific antibodies or sensitised T cells participate, release of inflammatory mediators by non-specific immunological recognition may also occur. Within this category are one of the most common groups of drugs, the non-steroidal anti-inflammatory drugs. In addition to chemical drugs new emerging ones with an increasing protagonism are biological agents like humanised antibodies and others. For IgE dependent reactions both in vivo and in vitro tests can be used for the immunological evaluation. Sensitivity of these is not optimal and very often a drug provocation test must be considered for knowing the mechanism involved and/or establishing the diagnosis. For non-immediate reactions also both in vivo and in vitro tests can be used. Sensitivity for in vivo tests is generally low and in vitro tests may be needed for the immunological evaluation. Immunohistochemical studies of the affected tissue enable a more precise classification of non-immediate reactions. The monitorization of the acute response of the reactions has given clues for understanding these reactions and has promising results for the future of the immunological evaluation of HDR. PMID:22950030

  5. Experimental study and evaluation of radioprotective drugs

    NASA Technical Reports Server (NTRS)

    Smith, D. E.; Thomson, J. F.

    1968-01-01

    Experimental study evaluates radioprotective drugs administered before exposure either orally or intravenously. Specifically studied are the sources of radiation, choice of radiation dose, choice of animals, administration of drugs, the toxicity of protective agents and types of protective drug.

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

    PubMed

    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

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

    PubMed Central

    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

  8. An In vivo Drug Screening Model Using Glucose-6-Phosphate Dehydrogenase Deficient Mice to Predict the Hemolytic Toxicity of 8-Aminoquinolines

    PubMed Central

    Zhang, Peng; Gao, Xiugong; Ishida, Hiroshi; Amnuaysirikul, Jack; Weina, Peter J.; Grogl, Max; O'Neil, Michael T.; Li, Qigui; Caridha, Diana; Ohrt, Colin; Hickman, Mark; Magill, Alan J.; Ray, Prabhati

    2013-01-01

    Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential. PMID:23530079

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

    PubMed Central

    2012-01-01

    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. PMID:22333675

  10. Plasmodium vivax and Plasmodium falciparum ex vivo susceptibility to anti-malarials and gene characterization in Rondônia, West Amazon, Brazil

    PubMed Central

    2014-01-01

    Background Chloroquine (CQ), a cost effective antimalarial drug with a relatively good safety profile and therapeutic index, is no longer used by itself to treat patients with Plasmodium falciparum due to CQ-resistant strains. P. vivax, representing over 90% of malaria cases in Brazil, despite reported resistance, is treated with CQ as well as with primaquine to block malaria transmission and avoid late P. vivax malaria relapses. Resistance to CQ and other antimalarial drugs influences malaria control, thus monitoring resistance phenotype by parasite genotyping is helpful in endemic areas. Methods A total of 47 P. vivax and nine P. falciparum fresh isolates were genetically characterized and tested for CQ, mefloquine (MQ) and artesunate (ART) susceptibility in vitro. The genes mdr1 and pfcrt, likely related to CQ resistance, were analyzed in all isolates. Drug susceptibility was determined using short-term parasite cultures of ring stages for 48 to 72 hour and thick blood smears counts. Each parasite isolate was tested with the antimalarials to measure the geometric mean of 50% inhibitory concentration. Results The low numbers of P. falciparum isolates reflect the species prevalence in Brazil; most displayed low sensitivity to CQ (IC50 70 nM). However, CQ resistance was rare among P. vivax isolates (IC50 of 32 nM). The majority of P. vivax and P. falciparum isolates were sensitive to ART and MQ. One hundred percent of P. falciparum isolates carried non-synonymous mutations in the pfmdr1 gene in codons 184, 1042 and 1246, 84% in codons 1034 and none in codon 86, a well-known resistance mutation. For the pfcrt gene, mutations were observed in codons 72 and 76 in all P. falciparum isolates. One P. falciparum isolate from Angola, Africa, showing sensitivity to the antimalarials, presented no mutations. In P. vivax, mutations of pvmdr1 and the multidrug resistance gene 1 marker at codon F976 were absent. Conclusion All P. falciparum Brazilian isolates showed

  11. Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection

    PubMed Central

    Veljkovic, Veljko; Loiseau, Philippe M.; Figadere, Bruno; Glisic, Sanja; Veljkovic, Nevena; Perovic, Vladimir R.; Cavanaugh, David P.; Branch, Donald R.

    2015-01-01

    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. PMID:25717373

  12. Adherence to and acceptability of artemether-lumefantrine as first-line anti-malarial treatment: evidence from a rural community in Tanzania

    PubMed Central

    2010-01-01

    Background Controlled clinical trials have shown that a six-dose regimen of artemether-lumefantrine (AL) therapy for uncomplicated Plasmodium falciparum malaria results in cure rates >95% with good tolerability. Materials and methods A prospective study was carried out to document the adherence to and acceptability of AL administration. This was undertaken in the context of the ALIVE study, a prospective, community-based, observational study in a rural, malaria-endemic area of Tanzania. Following microscopic confirmation of P. falciparum infection, the first AL dose was taken under supervision, with the subsequent five doses taken unsupervised at home. Patients were randomized to receive a home-based assessment close to the scheduled time for one of the unsupervised doses, but were blinded to which follow-up visit they had been allocated. A structured questionnaire was administered by trained staff and AL consumption was confirmed by inspection of blister packs. Results A total of 552 patients were recruited of whom 352 (63.8%) were <13 years old. The randomization process allocated 112, 109, 110, 100 and 111 patients to a follow-up visit after doses 2, 3, 4, 5 and 6, respectively. For dose 2, 92.0% of patients (103/112) correctly took AL at 8 ± 1 hours after dose 1. The remaining doses were taken within four hours of the correct time in 87-95% of cases. Nine patients (1.7%) missed one dose. Blister packs were available for inspection in 548 of cases (99.3%) and confirmed patient-reported data that the previous dose had been administered. Nearly all patients took AL with water (549/552 [99.5%]). Two patients (0.4%) took the drug with food. The dosing pictogram and clustering of tablets within the blister packs was considered helpful by 91.8% and 100.0% of patients, respectively. Overall, 87.1% of patients (481/552) found AL easier to take/administer than sulphadoxine-pyrimethamine (SP) and 87.7% (484/552) believed that AL was more effective than SP. Discussion

  13. A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

    PubMed Central

    2013-01-01

    Background Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as β-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of β-artemether and lumefantrine FDC products. Methods Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30°C, were evaluated. β-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 μl injection volume. Quantification was performed at 210 nm and 335 nm for β-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0®. Results Both β-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (± RSD) of 99.7 % (± 0.7%) for β-artemether and 99.7 % (± 0.6%) for lumefantrine. All identified β-artemether-related impurities were predicted in Derek

  14. 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

    PubMed Central

    2010-01-01

    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 sales) Conclusions

  15. Students' Evaluations of Their Psychoactive Drug Use.

    ERIC Educational Resources Information Center

    Goldstein, Joel W.

    Evaluations were obtained with the same questionnaire item in 1968, 1969, 1970, and 1972 at Carnegie-Mellon University. The evaluations of marijuana and LSD experiences reported in 1968 were very similar to those at California Institute of Technology in 1967. Evaluations varied by drug, but were predominantly "beneficial and helpful" (marijuana,…

  16. 76 FR 45268 - Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-28

    ... HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research, Approach to... approach of the Center for Drug Evaluation and Research (CDER) to addressing drug shortages. This public... Benner, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire...

  17. Objective evaluation of generic drug information.

    PubMed

    Iijima, Hisashi; Kamei, Miwako; Koshimizu, Toshimasa; Shiragami, Makoto

    2004-06-01

    Pharmacists active in health care venues need to be able to evaluate generic drugs in terms of effectiveness, safety, and economy to ensure that they are used appropriately. As part of the ongoing study of these factors, we carried out an objective evaluation of information provided for generics. A minimum of 20 commercially available products was considered for each pharmaceutical ingredient. The information subjected to evaluation consisted of the text of drug package inserts and information noted on interview forms. Using our own criteria for evaluating drug information, we attempted to quantify the amounts of information provided. Then, based on the numerical values obtained, we calculated information quantities with reference to drug prices to study the relationship between prices and available information for original drugs and their later-developed, generic equivalents. A total of 14 different pharmaceutical ingredients (327 product items) were considered, with the information quantity for generics amounting to 27.9+/-17.8-46.3+/-21.4% (Mean+/-S.D.) that for the original drugs. Examined on the basis of individual pharmaceutical companies, the corresponding ratio came to 15.1+/-7.8-62.4+/-6.4% (Mean+/-S.D.). For generics, the relationship between drug price (expressed against a value of 1.0 for original drugs) and information quantity (Qua(i)) came to 0.79+/-0.46-1.90+/-0.79% (Mean+/-S.D.). These results clearly point to the importance of evaluating information quantity for generic drugs on a maker-by-maker basis. PMID:15170069

  18. Drug evaluation and registration in Hungary.

    PubMed

    Paál, T L; Káldor, A; Fäller, K

    1988-02-01

    In Hungary, the actual drug evaluation and registration system reflects international standards and national traditions. The compulsory drug registration system that was established in 1933 was among the first in Europe. Laboratory control (since 1927), clinical trials (since 1951) and human clinical pharmaceutical experiments (since 1967) are prerequisites for new-drug approval. Applications should be sent to the National Institute of Pharmacy, which has the overall responsibility for the registration of pharmaceutical products. Applications are assessed on the basis of the drug's quality, safety, and efficacy. The procedure follows several steps: evaluation of chemical and pharmaceutical data by the staff of the National Institute of Pharmacy; evaluation of toxicologic and pharmacologic documentation with the help of the Committee on Drug Administration; after consultation with the Committee on Medical Research Ethics (mandatory in cases of original new drugs), authorized clinical pharmacologic investigations are conducted in the units of the Clinical Pharmacological Network, which are supervised by the National Center for Clinical Pharmacology; clinical trials; application for registration (scientific evaluation); and finally, application to the Ministry of Health for a marketing authorization. The process may be facilitated appreciably for preparations already registered in another country. Moreover, Hungary is an active member in the World Health Organization (WHO), Pharmaceutical Inspection Convention of the European Free Trade Association (EFTA PIC), the Council of Mutual Economic Assistance (COMECON), and other international pharmaceutical and clinical pharmaceutical collaborations. PMID:3360964

  19. Why Evaluate Drug Education? Task Force Report.

    ERIC Educational Resources Information Center

    Southern Regional Council, Atlanta, GA.

    This publication provides some guidance to alcohol and drug education program administrators by clarifying the different levels of evaluation and the kinds of learning that can occur at each level. While it outlines the components and considerations for evaluation, it does not define a step-by-step procedure. In short, it serves as a diet rather…

  20. Students' Evaluations of Their Psychoactive Drug Use

    ERIC Educational Resources Information Center

    Goldstein, Joel W.

    1975-01-01

    Evaluations were obtained with the same questionnaire item in 1968, 1969, 1970, and 1972 at Carnegie-Mellon University. Evaluations varied by drug, but were predominantly "beneficial and helpful" (marijuana, hallucinogens, tranquilizers and barbiturates) or had "no particular effect" (amphetamines, beer, liquor, tobacco, and narcotics). (Author)

  1. Plasmodium falciparum drug resistance in Angola.

    PubMed

    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

  2. Evaluation of a Flipped Drug Literature Evaluation Course

    PubMed Central

    Moser, Lynette R.

    2016-01-01

    Objective. To evaluate a flipped drug literature evaluation course for first-year pharmacy students. Design. A drug literature evaluation course was flipped during the 2014 winter semester. Homework from 2013 was transformed into activities and lectures were transformed into multiple short YouTube videos. Assessment. Average examination scores increased from 75.6% to 86.1%. Eighty-two of 94 students completed the postcourse survey in 2014. Compared to traditional lecture, 59.8% of students indicated they preferred the flipped course. Additionally, students felt the course was important, the in-class activities were helpful, and some of the YouTube videos could be improved. We found length of the video to be significantly correlated with the percentage of videos viewed. Conclusion. The flipped model should be considered in drug literature evaluation courses that seek to increase the amount of active learning in the classroom. PMID:27293233

  3. Evaluation of a Flipped Drug Literature Evaluation Course.

    PubMed

    Giuliano, Christopher Alan; Moser, Lynette R

    2016-05-25

    Objective. To evaluate a flipped drug literature evaluation course for first-year pharmacy students. Design. A drug literature evaluation course was flipped during the 2014 winter semester. Homework from 2013 was transformed into activities and lectures were transformed into multiple short YouTube videos. Assessment. Average examination scores increased from 75.6% to 86.1%. Eighty-two of 94 students completed the postcourse survey in 2014. Compared to traditional lecture, 59.8% of students indicated they preferred the flipped course. Additionally, students felt the course was important, the in-class activities were helpful, and some of the YouTube videos could be improved. We found length of the video to be significantly correlated with the percentage of videos viewed. Conclusion. The flipped model should be considered in drug literature evaluation courses that seek to increase the amount of active learning in the classroom. PMID:27293233

  4. Evaluation of drug interactions with nanofibrillar cellulose.

    PubMed

    Kolakovic, Ruzica; Peltonen, Leena; Laukkanen, Antti; Hellman, Maarit; Laaksonen, Päivi; Linder, Markus B; Hirvonen, Jouni; Laaksonen, Timo

    2013-11-01

    Nanofibrillar cellulose (NFC) (also referred to as cellulose nanofibers, nanocellulose, microfibrillated, or nanofibrillated cellulose) has recently gotten wide attention in various research areas and it has also been studied as excipient in formulation of the pharmaceutical dosage forms. Here, we have evaluated the interactions between NFC and the model drugs of different structural characteristics (size, charge, etc.). The series of permeation studies were utilized to evaluate the ability of the drugs in solution to diffuse through the thin, porous, dry NFC films. An incubation method was used to determine capacity of binding of chosen model drugs to NFC as well as isothermal titration calorimetry (ITC) to study thermodynamics of the binding process. A genetically engineered fusion protein carrying double cellulose binding domain was used as a positive control since its affinity and capacity of binding for NFC have already been reported. The permeation studies revealed the size dependent diffusion rate of the model drugs through the NFC films. The results of both binding and ITC studies showed that the studied drugs bind to the NFC material and indicated the pH dependence of the binding and electrostatic forces as the main mechanism. PMID:23774185

  5. 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

    SciTech Connect

    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.

  6. Rapid pharmacokinetic evaluation of topical drug formulations.

    PubMed

    Garzouzi, V L

    1999-01-01

    A new in vitro test system was developed to efficiently determine the effect of formulation on topical drug delivery. Sheets of viable, excised pig skin were sandwiched betwween two standard 24-well plates. The lower wells contained receptor fluid and a magnetic stirrer. The upper wells were opened to the atmosphere for formulation application. Using 14C-salicylic acid as a model compound, eight different formulations were evaluated representing hydrophilic and lipophilic solutions, a suspension and o/w and w/o emulsions. Formulations were applied to the skin surface in six different wells on three sets of plates. Twenty-four hours after application, excess drug was wiped from the skin surface and assayed for radiolabel. The stratum corneum was removed by tape stripping. Radiolabel contained in the remaining epidermis, dermis and receptor fluid was also determined. Statistical analysis (ANOVA, Student-Newman-Keuls multiple-range test, p=0.05) of radiolabel penetrating into the dermis and receptor fluid revealed the following order of formulations: ethanol= aqueous surfactant less than o/w emulsion = w/o emulsion less than lipophilic solution. These results demonstrate the importance of vehicle in directing drug delivery using a test system capable of simultaneously evaluating a large number of formulations. PMID:23985716

  7. Evaluation of Drug Concentrations Delivered by Microiontophoresis.

    PubMed

    Kirkpatrick, Douglas C; Wightman, R Mark

    2016-06-21

    Microiontophoresis uses an electric current to eject a drug solution from a glass capillary and is often utilized for targeted delivery in neurochemical investigations. The amount of drug ejected, and its effective concentration at the tip, has historically been difficult to determine, which has precluded its use in quantitative studies. To address this, a method called controlled iontophoresis was developed which employs a carbon-fiber microelectrode incorporated into a multibarreled iontophoretic probe to detect the ejection of electroactive species. Here, we evaluate the accuracy of this method. To do this, we eject different concentrations of quinpirole, a D2 receptor agonist, into a brain slice containing the dorsal striatum, a brain region with a high density of dopamine terminals. Local electrical stimulation was used to evoke dopamine release, and inhibitory actions of quinpirole on this release were examined. The amount of drug ejected was estimated by detection of a coejected electrochemical marker. Dose response curves generated in this manner were compared to curves generated by conventional perfusion of quinpirole through the slice. We find several experimental conditions must be optimized for accurate results. First, selection of a marker with an identical charge was necessary to mimic the ejection of the cationic agonist. Next, evoked responses were more precise following longer periods between the end of the ejection and stimulation. Lastly, the accuracy of concentration evaluations was improved by longer ejections. Incorporation of these factors into existing protocols allows for greater certainty of concentrations delivered by controlled iontophoresis. PMID:27212615

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

    PubMed Central

    Lufesi, Norman N; Andrew, Marit; Aursnes, Ivar

    2007-01-01

    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 showing quantities dispensed

  9. Evaluation of novel lipid based formulation of β-Artemether and Lumefantrine in murine malaria model.

    PubMed

    Patil, Sushant; Suryavanshi, Shital; Pathak, Sulabha; Sharma, Shobhona; Patravale, Vandana

    2013-10-15

    The present investigation aims at formulating lipid based drug delivery system of β-Artemether and Lumefantrine and comparative pharmacological evaluation with innovator formulation. Commercial modified oil and indigenous natural fatty acids comprised the oily phase in developing lipidic formulation of β-Artemether and Lumefantrine. The developed system was characterized for mean globule size, stability by freeze thaw cycles, and birefringence. Developed formulation and innovator formulation were compared for their in vivo anti-malarial activity at different dose levels in male Swiss mice, infected with lethal ANKA strain of Plasmodium berghei. The percent parasitemia, activity against time and animal survival period were examined. On fourth day of antimalarial studies, at normal and ½ dose levels, formulations revealed zero percent parasitemia while control showed 33.92±6.00% parasitemia. At 1/10 dose level, developed and innovator formulations revealed zero percent parasitemia upto 11th day, however, three mice from innovator formulation demonstrated recrudescence after 12th day. Both the formulations at normal dose and ½ dose levels showed 100% activity and survival whereas at 1/10 dose level, innovator formulation showed, 62.5% survival. The developed lipidic system of β-Artemether and Lumefantrine exhibited excellent antimalarial activity with 100% survival. PMID:23886650

  10. Lessons Learned: The Evaluation of a Drug Education Program.

    ERIC Educational Resources Information Center

    Royse, David; And Others

    1982-01-01

    Discusses problems encountered in evaluating a mass drug education program including instrument selection, logistical constraints, and data analysis. Offers suggestions as to program evaluation improvement. (Author/RC)

  11. 76 FR 60505 - Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ... notice of public workshop published in the Federal Register of July 28, 2011 (76 FR 45268). In that... HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop; Request for Comments AGENCY: Food and Drug Administration,...

  12. Evaluation of bioreductive drugs in multicell spheroids.

    PubMed

    Durand, R E; Olive, P L

    1992-01-01

    The therapeutic potential of a variety of bioreductive agents, including misonidazole, RSU-1069, NFVO, mitomycin C, porfiromycin, and SR-4233 was evaluated using Chinese hamster V79 multicell spheroids in vitro. Fluorescence-activated cell sorting techniques were used to selectively recover cells from various depths within the spheroids to measure the differential cytotoxicity in the cells near the hypoxic core of the spheroid relative to the well oxygenated peripheral cells. At the high cell density found in spheroids (as in tissues in vivo) the differential toxicity observed was typically much less than expected, based on data from single cell systems. In some cases, this was due to lack of sufficient hypoxia in the spheroids; in other cases, drug treatment itself produced reoxygenation through metabolic or toxic effects during treatment. An unexpected observation of considerable concern was rapid bioreduction of the more active agents; this sometimes occurred at rates that exceeded drug delivery, resulting in considerably less efficacy when large hypoxic fractions were present (e.g. mitomycin C, NFVO, and SR-4233). This suggests that induction of hypoxia prior to bioreductive agent therapy may not be the most productive approach. Though none of the agents showed "ideal" properties, porfiromycin was judged to give the best combination of differential toxicity, longevity in situ, and ability to reach the entire hypoxic cell subpopulation. PMID:1544838

  13. Hospital pharmacists' evaluation of drug wholesaler services.

    PubMed

    Allen, W O; Ryan, M R; Roberts, K B

    1983-10-01

    Services provided by drug wholesalers were evaluated by hospital pharmacists. A survey was mailed to 1500 randomly selected pharmacy directors. Respondents indicated availability and use of 26 customer services. Pharmacists rated the services that they used on the basis of importance of the service and satisfaction with the service. The 644 returned questionnaires indicated that most services were available to a large majority of respondents. Most services used were rated as important or essential. Most respondents were satisfied with wholesaler services; the service with which the most respondents were dissatisfied was stocking of pharmaceuticals in single-unit packaging. Of other services that were widely used and rated important, prompt crediting for delivery errors, few out-of-stock items, frequent pickup of return merchandise, and stocking of injectable pharmaceuticals received low satisfaction ratings. Same-day delivery service and emergency delivery of prescription items were unavailable to more than 40% of respondents. Hospital pharmacists were generally satisfied with services provided by drug wholesalers. Wholesalers should be aware of the particular service needs of hospital pharmacists, and further studies of these needs should be conducted. PMID:6638028

  14. Leachables evaluation for bulk drug substance.

    PubMed

    Tsui, Victor; Somma, Maria S; Zitzner, Linda A

    2009-01-01

    This study describes a comprehensive analytical approach for evaluating potential leachables from product-contacting material surfaces in the manufacture of bulk drug substance (BDS) for use in parenteral products. A qualitative step-by-step evaluation of the process stream for the production, purification, and storage of the BDS was performed. The product-contact equipment surfaces were then grouped based on their materials of construction and prioritized according to the potential risk of contributing leachables to the BDS. Based on this evaluation, 13 potential leachable species were identified and classified either as volatile organic compounds (VOCs), semi-volatile organic compounds (SVOCs), anions, cations, or trace metals. The BDS was first screened for the presence of VOCs, SVOCs, anions, cations, and trace metals using analytical methods that were qualified for their application with the BDS. Thirteen potential leachables were then spiked in the BDS and in the water for injection for spike-recovery studies. The analysis of the BDS for potential leachables showed that the potential impurities were not present in the BDS except for a trace amount of silicon, and that the residual solvent concentrations were lower than the recommended limits established by the International Committee on Harmonisation. The spike-recovery studies confirmed that the analytical methods could effectively determine the leachable compounds in the BDS. Moreover, the 13 contaminants did not form a complex with the protein in the BDS and did not represent a potential risk to the BDS's safety and stability. PMID:19634355

  15. Pattern of drug utilization for treatment of uncomplicated malaria in urban Ghana following national treatment policy change to artemisinin-combination therapy

    PubMed Central

    Dodoo, Alexander NO; Fogg, Carole; Asiimwe, Alex; Nartey, Edmund T; Kodua, Augustina; Tenkorang, Ofori; Ofori-Adjei, David

    2009-01-01

    Background Change of first-line treatment of uncomplicated malaria to artemisinin-combination therapy (ACT) is widespread in Africa. To expand knowledge of safety profiles of ACT, pharmacovigilance activities are included in the implementation process of therapy changes. Ghana implemented first-line therapy of artesunate-amodiaquine in 2005. Drug utilization data is an important component of determining drug safety, and this paper describes how anti-malarials were prescribed within a prospective pharmacovigilance study in Ghana following anti-malarial treatment policy change. Methods Patients with diagnosis of uncomplicated malaria were recruited from pharmacies of health facilities throughout Accra in a cohort-event monitoring study. The main drug utilization outcomes were the relation of patient age, gender, type of facility attended, mode of diagnosis and concomitant treatments to the anti-malarial regimen prescribed. Logistic regression was used to predict prescription of nationally recommended first-line therapy and concomitant prescription of antibiotics. Results The cohort comprised 2,831 patients. Curative regimens containing an artemisinin derivative were given to 90.8% (n = 2,574) of patients, although 33% (n = 936) of patients received an artemisinin-based monotherapy. Predictors of first-line therapy were laboratory-confirmed diagnosis, age >5 years, and attending a government facility. Analgesics and antibiotics were the most commonly prescribed concomitant medications, with a median of two co-prescriptions per patient (range 1–9). Patients above 12 years were significantly less likely to have antibiotics co-prescribed than patients under five years; those prescribed non-artemisinin monotherapies were more likely to receive antibiotics. A dihydroartemisinin-amodiaquine combination was the most used therapy for children under five years of age (29.0%, n = 177). Conclusion This study shows that though first-line therapy recommendations may change

  16. U.S. Food and Drug Administration. "Evaluation Criteria" for Difficult to Compound Drugs.

    PubMed

    Allen, Loyd V

    2015-01-01

    This is part 2 of a 2-part article on the topic of Nominations of Difficult to Compound Drugs to the FDA-PCAC. Part 1 provided a current list of Nominations of Difficult to Compound Drugs to the FDA-PCAC. This article discusses the evaluation procedure for determining which drugs are demonstrably difficult to compound. PMID:26891563

  17. 78 FR 8446 - Center for Drug Evaluation and Research; Prescription Drug Labeling Improvement and Enhancement...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-06

    ... content and format requirements for labeling to make it easier to access, read, and use (71 FR 3922... HUMAN SERVICES Food and Drug Administration 21 CFR Parts 201, 314, and 601 Center for Drug Evaluation... . Submit written comments to the Division of Dockets Management (HFA- 301), Food and Drug...

  18. Evaluation of anticoccidial drugs in chicken embryos.

    PubMed

    Xie, M Q; Fukata, T; Gilbert, J M; McDougald, L R

    1991-01-01

    Infections of Eimeria tenella in chicken embryos were used to compare the anticoccidial activity of ten drugs. The minimal inhibitory concentration (MIC) and minimal toxic concentration (MTC) were affected by the time of inoculation into the embryos and by the chemical nature of the compounds. Some compounds (nicarbazin, amprolium) had no effect on the development of coccidia when they were injected into embryos after the day of infection. Drugs that act early in the life cycle of coccidia (robenidine, clopidol, decoquinate, diclazuril, halofuginone, monensin, salinomycin, and lasalocid) were active at 5-125 micrograms/embryo when they were injected on the day of infection. The ionophores and halofuginone were highly toxic to embryos; most synthetic compounds were nontoxic. The incubation of merozoites in drug suspensions prior to the infection of embryos did not result in embryo toxicity, but the resultant MICs were much higher than those obtained when drugs were injected directly into the embryos. Several products were essentially inactive. Neither nicarbazin nor amprolium prevented oocyst formation. The widely divergent endpoints for the MIC and MTC of anticoccidials in embryos seriously limits the application of this technique as a screen for anticoccidial drugs. PMID:1792230

  19. Consensus Recommendations for Systematic Evaluation of Drug-Drug Interaction Evidence for Clinical Decision Support

    PubMed Central

    Scheife, Richard T.; Hines, Lisa E.; Boyce, Richard D.; Chung, Sophie P.; Momper, Jeremiah; Sommer, Christine D.; Abernethy, Darrell R.; Horn, John; Sklar, Stephen J.; Wong, Samantha K.; Jones, Gretchen; Brown, Mary; Grizzle, Amy J.; Comes, Susan; Wilkins, Tricia Lee; Borst, Clarissa; Wittie, Michael A.; Rich, Alissa; Malone, Daniel C.

    2015-01-01

    Background Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. Objective To provide recommendations for systematic evaluation of evidence from the scientific literature, drug product labeling, and regulatory documents with respect to DDIs for clinical decision support. Methods A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 15 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. Results We developed expert-consensus answers to three key questions: 1) What is the best approach to evaluate DDI evidence?; 2) What evidence is required for a DDI to be applicable to an entire class of drugs?; and 3) How should a structured evaluation process be vetted and validated? Conclusion Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug information systems that implement these recommendations should be able to provide higher quality information about DDIs in drug compendia and clinical decision support tools. PMID:25556085

  20. Biomimetic microfluidic device for in vitro antihypertensive drug evaluation.

    PubMed

    Li, Lei; Lv, Xiaoqing; Ostrovidov, Serge; Shi, Xuetao; Zhang, Ning; Liu, Jing

    2014-07-01

    Microfluidic devices have emerged as revolutionary, novel platforms for in vitro drug evaluation. In this work, we developed a facile method for evaluating antihypertensive drugs using a microfluidic chip. This microfluidic chip was generated using the elastic material poly(dimethylsiloxane) (PDMS) and a microchannel structure that simulated a blood vessel as fabricated on the chip. We then cultured human umbilical vein endothelial cells (HUVECs) inside the channel. Different pressures and shear stresses could be applied on the cells. The generated vessel mimics can be used for evaluating the safety and effects of antihypertensive drugs. Here, we used hydralazine hydrochloride as a model drug. The results indicated that hydralazine hydrochloride effectively decreased the pressure-induced dysfunction of endothelial cells. This work demonstrates that our microfluidic system provides a convenient and cost-effective platform for studying cellular responses to drugs under mechanical pressure. PMID:24673554

  1. Need for multicriteria evaluation of generic drug policies.

    PubMed

    Kaló, Zoltán; Holtorf, Anke-Peggy; Alfonso-Cristancho, Rafael; Shen, Jie; Ágh, Tamás; Inotai, András; Brixner, Diana

    2015-03-01

    Policymakers tend to focus on improving patented drug policies because they are under pressure from patients, physicians, and manufacturers to increase access to novel therapies. The success of pharmaceutical innovation over the last few decades has led to the availability of many off-patent drugs to treat disease areas with the greatest public health need. Therefore, the success of public health programs in improving the health status of the total population is highly dependent on the efficiency of generic drug policies. The objective of this article was to explore factors influencing the true efficiency of generic prescription drug policies in supporting public health initiatives in the developed world. Health care decision makers often assess the efficiency of generic drug policies by the level of price erosion and market share of generics. Drug quality, bioequivalence, in some cases drug formulations, supply reliability, medical adherence and persistence, health outcomes, and nondrug costs, however, are also attributes of success for generic drug policies. Further methodological research is needed to measure and improve the efficiency of generic drug policies. This also requires extension of the evidence base of the impact of generic drugs, partly based on real-world evidence. Multicriteria decision analysis may assist policymakers and researchers to evaluate the true value of generic drugs. PMID:25773570

  2. Evaluation of aqueous preparations from herbal drugs.

    PubMed

    Vitková, Zuzana; Brázdovicová, Bronislava; Ralbovská, Katarína; Halenárová, Andrea

    2010-01-01

    The paper presents results obtained within analysis of aqueous preparations obtained from the herbal drugs, (APHD) which are available in pharmacy as mass produced drugs. In particular, the following drugs were analyzed: CYNAROFIT, L'ALIAFIT, Tinctura belladonnae, Tinctura gentianae, Tinctura chinae a Tinctura valerianae made by Calendula, j.s.c.--Slovakia and Tinctura valerianae made by IVAX-Czech republic. Tictura valerianae magistraliter was prepared in a laboratory. The APHDs were analyzed under the following aspects: amount of dry matter, density, index of refraction, pH value, content of ethanol, influence of the light on these parameters as well as the global appearance of samples. In parallel to that, the stability of samples Tinctura valerianae prepared by two different manufacturers and the samples of magistraliter preparations were compared. It was found that storing samples delivered by Calendula j.s.c. does not significantly influenced their stability neither in the light nor in the dark, kept at the temperature of 20-25 degrees C over the time interval of 6 months. All samples were in agreement with the norms of companies as well as with both Czechoslovak (CSL 4) and Slovak (SL 1) pharmacopoeias. Besides, the results obtained show that a kind of extraction methods (percolation, maceration) does not influence neither quality nor stability of the samples Tinctura valerianae. PMID:20210084

  3. 75 FR 34452 - Center for Drug Evaluation and Research Data Standards Plan; Availability for Comment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-17

    ... HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research Data Standards Plan... development of a comprehensive data standards program in the Center for Drug Evaluation and Research (CDER... Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903...

  4. Malaria in South America: a drug discovery perspective

    PubMed Central

    2013-01-01

    The challenge of controlling and eventually eradicating malaria means that new tools are urgently needed. South America’s role in this fight spans both ends of the research and development spectrum: both as a continent capable of discovering and developing new medicines, and also as a continent with significant numbers of malaria patients. This article reviews the contribution of groups in the South American continent to the research and development of new medicines over the last decade. Therefore, the current situation of research targeting malaria control and eradication is discussed, including endemicity, geographical distribution, treatment, drug-resistance and diagnosis. This sets the scene for a review of efforts within South America to discover and optimize compounds with anti-malarial activity. PMID:23706107

  5. Validating Self-Reports of Illegal Drug Use to Evaluate National Drug Control Policy: A Reanalysis and Critique

    ERIC Educational Resources Information Center

    Magura, Stephen

    2010-01-01

    Illicit drug use remains at high levels in the U.S. The federal Office of National Drug Control Policy evaluates the outcomes of national drug demand reduction policies by assessing annual changes in drug use from several federally sponsored annual national surveys. Such survey methods, relying exclusively on drug use as self-reported on…

  6. Drug-resistant malaria in Sudan: A review of evidence and scenarios for the future

    PubMed Central

    Adeel, Ahmed Awad

    2012-01-01

    Resistance of falciparum malaria to chloroquine (CQ) has gradually emerged in the late 1970s, reaching unacceptably high proportions over the following three decades of use as frst line treatment in Sudan. By 2004–2006 CQ was replaced by artemisinin-based combination treatment (ACTs), with combination of sulfadoxine-pyrimethamine (SP) and artesunate (AS) deployed as frst-line drug against falciparum malaria. The present review follows the evolution of CQ resistance in Sudan and the available evidence on the response to the present frst-line drugs. The fndings in Sudan are analyzed in view of developments in other African countries and at the global level, with the hope of elucidating possible scenarios for the course of events in the Sudan. Northern Sudan has been one of the areas where signals indicating the emergence of drug resistant malaria parasites have frst originated in Africa. The pattern of low endemicity and low population immunity to malaria, together with massive deployment and improper use of anti-malarial drugs created the ideal environment for creation of anti-malarial drug resistance. Such an environment existed in certain areas in South East Asia that had historically been the epicenter from which falciparum malaria parasites resistant to pyrimethamine and chloroquine have spread to the rest of the world. The alarming recent reports about the emergence of artemisinin (ART) resistance in South East Asia have lead WHO to take specifc measures for prevention, early detection and containment of drug resistance. What could be applicable in Sudan in these measures is discussed here.

  7. Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

    PubMed Central

    Miller, Laurence L.

    2014-01-01

    Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing. PMID:24973197

  8. Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)

    PubMed Central

    Liu, Zhichao; Shi, Qiang; Ding, Don; Kelly, Reagan; Fang, Hong; Tong, Weida

    2011-01-01

    Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity. PMID:22194678

  9. Ecotoxicological evaluation of the antimalarial drug chloroquine.

    PubMed

    Zurita, Jorge L; Jos, Angeles; del Peso, Ana; Salguero, Manuel; López-Artíguez, Miguel; Repetto, Guillermo

    2005-10-15

    There is limited information available about the potential environmental effects of chloroquine (CQ), a widely used antimalarial agent and a promising inexpensive drug in the management of HIV disease. The acute effects of CQ were studied using four ecotoxicological model systems. The most sensitive bioindicator was the immobilization of the cladoceran Daphnia magna, with an EC50 of 12 microM CQ at 72 h and a non-observed adverse effect level of 2.5 microM CQ, followed very closely by the decrease of the uptake of neutral red and the reduction of the lysosomal function in the fish cell line PLHC-1 derived from the top minnow Poeciliopsis lucida, probably due to the selective accumulation of the drug into the lysosomes. There was significant cellular stress as indicated by the increases on metallothionein and glucose-6P dehydrogenase levels after 24 h of exposure and succinate dehydrogenase activity mainly after 48 h. No changes were observed for ethoxyresorufin-O-deethylase (EROD) activity. The least sensitive model was the inhibition of bioluminescence in the bacterium Vibrio fischeri. An increase of more than five-fold in the toxicity from 24 to 72 h of exposure was observed for the inhibition of the growth in the alga Chlorella vulgaris and the content of total protein and MTS tetrazolium salt metabolization in PLHC-1 cells. At the morphological level, the most evident alterations in PLHC-1 cultures were hydropic degeneration from 25 microM CQ after 24h of exposure and the presence of many cells with pyknotic nuclei, condensed cytoplasm and apoptosis with concentrations higher than 50 microM CQ after 48 h of exposure. In conclusion, CQ should be classified as harmful to aquatic organisms. PMID:16153718

  10. Evaluation of certain veterinary drug residues in food.

    PubMed

    2009-01-01

    This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues in food. The first part of the report considers general principles regarding the evaluation of veterinary drugs within the terms of reference of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), including a hypothesis-driven decision tree approach for the safety evaluation of residues of veterinary drugs; comments on the Committee for Veterinary Products for Medicinal Use reflection paper on the new approach developed by JECFA for exposure and maximum residue limit (MRL) assessment of residues; residues of veterinary drugs in honey and possible approaches to derive MRLs for this commodity; comments on a paper entitled "Risk-assessment policies: Differences among jurisdictions"; and the use of no-observed-effect level (NOEL) and no-observed-adverse-effect level (NOAEL) in JECFA assessments. Summaries follow of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: three antimicrobial agents (avilamycin, tilmicosin, tylosin), one anthelminthic (triclabendazole), one production aid (melengestrol acetate), two antimicrobial agents and production aids (monensin and narasin), a glucocarticosteroid (dexamethasone) and an antimicrobial agent and contaminant (malachite green). Annexed to the report is a summary of the Committee's recommendations on these drugs, including acceptable daily intakes (ADIs) and proposed MRLs. PMID:20112498

  11. Food and Drug Administration Evaluation and Cigarette Smoking Risk Perceptions

    ERIC Educational Resources Information Center

    Kaufman, Annette R.; Waters, Erika A.; Parascandola, Mark; Augustson, Erik M.; Bansal-Travers, Maansi; Hyland, Andrew; Cummings, K. Michael

    2011-01-01

    Objectives: To examine the relationship between a belief about Food and Drug Administration (FDA) safety evaluation of cigarettes and smoking risk perceptions. Methods: A nationally representative, random-digit-dialed telephone survey of 1046 adult current cigarette smokers. Results: Smokers reporting that the FDA does not evaluate cigarettes for…

  12. Implementing School Drug and Alcohol Curricula: A Descriptive Evaluation.

    ERIC Educational Resources Information Center

    Tricker, Ray; Davis, Lorraine G.

    1987-01-01

    Two Oregon school district drug and alcohol programs were evaluated based on seven criteria: (1) cost of implementation; (2) teacher inservice participation; (3) attitudes of teachers toward program implementation; (4) administrative support; (5) teacher compliance with the curriculum; (6) school district program evaluation; and (7) community…

  13. Cellular Biomechanics in Drug Screening and Evaluation: Mechanopharmacology

    PubMed Central

    Krishnan, Ramaswamy; Park, Jin-Ah; Seow, Chun Y.; Lee, Peter V-S.; Stewart, Alastair G.

    2016-01-01

    The study of mechanobiology is now widespread. The impact of cell and tissue mechanics on cellular responses is well appreciated. However, knowledge of the impact of cell and tissue mechanics on pharmacological responsiveness, and its application to drug screening and mechanistic investigations, have been very limited in scope. We emphasize the need for a heightened awareness of the important bidirectional influence of drugs and biomechanics in all living systems. We propose that the term ‘mechanopharmacology’ be applied to approaches that employ in vitro systems, biomechanically appropriate to the relevant (patho)physiology, to identify new drugs and drug targets. This article describes the models and techniques that are being developed to transform drug screening and evaluation, ranging from a 2D environment to the dynamic 3D environment of the target expressed in the disease of interest. PMID:26651416

  14. Multi-wavelength pulse plethysmography for real-time drug delivery monitoring

    NASA Astrophysics Data System (ADS)

    Adhikari, Pratik; Magaña, Isidro B.; O'Neal, Patrick D.

    2014-02-01

    A novel multi-wavelength photoplethysmograph (PPG), previously utilized to quantify optically absorptive circulating gold nanoparticles, has demonstrated the potential to enhance therapeutic treatment predictability as pharmacokinetic metrics are provided throughout the intravenous delivery phase of quinine in real-time. This report demonstrates how the PPG could be used to assess the real-time bioavailability of other types of intravenously delivered optically-absorbing nanoparticles and drugs. The drug currently under investigation is anti-malarial quinine (absorption peak ~350 nm). We describe how the algorithm has been adapted to quantify the concentration of quinine in the pulsatile, circulating blood based on its extinction at three wavelengths (340, 660 and 940 nm). We show an example of the system collecting data representing the baseline, injection, and the clearance phases. An examination of the raw signal suggests that the system is well suited to sense the concentration of quinine in the therapeutic range (10mg/kg).

  15. Comprehensive non-clinical respiratory evaluation of promising new drugs

    SciTech Connect

    Murphy, Dennis J. . E-mail: dennis.j.murphy@GSK.com

    2005-09-01

    The need to evaluate the potential for new drugs to produce adverse effects on respiratory function in non-clinical safety assessment is based on the known effects of drugs from a variety of pharmacological/therapeutic classes on the respiratory system, the life-threatening consequences of respiratory dysfunction, and compliance with world-wide regulatory safety guidelines. The objective of this article is to provide a brief overview of the functional disorders of the respiratory system and to present the strategy and techniques considered to be most appropriate for detecting and characterizing drug-induced respiratory disorders in non-clinical safety studies.

  16. Objective evaluation of generic-specific drug information.

    PubMed

    Iijima, Hisashi; Koshimizu, Toshimasa; Shiragami, Makoto

    2007-03-01

    Growth in the use of generic drugs remains flat in Japan, and one of the reasons cited is information availability. We previously showed that the amount of information available on generic drugs differs greatly from one pharmaceutical industry to another, though, on average, it is inferior to that for original, brand name drugs. This report looks at information on individual generic drug products, rather than the active ingredients contained therein. In May 2004, we studied ingredients sold by at least 20 pharmaceutical industries. Here, for the same, particular ingredient, we evaluate current availability of generic-specific information (as of August 2005), as well as change over time. On the basis of ingredient, the amount of information provided for generic drugs is 31.1+/-17.5-57.3+/-11.7% that for the corresponding original drugs (Mean+/-S.D.), but in the company-by-company comparison, a large dispersion of 16.6+/-5.0-69.4+/-11.9% (Mean +/-S.D.) is observed. In terms of information content, generic drugs provided less than 50% as much information on "drug interactions", "clinical efficacy", and "outline of side effects", as that for original drugs. The difference between generic and original drugs was smaller in comparisons focusing on information specific to generics than on those including all drug information. Our study also revealed that, over time, some pharmaceutical industries have added to the amount of information provided. When information is a deciding factor, the quantity available at the current time is not the only relevant aspect; it is best to select a pharmaceutical industry that is proactive about supplementing information post-release. PMID:17329940

  17. A cluster-randomized trial of mass drug administration with a gametocytocidal drug combination to interrupt malaria transmission in a low endemic area in Tanzania

    PubMed Central

    2011-01-01

    Background Effective mass drug administration (MDA) with anti-malarial drugs can clear the human infectious reservoir for malaria and thereby interrupt malaria transmission. The likelihood of success of MDA depends on the intensity and seasonality of malaria transmission, the efficacy of the intervention in rapidly clearing all malaria parasite stages and the degree to which symptomatic and asymptomatic parasite carriers participate in the intervention. The impact of MDA with the gametocytocidal drug combination sulphadoxine-pyrimethamine (SP) plus artesunate (AS) plus primaquine (PQ, single dose 0.75 mg/kg) on malaria transmission was determined in an area of very low and seasonal malaria transmission in northern Tanzania. Methods In a cluster-randomized trial in four villages in Lower Moshi, Tanzania, eight clusters (1,110 individuals; cluster size 47- 209) were randomized to observed treatment with SP+AS+PQ and eight clusters (2,347 individuals, cluster size 55- 737) to treatment with placebo over three days. Intervention and control clusters were 1km apart; households that were located between clusters were treated as buffer zones where all individuals received SP+AS+PQ but were not selected for the evaluation. Passive case detection was done for the entire cohort and active case detection in 149 children aged 1-10 year from the intervention arm and 143 from the control arm. Four cross-sectional surveys assessed parasite carriage by microscopy and molecular methods during a five-month follow-up period. Results The coverage rate in the intervention arm was 93.0% (1,117/1,201). Parasite prevalence by molecular detection methods was 2.2-2.7% prior to the intervention and undetectable during follow-up in both the control and intervention clusters. None of the slides collected during cross-sectional surveys had microscopically detectable parasite densities. Three clinical malaria episodes occurred in the intervention (n = 1) and control clusters (n = 2). Conclusions

  18. Evaluation of aminohydantoins as a novel class of antimalarial agents.

    PubMed

    Meyers, Marvin J; Tortorella, Micky D; Xu, Jing; Qin, Limei; He, Zhengxiang; Lang, Xingfen; Zeng, Wentian; Xu, Wanwan; Qin, Li; Prinsen, Michael J; Sverdrup, Francis M; Eickhoff, Christopher S; Griggs, David W; Oliva, Jonathan; Ruminski, Peter G; Jacobsen, E Jon; Campbell, Mary A; Wood, David C; Goldberg, Daniel E; Liu, Xiaorong; Lu, Yongzhi; Lu, Xin; Tu, Zhengchao; Lu, Xiaoyun; Ding, Ke; Chen, Xiaoping

    2014-01-01

    Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure-activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice. PMID:24900778

  19. NOTE: A rapid procedure for initial drug evaluation

    NASA Astrophysics Data System (ADS)

    Macpherson, A. K.; Neti, S.; Macpherson, P. A.

    2001-06-01

    The overall aim of this work is to develop computer simulations to aid in the selection of proposed medicines and identify those most likely to succeed. One important feature is a systems approach to simulate both the target area with which the drug is designed to interact as well as the surrounding areas where feedback mechanisms may alter the expected effect. The simulation must be rapid if it is to be used to evaluate large numbers of potential drugs. Thus the procedure simplifies many of the known complex phenomena to provide a general framework and feedback mechanisms. An example of the use of the simulation to study a drug used to treat hypertension is given. A possible use of the technique is shown using the example of the effect of varying the drug dosage on the contraction of the arteriole muscle.

  20. Bar-code technology applied to drug-use evaluation.

    PubMed

    Zarowitz, B J; Petitta, A; Mlynarek, M; Touchette, M; Peters, M; Long, P; Patel, R

    1993-05-01

    Bar-code technology was used to determine: (1) patterns in histamine H2-receptor antagonist use and (2) the occurrence of adverse drug effects and drug interactions associated with the use of these agents in critically ill patients. Patients at Henry Ford Hospital (Detroit) receiving histamine H2-receptor antagonists over a two-month period were evaluated. Clinical information was collected in the intensive care units by using a bar-code system. The data-capture menu was based on drug-use-evaluation criteria for H2-receptor antagonists. Data collected in the scanning wands were uploaded into a computer database and were analyzed at the end of the study. Data were collected for 207 patients. Cimetidine was the predominant H2-receptor antagonist used, and the predominant indication was stress-ulcer prophylaxis. Dosing trends followed accepted guidelines for cimetidine dosage adjustment in renal and hepatic failure. Two drug interactions and six adverse drug reactions occurred. Pharmacists made 92 recommendations to the medical staff regarding modification in therapy, involving 32% of the patients. Data collection required an average of 10 minutes per day each for three pharmacists. H2-receptor antagonist use patterns were evaluated in intensive care units through the application of bar-code technology. The speed and efficiency of this automated tool facilitated collection of a large amount of data. PMID:8099468

  1. [Evaluation of educational effects on drug dependence abstinence for convicts].

    PubMed

    Sakurai, Tomoko; Nishikawa, Kyoko; Tanaka, Takanori

    2011-06-01

    The object of this study is to evaluate the educational effects of group work sessions on drug dependence abstinence for convicts in Fukui Prison. Questionnaire surveys were conducted among participants on the first and last session. The results of surveys were analyzed quantitatively. The average ages of 50 respondents were 39 years. 95.9% of them used methamphetamine among drugs and the majority has used drugs for the past 5 years. 93.9% of respondents had no medical treatment histories and 95.8% of them have not used any formal consultations. The survey result before the sessions showed that 75.5% of respondents showed positive stances towards participations on educational group work sessions. The survey after the sessions showed 67.4% of respondents were able to talk their drug problems in group meetings and 87.0% responded that group work sessions were helpful for solving drug problems. Also, 80.0% responded that they can stop using drugs and the percentage dropped by 11.0% from the first session. In terms of the participation in self-help groups after releases from the prison, the majority responded negatively, although 78.0% showed positive responses to using consultation services. The outcomes by means of evaluation scale also showed a significant improvement on denial and no relevant change on interpersonal trusts. This study revealed that it was possible to confirm the effectiveness of drug abstinence education through group work. It is important to consider three points in further studies; 1) cooperation between judicial and medical institutions for introducing consultation and medical treatments among convicts; 2) follow-up programs for reinforcing education on drug abstinence; 3) social welfare services in cooperation with educational effects to prevent repeated offences. PMID:21861335

  2. Evaluation of certain veterinary drug residues in food.

    PubMed

    2001-01-01

    This report presents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues in food. The first part of the report considers the interpretation of data on inhibition of cholinesterase activity and recommendations arising from an informal meeting on harmonization with the Joint FAO/WHO Meeting on Pesticide Residues. A summary follows of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: one anthelminthic agent (ivermectin); four antimicrobial agents (flumequine, lincomycin, oxytetracycline and tilmicosin); six insecticides (cyhalothrin, cypermethrin, alpha-cypermethrin, dicyclanil, permethrin and metrifonate (trichlorfon)); and one production aid (melengestrol acetate). Annexed to the report are a summary of the Committee's recommendations on these drugs, including Acceptable Daily Intakes and Maximum Residue Limits and further information required. PMID:11402526

  3. Evaluation of certain veterinary drug residues in food.

    PubMed

    2002-01-01

    This report presents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues in food. The first part of the report considers risk assessment principles and presents the views of the Committee on the FAO/WHO Project to update principles and methods for the risk assessment of chemicals in food. Summaries follow of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: three anthelminthic agents (doramectin, ivermectin and tiabendazole), seven antimicrobial agents (cefuroxime, dihydrostreptomycin and streptomycin, lincomycin, neomycin, oxytetracycline and thiamphenicol), four insecticides (cyhalothrin, cypermethrin and alpha-cypermethrin, and phoxim) and one production aid (melengestrol acetate). Annexed to the report is a summary of the Committee's recommendations on these drugs, including Acceptable Daily Intakes and Maximum Residue Limits and further information required. PMID:12592988

  4. US-based Drug Cost Parameter Estimation for Economic Evaluations

    PubMed Central

    Levy, Joseph F; Meek, Patrick D; Rosenberg, Marjorie A

    2014-01-01

    Introduction In the US, more than 10% of national health expenditures are for prescription drugs. Assessing drug costs in US economic evaluation studies is not consistent, as the true acquisition cost of a drug is not known by decision modelers. Current US practice focuses on identifying one reasonable drug cost and imposing some distributional assumption to assess uncertainty. Methods We propose a set of Rules based on current pharmacy practice that account for the heterogeneity of drug product costs. The set of products derived from our Rules, and their associated costs, form an empirical distribution that can be used for more realistic sensitivity analyses, and create transparency in drug cost parameter computation. The Rules specify an algorithmic process to select clinically equivalent drug products that reduce pill burden, use an appropriate package size, and assume uniform weighting of substitutable products. Three diverse examples show derived empirical distributions and are compared with previously reported cost estimates. Results The shapes of the empirical distributions among the three drugs differ dramatically, including multiple modes and different variation. Previously published estimates differed from the means of the empirical distributions. Published ranges for sensitivity analyses did not cover the ranges of the empirical distributions. In one example using lisinopril, the empirical mean cost of substitutable products was $444 (range $23–$953) as compared to a published estimate of $305 (range $51–$523). Conclusions Our Rules create a simple and transparent approach to create cost estimates of drug products and assess their variability. The approach is easily modified to include a subset of, or different weighting for, substitutable products. The derived empirical distribution is easily incorporated into one-way or probabilistic sensitivity analyses. PMID:25532826

  5. Drug Abuse Prevention: Report of the Temporary State Commission to Evaluate the Drug Laws.

    ERIC Educational Resources Information Center

    Betros, Emeel S.; And Others

    The findings and recommendations of the Temporary State Commission to Evaluate the Drug Laws, set forth in the introduction to this report, are based on questionnaires to prevention experts and professionals responsible for child and adolescent care, on communications with community agencies, and on statewide public hearings. The committee found…

  6. Evaluation of Ebola Virus Inhibitors for Drug Repurposing.

    PubMed

    Madrid, Peter B; Panchal, Rekha G; Warren, Travis K; Shurtleff, Amy C; Endsley, Aaron N; Green, Carol E; Kolokoltsov, Andrey; Davey, Robert; Manger, Ian D; Gilfillan, Lynne; Bavari, Sina; Tanga, Mary J

    2015-07-10

    A systematic screen of FDA-approved drugs was performed to identify compounds with in vitro antiviral activities against Ebola virus (EBOV). Compounds active (>50% viral inhibition and <30% cellular toxicity) at a single concentration were tested in dose-response assays to quantitate the antiviral activities in replication and viral entry assays as well as cytotoxicity in the Vero cell line used to conduct these assays. On the basis of the approved human dosing, toxicity/tolerability, and pharmacokinetic data, seven of these in vitro hits from different pharmacological classes (chloroquine (CQ), amiodarone, prochlorperazine, benztropine, azithromycin, chlortetracycline, and clomiphene) were evaluated for their in vivo efficacy at a single dose and were administered via either intraperitoneal (ip) or oral route. Initially, azithromycin (100 mg/kg, twice daily, ip), CQ (90 mg/kg, twice daily, ip), and amiodarone (60 mg/kg, twice daily, ip) demonstrated significant increases in survival in the mouse model. After repeat evaluation, only CQ was found to reproducibly give significant efficacy in the mouse model with this dosing regimen. Azithromycin and CQ were also tested in a guinea pig model of EBOV infection over a range of doses, but none of the doses increased survival, and drug-related toxicity was observed at lower doses than in the mouse. These results show the benefits and specific challenges associated with drug repurposing and highlight the need for careful evaluation of approved drugs as rapidly deployable countermeasures against future pandemics. PMID:27622822

  7. The wisdom of crowds and the repurposing of artesunate as an anticancer drug.

    PubMed

    Augustin, Yolanda; Krishna, Sanjeev; Kumar, Devinder; Pantziarka, Pan

    2015-01-01

    Artesunate, a semi-synthetic and water-soluble artemisinin-derivative used as an anti-malarial agent, has attracted the attention of cancer researchers due to a broad range of anti-cancer activity including anti-angiogenic, immunomodulatory and treatment-sensitisation effects. In addition to pre-clinical evidence in a range of cancers, a recently completed randomised blinded trial in colorectal cancer has provided a positive signal for further clinical investigation. Used perioperatively artesunate appears to reduce the rate of disease recurrence - and the Neo-Art trial, a larger Phase II RCT, is seeking to confirm this positive effect. However, artesunate is a generic medication, and as with other trials of repurposed drugs, the Neo-Art trial does not have commercial sponsorship. In an innovative move, the trial is seeking funds directly from members of the public via a crowd-funding strategy that may have resonance beyond this single trial. PMID:26557887

  8. The wisdom of crowds and the repurposing of artesunate as an anticancer drug

    PubMed Central

    Augustin, Yolanda; Krishna, Sanjeev; Kumar, Devinder; Pantziarka, Pan

    2015-01-01

    Artesunate, a semi-synthetic and water-soluble artemisinin-derivative used as an anti-malarial agent, has attracted the attention of cancer researchers due to a broad range of anti-cancer activity including anti-angiogenic, immunomodulatory and treatment-sensitisation effects. In addition to pre-clinical evidence in a range of cancers, a recently completed randomised blinded trial in colorectal cancer has provided a positive signal for further clinical investigation. Used perioperatively artesunate appears to reduce the rate of disease recurrence - and the Neo-Art trial, a larger Phase II RCT, is seeking to confirm this positive effect. However, artesunate is a generic medication, and as with other trials of repurposed drugs, the Neo-Art trial does not have commercial sponsorship. In an innovative move, the trial is seeking funds directly from members of the public via a crowd-funding strategy that may have resonance beyond this single trial. PMID:26557887

  9. Evaluation of Factors Affecting Powdered Drug Reconstitution in Microgravity

    NASA Technical Reports Server (NTRS)

    Schaffner, Grant; Johnston, Smith; Marshburn, Tom

    1999-01-01

    Owing to the high cost of transporting mass into space, and the small volume available for equipment in the Space Shuttle Orbiter and the International Space Station, refrigeration space is extremely limited. For this reason, there exists strong motivation for transporting certain drugs in powdered form so that they do not require refrigeration. When needed, the powdered drug will be mixed with saline to obtain a liquid form that may be injected intravenously. While this is a relatively simple task in a 1-G environment, there are some difficulties that may be encountered in 0-G. In non-accelerated spaceflight, gravitational and inertial forces are eliminated allowing other smaller forces, such as capillary forces and surface tension, to dominate the behavior of fluids. For instance, water slowly ejected from a straw will tend to form a sphere, while fluid in a container will tend to wet the inside surface forming a highly rounded meniscus. Initial attempts at mixing powdered drugs with saline in microgravity have shown a tendency toward forming foamy emulsions instead of the desired homogeneous solution. The predominance of adhesive forces between the drug particles and the interface tensions at the gas/liquid and solid/liquid interfaces drastically reduce the rate of deaggregation of the drug powder and also reduce the rate of absorption of saline by the powder mass. In addition, the capillary forces cause the saline to wet the inside of the container, thus trapping air bubbles within the liquid. The rate of dissolution of a powder drug is directly proportional to the amount of surface area of the solid that is exposed to liquid solvent. The surface area of drug that is in contact with the liquid is greatly reduced in microgravity and, as a result, the dissolution rate is reduced as well. The KC-135 research described here was aimed at evaluating the extent to which it is possible to perform drug reconstitution in the weightlessness of parabolic flight using

  10. Biological evaluation of layered double hydroxides as efficient drug vehicles.

    PubMed

    Li, Yan; Liu, Dan; Ai, Hanhua; Chang, Qing; Liu, Dandan; Xia, Ying; Liu, Shuwen; Peng, Nanfang; Xi, Zhuge; Yang, Xu

    2010-03-12

    Recently there has been a rapid expansion of the development of bioinorganic hybrid systems for safe drug delivery. Layered double hydroxides (LDH), a variety of available inorganic matrix, possess great promise for this purpose. In this study, an oxidative stress biomarker system, including measurement of reactive oxygen species, glutathione content, endogenous nitric oxide, carbonyl content in proteins, DNA strand breaks and DNA-protein crosslinks, was designed to evaluate the biocompatibility of different concentrations of nano-Zn/Al-LDH with a Hela cell line. The drug delivery activity of the LDH-folic-acid complex was also assessed. The resulting data clearly demonstrated that nano-LDH could be applied as a relatively safe drug vehicle with good delivery activity, but with the caveat that the effects of high dosages observed here should not be ignored when attempting to maximize therapeutic activity by increasing LDH concentration. PMID:20154371

  11. Formulation and evaluation of Ketoconazole niosomal gel drug delivery system

    PubMed Central

    Shirsand, SB; Para, MS; Nagendrakumar, D; Kanani, KM; Keerthy, D

    2012-01-01

    Purpose: Niosomes play an increasingly important role in drug delivery as they can reduce toxicity and modify pharmacokinetic and bio-availability. Topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. It can act as drug containing reservoirs and the modification of the vesicular compositions or surface properties can adjust the drug release rate and the affinity for the target site. Ketoconazole is a broad spectrum Imidazole derivative useful in the treatment of superficial and systemic fungal infections. Materials and Methods: In order to improve the low skin penetration and to minimize the side effects associated with topical conventional drug administration, Ketoconazole niosomes were prepared by a thin film hydration method using different ratios of non-ionic surfactants (Span 40, 60 and Tween 60) along with cholesterol (CHO). The formulations were evaluated for size, shape, entrapment efficiency and in vitro drug release. Results: Niosomes appeared spherical in shape and size range was found to be 4.86 ± 1.24-7.38 ± 3.64 μm. The entrapment efficiency was found in the range of 55.14 ± 2.29-78.63 ± 0.91% and in vitro drug release in the range of 46.63 ± 0.95-72.37 ± 0.59% in 24 h. Ketoconazole niosomes formulated with Span 60 and CHO in the ratio of 1:0.2 were found to be promising and were incorporated into 1% Carbopol gel. The formulated gel was evaluated for various physicochemical parameters and antifungal activity. The in vitro drug release study was carried out using phosphate buffer saline pH 7.4 and was found to be 36.18 ± 1.50% in 12 h. Conclusion: Gel formulation containing niosomes loaded with Ketoconazole showed prolonged action than formulations containing Ketoconazole in non-niosomal form and it can be developed successfully to improve the antifungal activity. PMID:23580936

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

    PubMed Central

    2013-01-01

    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. In addition, the monomeric

  13. Bimodal Gastroretentive Drug Delivery Systems of Lamotrigine: Formulation and Evaluation

    PubMed Central

    Poonuru, R. R.; Gonugunta, C. S. R

    2014-01-01

    Gastroretentive bimodal drug delivery systems of lamotrigine were developed using immediate release and extended release segments incorporated in a hydroxypropyl methylcellulose capsule and in vitro and in vivo evaluations were conducted. In vivo radiographic studies were carried out for the optimized formulation in healthy human volunteers with replacement of drug polymer complex by barium sulphate and the floating time was noted. Here the immediate release segment worked as loading dose and extended release segment as maintenance dose. The results of release studies of formulations with hydrophillic matrix to formulations with dual matrix hydroxypropyl methylcellulose acetate succinate shown that as the percentage of polymer increased, the release decreased. Selected formulation F2 having F-Melt has successfully released the drug within one hour and hydrophillic matrix composing polyethylene oxide with 5% hydroxypropyl methylcellulose acetate succinate showed a lag time of one hour and then extended its release up to 12th hour with 99.59% drug release following zero order kinetics with R2 value of 0.989. The Korsmeyer-Peppas equation showed the R2 value to be 0.941 and n value was 1.606 following non-Fickian diffusion pattern with supercase II relaxation mechanism. Here from extended release tablet the drug released slowly from the matrix while floating. PMID:25593380

  14. Miniaturized three-dimensional cancer model for drug evaluation.

    PubMed

    Lovitt, Carrie J; Shelper, Todd B; Avery, Vicky M

    2013-09-01

    A more relevant in vitro cell culture model that closely mimics tumor biology and provides better predictive information on anticancer therapies has been the focus of much attention in recent years. We have developed a three-dimensional (3D) human tumor cell culture model that attempts to recreate the in vivo microenvironment and tumor biology in a miniaturized 384-well plate format. This model aims to exploit the potential of 3D cell culture as a screening tool for novel therapeutics for discovery programs. Here we have evaluated a Matrigel™ based induction of 3D tumor formation using standard labware and plate reading equipment. We have demonstrated that with an optimized protocol, reproducible proliferation, and cell viability data can be obtained across a range of cell lines and reagent batches. A panel of reference drugs was used to validate the suitability of the assays for a high throughput drug discovery program. Indicators of assay reproducibility, such as Z'-factor and coefficient of variation, as well as dose response curves confirmed the robustness of the assays. Several methods of drug activity determination were examined, including metabolic and imaging based assays. These data demonstrate this model as a robust tool for drug discovery bridging the gap between monolayer cell culture and animal models, providing insights into drug efficacy at an earlier time point, ultimately reducing costs and high attrition rates. PMID:25310845

  15. Content and Usability Evaluation of Patient Oriented Drug-Drug Interaction Websites.

    PubMed

    Adam, Terrence J; Vang, Joseph

    2015-01-01

    Drug-Drug Interactions (DDI) are an important source of preventable adverse drug events and a common reason for hospitalization among patients on multiple drug therapy regimens. DDI information systems are important patient safety tools with the capacity to identify and warn health professionals of clinically significant DDI risk. While substantial research has been completed on DDI information systems in professional settings such as community, hospital, and independent pharmacies; there has been limited research on DDI systems offered through online websites directly for use by ambulatory patients. The focus of this project is to test patient oriented website capacity to correctly identify drug interactions among well established and clinically significant medication combinations and convey clinical risk data to patients. The patient education capability was assessed by evaluating website Information Capacity, Patient Usability and Readability. The study results indicate that the majority of websites identified which met the inclusion and exclusion criteria operated similarly, but vary in risk severity assessment and are not optimally patient oriented to effectively deliver risk information. The limited quality of information and complex medical term content complicate DDI risk data conveyance and the sites may not provide optimal information delivery to allow medication consumers to understand and manage their medication regimens. PMID:26958159

  16. Content and Usability Evaluation of Patient Oriented Drug-Drug Interaction Websites

    PubMed Central

    Adam, Terrence J.; Vang, Joseph

    2015-01-01

    Drug-Drug Interactions (DDI) are an important source of preventable adverse drug events and a common reason for hospitalization among patients on multiple drug therapy regimens. DDI information systems are important patient safety tools with the capacity to identify and warn health professionals of clinically significant DDI risk. While substantial research has been completed on DDI information systems in professional settings such as community, hospital, and independent pharmacies; there has been limited research on DDI systems offered through online websites directly for use by ambulatory patients. The focus of this project is to test patient oriented website capacity to correctly identify drug interactions among well established and clinically significant medication combinations and convey clinical risk data to patients. The patient education capability was assessed by evaluating website Information Capacity, Patient Usability and Readability. The study results indicate that the majority of websites identified which met the inclusion and exclusion criteria operated similarly, but vary in risk severity assessment and are not optimally patient oriented to effectively deliver risk information. The limited quality of information and complex medical term content complicate DDI risk data conveyance and the sites may not provide optimal information delivery to allow medication consumers to understand and manage their medication regimens. PMID:26958159

  17. [Evaluation of liberation of caffeine from dermal semisolids drugs].

    PubMed

    Kodadová, Alexandra; Vitková, Zuzana; Herdová, Petra

    2013-10-01

    The paper deals with formulation of caffeine into dermal semisolid dosage forms - hydrogels. Caffeine was chosen as a model drug because its properties can be successfully used just in hydrogels. Protective and tranquilization effects can be used in the preparations for sunbathing, and its lipolytic and regenerative effect can be used for the treatment of androgenic alopecia or cellular bioprotection. The aim of the study was to investigate the influence of different concentrations of chitosan and caffeine on the liberation of gels. Besides, stability of the prepared samples was evaluated by means of the evaluation of their rheological parameters. Based on the obtained results, there was determined the optimal drug concentration - caffeine 0.2% (w/w) and also the gel forming substance - chitosan 2.3% (w/w). PMID:24237472

  18. Drug interactions evaluation: An integrated part of risk assessment of therapeutics

    SciTech Connect

    Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping; Huang, Shiew-Mei

    2010-03-01

    Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.

  19. Economic evaluation of drugs in peripheral vascular disease and stroke.

    PubMed

    Drummond, M; Davies, L

    1994-01-01

    Increased pressures on health-care budgets mean that governments require good value for money from the resources devoted to health care. In many countries, measures have been introduced to increase efficiency or to contain health-care costs. These include price controls, limitations on reimbursement of health technologies, budgetary reform in health-care institutions, and the encouragement of competition. Given this changing environment, it is important that drugs and other health technologies be shown to give good value for money. The methods of economic evaluation, such as cost-benefit and cost-effectiveness analysis, can be used to assess the value of drugs and other health technologies. They have been widely applied. The economic evaluation of drugs in peripheral vascular disease and stroke would compare the cost of adding the drug with its benefits. These would include improvements in length and quality of life and the savings in treating vascular events that may be postponed, or lessened in intensity, by effective drug therapy. One study, following a clinical trial of naftidrofuryl in stroke, suggested that there would be significant reductions in costs through reductions in hospital stay if recovery was aided. Further research and a large multicenter trial are under way to confirm these findings. In peripheral artery disease there are no economic data collected alongside clinical trials. It is known, however, that the costs of leg ischemia can be significant. A study in the U.K. found that arterial construction would cost around pounds 7,750 per person (1989 prices) and amputation around pounds 11,000 per person.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7517476

  20. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Commissioner of Food and Drugs from the National Academy of Sciences (1969).” As the report notes, this...

  1. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Commissioner of Food and Drugs from the National Academy of Sciences (1969).” As the report notes, this...

  2. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Disclosure of drug efficacy study evaluations in labeling and advertising. 201.200 Section 201.200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Commissioner of Food and Drugs from the National Academy of Sciences (1969).” As the report notes, this...

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

    PubMed

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

    2010-03-01

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

  4. Titrating and evaluating multi-drug regimens within subjects.

    PubMed

    Shih, Margaret; Gennings, Chris; Chinchilli, Vernon M; Carter, Walter H

    2003-07-30

    The dosing of combination therapies is commonly undertaken empirically by practising physicians, and a coherent algorithm to approach the problem of combination dosing is currently lacking. Current methods of evaluating multiple drug combinations in clinical trials fail to provide information regarding the location of more effective doses when the combination is not found to differ from the standard, even though the absence of a difference does not necessarily mean the new combination is ineffective. Moreover, in studies where the new combination is found more effective, often a large proportion of the study participants obtain no benefit from the trial. Even with early stopping rules, the time these subjects spend on inferior treatments can have lasting detrimental effects, leading to problems with patient enrolment and adherence to study protocol. This paper describes an evolutionary operation (EVOP) direct-search procedure to titrate combination doses within individual patients. The Nelder-Mead simplex direct-search algorithm is used to titrate combinations of drugs within individual subjects. Desirability functions are utilized to define the main response of interest and additional responses or constraints. Statistical methodology for determining whether the titrated treatment combination has resulted in an improvement in subject response and for evaluating for therapeutic synergism is developed. Inferences can then be made about the efficacy of the combination or about the individual drugs that comprise the combination. The advantages of this approach include affording every patient the potential to benefit from the combination under study and permitting the consideration of multiple endpoints simultaneously. PMID:12854092

  5. Animal models of cerebral ischemia for evaluation of drugs.

    PubMed

    Gupta, Y K; Briyal, Seema

    2004-10-01

    Stroke is a major cause of death and disability worldwide. The resulting burden on the society continues to grow, with increase in the incidence of stroke. Brain attack is a term introduced to describe the acute presentation of stroke, which emphasizes the need for urgent action to remedy the situation. Though a large number of therapeutic agents like thrombolytics, NMDA receptor antagonists, calcium channel blockers and antioxidants, have been used or being evaluated, there remains a large gap between the benefits by these agents and properties an ideal drug for stroke should offer. In recent years much attention is being paid towards the exploration of herbal preparation, antioxidant agents and combination therapies including COX-2 inhibitors in experimental model of stroke. For better evaluation of the drugs and enhancement of their predictability from animal experimentation to clinical settings, it has been realized that the selection of animal models, the parameters to be evaluated should be critically assessed. Focal and global cerebral ischemia represents diseases that are common in the human population. Understanding the mechanisms of injury and neuroprotection in these diseases is important to learn new target sites to treat ischemia. There are many animal models available to investigate injury mechanisms and neuroprotective strategies. In this article we attempted to summarize commonly explored animal models of focal and global cerebral ischemia and evaluate their advantages and limitations. PMID:15907047

  6. Animal models to evaluate anti-atherosclerotic drugs.

    PubMed

    Priyadharsini, Raman P

    2015-08-01

    Atherosclerosis is a multifactorial condition characterized by endothelial injury, fatty streak deposition, and stiffening of the blood vessels. The pathogenesis is complex and mediated by adhesion molecules, inflammatory cells, and smooth muscle cells. Statins have been the major drugs in treating hypercholesterolemia for the past two decades despite little efficacy. There is an urgent need for new drugs that can replace statins or combined with statins. The preclinical studies evaluating atherosclerosis require an ideal animal model which resembles the disease condition, but there is no single animal model which mimics the disease. The animal models used are rabbits, rats, mice, hamsters, mini pigs, etc. Each animal model has its own advantages and disadvantages. The method of induction of atherosclerosis includes diet, chemical induction, mechanically induced injuries, and genetically manipulated animal models. This review mainly focuses on the various animal models, method of induction, the advantages, disadvantages, and the current perspectives with regard to preclinical studies on atherosclerosis. PMID:26095240

  7. Food and Drug Administration Evaluation and Cigarette Smoking Risk Perceptions

    PubMed Central

    Kaufman, Annette R.; Waters, Erika A.; Parascandola, Mark; Augustson, Erik M.; Bansal-Travers, Maansi; Hyland, Andrew; Cummings, K. Michael

    2013-01-01

    Objectives To examine the relationship between a belief about Food and Drug Administration (FDA) safety evaluation of cigarettes and smoking risk perceptions. Methods A nationally representative, random-digit-dialed telephone survey of 1046 adult current cigarette smokers. Results Smokers reporting that the FDA does not evaluate cigarettes for safety (46.1%), exhibited greater comprehension of the health risks of smoking and were more likely (48.5%) than other participants (33.6%) to report quit intentions. Risk perceptions partially mediated the relationship between FDA evaluation belief and quit intentions. Conclusions These findings highlight the need for proactive, effective communication to the public about the aims of new tobacco product regulations. PMID:22251767

  8. Food and Drug Administration regulation and evaluation of vaccines.

    PubMed

    Marshall, Valerie; Baylor, Norman W

    2011-05-01

    The vaccine-approval process in the United States is regulated by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. Throughout the life cycle of development, from preclinical studies to after licensure, vaccines are subject to rigorous testing and oversight. Manufacturers must adhere to good manufacturing practices and control procedures to ensure the quality of vaccines. As mandated by Title 21 of the Code of Regulations, licensed vaccines must meet stringent criteria for safety, efficacy, and potency. PMID:21502242

  9. In Vitro Evaluation of Drug Susceptibilities of Babesia divergens Isolates

    PubMed Central

    Brasseur, Philippe; Lecoublet, Sophie; Kapel, Nathalie; Favennec, Loic; Ballet, Jean J.

    1998-01-01

    The susceptibilities of three bovine and two human Babesia divergens isolates to antimicrobial agents were evaluated in vitro by a tritiated hypoxanthine incorporation assay. The MICs at which 50% of isolates are inhibited (MIC50s) for mefloquine (chlorhydrate), chloroquine (sulfate), quinine (chlorhydrate), clindamycin (phosphate), pentamidine (isethionate), phenamidine (isethionate) plus oxomemazine (chlorhydrate), lincomycin (chlorhydrate monohydrate), and imidocarb (dipropionate) were determined. Except for imidocarb, the MIC50s observed for the different isolates were close. Imidocarb and the combination of phenamidine plus oxomemazine exhibited the highest in vitro activity, while antimalarial agents such as mefloquine, choroquine, and quinine were inactive. Other drugs had intermediate activities. The data support further in vitro evaluation of antimicrobial agents active against B. divergens for the improvement of therapeutic strategies. PMID:9559789

  10. In vitro evaluation of drug susceptibilities of Babesia divergens isolates.

    PubMed

    Brasseur, P; Lecoublet, S; Kapel, N; Favennec, L; Ballet, J J

    1998-04-01

    The susceptibilities of three bovine and two human Babesia divergens isolates to antimicrobial agents were evaluated in vitro by a tritiated hypoxanthine incorporation assay. The MICs at which 50% of isolates are inhibited (MIC50s) for mefloquine (chlorhydrate), chloroquine (sulfate), quinine (chlorhydrate), clindamycin (phosphate), pentamidine (isethionate), phenamidine (isethionate) plus oxomemazine (chlorhydrate), lincomycin (chlorhydrate monohydrate), and imidocarb (dipropionate) were determined. Except for imidocarb, the MIC50s observed for the different isolates were close. Imidocarb and the combination of phenamidine plus oxomemazine exhibited the highest in vitro activity, while antimalarial agents such as mefloquine, choroquine, and quinine were inactive. Other drugs had intermediate activities. The data support further in vitro evaluation of antimicrobial agents active against B. divergens for the improvement of therapeutic strategies. PMID:9559789

  11. [Effectiveness evaluation of the drug dependency outpatient program "STEM"].

    PubMed

    Kondo, Ayumi; Satou, Yoshitaka; Matsumoto, Toshihiko

    2016-02-01

    A cognitive behavioral therapy program entitled "STEM" was implemented with 42 drug dependent outpatients at Okayama Psychiatric Medical Center. Characteristics of 1 group who completed the program were examined, with the effectiveness of the program evaluated through monitoring longitudinal changes over a period of 8.5 months. Results showed that the percentage of patients who completed the program was 52.4% (22 out of 42 people), those who completed had a longer educational history than the dropouts, a high proportion of those who completed held some form of employment and that their motivation to recover was high. Evaluation results of the program effectiveness showed significant improvement in short-term drug self-efficacy, with a tendency for later improvement in feelings and emotions also observed. While a certain level of effectiveness was proven, approximately half the group dropped out; so it is necessary to consider alternative options at an early stage for participants with a high risk of dropout, such as strengthening individual support based on their specific characteristics. PMID:27295822

  12. Drug Education and the College Athlete: Evaluation of a Decision- Making Model.

    ERIC Educational Resources Information Center

    Tricker, Raymond; Connolly, Declan

    1996-01-01

    Evaluates a 10-week drug education and prevention program (DEPP) as a means to increase information about the efficacy of such efforts in deterring college athlete drug abuse. Data obtained from 635 student athletes shows improvements in knowledge, attitudes toward performance-enhancing and recreational drugs, and perceptions of drug education…

  13. Alcohol, Drugs and Driving: Implications for Evaluating Driver Impairment

    PubMed Central

    Brown, Timothy; Milavetz, Gary; Murry, Daryl J.

    2013-01-01

    Impaired driving is a significant traffic safety problem, and alcohol and drugs taken before driving contribute substantially to this problem. With the increase in use of prescription medication and the decriminalization of some drugs, it has become increasingly important to understand the manifestation of driver impairment. Building upon previous alcohol research conducted at the National Advanced Driving Simulator (NADS), this study enrolled commercial bus drivers to evaluate the effect of triazolam on driving performance to assess difference between placebo, 0.125, and 0.25 mg doses in a randomized and double-blind design. On each of three randomized visits, subjects drove a simulator scenario that had previously been used to demonstrate effects of alcohol on driving performance. Plasma triazolam levels were obtained before the simulator drive. The protocol included participants receiving study medication and placebo over a 3-week period of time one to two weeks apart. The simulator drives used for this analysis occurred approximately 140 minutes after dosing—after the subjects had completed four bus simulator drives and neuropsychological tests over a 2-hour period of time surrounding dosing. The driving scenario contained representative situations on three types of roadways (urban, freeway, and rural) under nighttime driving conditions. Lane keeping performance (ability to drive straight in the lane) under the three doses of triazolam demonstrates that at the 0.25 mg dose, statistically significant effects on performance are observed, but no effects are found at the 0.125 mg level when testing at this time period after dosing. This differs from the effects of alcohol, which shows impairing effects at a 0.05% blood alcohol concentration (BAC) and a greater effect at 0.10% BAC. These results demonstrate the importance of understanding how different types of drugs affect driving performance in realistic driving environments. Although some compounds may have an

  14. Culture-adapted Plasmodium falciparum isolates from UK travellers: in vitro drug sensitivity, clonality and drug resistance markers

    PubMed Central

    2013-01-01

    Background The screening of lead compounds against in vitro parasite cultures is an essential step in the development of novel anti-malarial drugs, but currently relies on laboratory parasite lines established in vitro during the last century. This study sought to establish in continuous culture a series of recent Plasmodium falciparum isolates to represent the current parasite populations in Africa, all of which are now exposed to artemisinin combination therapy. Methods Pre-treatment P. falciparum isolates were obtained in EDTA, and placed into continuous culture after sampling of DNA. One post-treatment blood sample was also collected for each donor to monitor parasite clonality during clearance in vivo. IC50 estimates were obtained for 11 anti-malarial compounds for each established parasite line, clonal multiplicity measured in vivo and in vitro, and polymorphic sites implicated in parasite sensitivity to drugs were investigated at the pfmdr1, pfcrt, pfdhfr, pfdhps and pfap2mu loci before and after treatment, and in the cultured lines. Results Plasmodium falciparum isolates from seven malaria patients with recent travel to three West African and two East African countries were successfully established in long-term culture. One of these, HL1211, was from a patient with recrudescent parasitaemia 14 days after a full course of artemether-lumefantrine. All established culture lines were shown to be polyclonal, reflecting the in vivo isolates from which they were derived, and at least two lines reliably produce gametocytes in vitro. Two lines displayed high chloroquine IC50 estimates, and carried the CVIET haplotype at codons 72–76, whereas the remaining five lines carried the CVMNK haplotype and were sensitive in vitro. All were sensitive to the endoperoxides dihydroartemisinin and OZ277, but IC50 estimates for lumefantrine varied, with the least sensitive parasites carrying pfmdr1 alleles encoding Asn at codon 86. Conclusions This study describes the

  15. 78 FR 16679 - Center for Drug Evaluation and Research Medical Policy Council; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-18

    ... HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research Medical Policy... interested organizations, on medical policy issues that may be considered by the CDER Medical Policy Council (Council) in FDA's Center for Drug Evaluation and Research (CDER). These comments will help the...

  16. Where the Drug Films Are: A Guide to Evaluation Services and Distributors.

    ERIC Educational Resources Information Center

    National Inst. on Drug Abuse (DHEW/PHS), Rockville, MD.

    This guide to evaluation services and distributors of drug audiovisuals is intended to aid in the location and selection of drug films, slides, and recordings. Evaluators of drug abuse audiovisuals, film libraries, sources for Federal materials, and commercial and nonprofit distributors are listed. (Author/JLL)

  17. Regulatory aspects of oncology drug safety evaluation: Past practice, current issues, and the challenge of new drugs

    SciTech Connect

    Rosenfeldt, Hans; Kropp, Timothy; Benson, Kimberly; Ricci, M. Stacey; McGuinn, W. David; Verbois, S. Leigh

    2010-03-01

    The drug development of new anti-cancer agents is streamlined in response to the urgency of bringing effective drugs to market for patients with limited life expectancy. FDA's regulation of oncology drugs has evolved from the practices set forth in Arnold Lehman's seminal work published in the 1950s through the current drafting of a new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) safety guidance for anti-cancer drug nonclinical evaluations. The ICH combines the efforts of the regulatory authorities of Europe, Japan, and the United States and the pharmaceutical industry from these three regions to streamline the scientific and technical aspects of drug development. The recent development of new oncology drug classes with novel mechanisms of action has improved survival rates for some cancers but also brings new challenges for safety evaluation. Here we present the legacy of Lehman and colleagues in the context of past and present oncology drug development practices and focus on some of the current issues at the center of an evolving harmonization process that will generate a new safety guidance for oncology drugs, ICH S9. The purpose of this new guidance will be to facilitate oncology drug development on a global scale by standardizing regional safety requirements.

  18. Cryopreservation of glucose-6-phosphate dehydrogenase activity inside red blood cells: developing a specimen repository in support of development and evaluation of glucose-6-phosphate dehydrogenase deficiency tests

    PubMed Central

    2013-01-01

    Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human enzyme deficiency. It is characterized by abnormally low levels of G6PD activity. Individuals with G6PD deficiency are at risk of undergoing acute haemolysis when exposed to 8‒aminoquinoline-based drugs, such as primaquine. For this reason it is imperative to identify individuals with G6PD deficiency prior to administering these anti-malarial drugs. There is a need for the development and evaluation of point-of-care G6PD deficiency screening tests suitable for areas of the developing world where malarial treatments are frequently administered. The development and evaluation of new G6PD tests will be greatly assisted with the availability of specimen repositories. Methods Cryopreservation of erythrocytes was evaluated as a means to preserve G6PD activity. Blood specimens from 31 patients including ten specimens with normal G6PD activity, three with intermediate activity, and 18 with deficient activity were cryopreserved for up to six months. Results Good correlation in G6PD activity between fresh and cryopreserved specimens (R2 = 0.95). The cryopreserved specimens show an overall small drop in mean G6PD activity of 0.23 U/g Hb (P=0.23). Cytochemical staining showed that intracellular G6PD activity distribution within the red blood cell populations is preserved during cryopreservation. Furthermore, the mosaic composition of red blood cells in heterozygous women is also preserved for six months or more. The fluorescent spot and the BinaxNOW qualitative tests for G6PD deficiency also showed high concordance in G6PD status determination between cryopreserved specimens and fresh specimens. Conclusions A methodology for establishing a specimen panel for evaluation of G6PD tests is described. The approach is similar to that used in several malaria research facilities for the cryopreservation of parasites in clinical specimens and axenic cultures. Specimens stored in this manner will aid

  19. Comparative evaluation of drug release from aged prolonged polyethylene oxide tablet matrices: effect of excipient and drug type.

    PubMed

    Shojaee, Saeed; Kaialy, Waseem; Cumming, Kenneth Iain; Nokhodchi, Ali

    2016-03-01

    Polyethylene oxide (PEO) undergoes structural adjustments caused by elevated temperatures, which results in loss of its stability within direct compression tablets. The aim of this study was to evaluate the influence of filler solubility on the drug delivery process of matrix tablets containing drugs with different water-solubility properties and stored at elevated temperature. The results demonstrated that in the case of propranolol HCl (highly water-soluble) tablet matrices, soluble lactose promoted drug release, whereas, a stable release of drug was observed with insoluble DCP. A drug release pattern similar to the propranolol HCl formulation containing DCP was obtained for hydrophilic matrix tablets containing either lactose or DCP for the less water-soluble drug, zonisamide. In the case of the partially water-soluble drug, theophylline, formulated with lower molecular weight PEO 750, drug release increased considerably in the presence of both fillers with increasing storage time, however a stable release rate (similar to fresh samples) was observed in the case of higher molecular weight PEO 303 tablet matrices containing theophylline with either lactose or DCP. The hydration properties (e.g. solubility) of the diluents had a considerable effect on drug release behavior from various model matrices; this effect was dependent on both molecular weight of PEO and solubility of drug. PMID:25410967

  20. Evaluation of immunomodulatory drugs in multiple myeloma: single center experience

    PubMed Central

    Ozkan, Melda Comert; Tombuloglu, Murat; Sahin, Fahri; Saydam, Guray

    2015-01-01

    Objective: Multiple myeloma (MM) comprises 1% of all cancers and 10% of hematologic malignancies and known as an incurable disease. The introduction of immunomodulatory drugs (IMiDs) has brought a major shift in therapeutic paradigm in the treatment of newly diagnosed and relapsed/refractory MM patients. The aim of this study was to evaluate the relationship between response status and hematological parameters in patients with MM treated with thalidomide or lenalidomide. Methods: Sixty-eight patients who were treated with IMiDs in Ege University, School of Medicine, Department of Hematology, between 2005 and 2012, were evaluated, retrospectively. Results and Conclusion: We could not find any difference between the hematological parameters before and after the treatment neither with thalidomide nor lenalidomide. However, the heterogenity of our groups, the difference in treatment strategies and potential side effects would have an impact on this result. It is needed to perform prospective clinical trials to prove that whether correction of hematological parameters would reflect the response status in patients with myeloma that treated with IMiDs. PMID:27069758

  1. Evaluation of Idaho's DARE "Drug Abuse Resistance Education Projects."

    ERIC Educational Resources Information Center

    Silva, Roberta K.

    The goal of DARE (Drug Abuse Resistance Education) is not to completely eliminate the drug and alcohol problems of society. It is a proactive prevention program designed to equip youth (focusing on elementary school) with skills for resisting peer pressure to experiment with drugs, and to manage anger without resorting to violence or the use of…

  2. Evaluation of Idaho's DARE "Drug Abuse Resistance Education" Projects.

    ERIC Educational Resources Information Center

    Silva, Roberta K.

    The DARE (Drug Abuse Resistance Education) program teaches students decision-making skills, shows them how to resist peer pressure to experiment with drugs and alcohol, and provides positive alternatives to drug use. This report looks at one state's DARE programs. Included are an overview of the implementation process, a program appraisal with…

  3. An Evaluation of the "Drugs Are Like That" Program.

    ERIC Educational Resources Information Center

    Moodie, Allan G.

    The purpose of this study is to assess in selected Vancouver elementary schools the drug education program utilizing the film "Drugs Are Like That." Questionnaire responses are summarized for: (1) parents who attended the advanced showings of the film with the subsequent discussions on drug abuse, and (2) principals, teacher, counsellors, nurses…

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

    PubMed

    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

  5. Drugs for treating urinary schistosomiasis

    PubMed Central

    Kramer, Christine V; Zhang, Fan; Sinclair, David; Olliaro, Piero L

    2014-01-01

    , another anti-malarial mefloquine has been evaluated in two small trials with inconsistent e

  6. Central Nervous System Drug Evaluation Using Positron Emission Tomography

    PubMed Central

    Maeda, Jun; Shimada, Hitoshi; Nogami, Tsuyoshi; Arakawa, Ryosuke; Takano, Harumasa; Higuchi, Makoto; Ito, Hiroshi; Okubo, Yoshiro; Suhara, Tetsuya

    2011-01-01

    In conventional pharmacological research in the field of mental disorders, pharmacological effect and dose have been estimated by ethological approach and in vitro data of affinity to the site of action. In addition, the frequency of administration has been estimated from drug kinetics in blood. However, there is a problem regarding an objective index of drug effects in the living body. Furthermore, the possibility that the concentration of drug in blood does not necessarily reflect the drug kinetics in target organs has been pointed out. Positron emission tomography (PET) techniques have made progress for more than 20 years, and made it possible to measure the distribution and kinetics of small molecule components in living brain. In this article, we focused on rational drug dosing using receptor occupancy and proof-of-concept of drugs in the drug development process using PET. PMID:23431048

  7. New mixed ligand zinc(II) complexes based on the antiepileptic drug sodium valproate and bioactive nitrogen-donor ligands. Synthesis, structure and biological properties.

    PubMed

    Darawsheh, Mohanad; Abu Ali, Hijazi; Abuhijleh, A Latif; Rappocciolo, Emilia; Akkawi, Mutaz; Jaber, Suhair; Maloul, Salam; Hussein, Yasmeen

    2014-07-23

    Starting from the precursor [Zinc Valproate complex] (1), new mixed ligand zinc(II) complexes of valproic acid and nitrogen-based ligands, formulating as, [Zn(valp)22,9-dmphen] (2), [Zn2(valp)4(quin)2] (3), [Zn(valp)2(2-ampy)2] (4), and [Zn(valp)2(2-ampic)2] (5) (valp = valproate, 2,9-dmphen = 2,9-dimethyl-1,10-phenanthroline, quin = quinoline, 2-ampy = 2-aminopyridine, 2-ampic = 2-amino-6-picoline) were synthesized and characterized using IR, (1)H NMR, (13)C{(1)H} NMR and UV-Vis spectrometry. The crystal structures of complexes 2, 3 and 4 were determined using single-crystal X-ray diffraction. The complexes were also evaluated for their anti-bacterial activity using in-vitro agar diffusion method against three Gram-positive (Micrococcus luteus, Staphylococcus aureus, and Bacillus subtilis) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) species. Complex 2 showed considerable activity against all tested microorganisms and the effect of complexation on the anti-bacterial activity of the parent ligand of 2 was also investigated. The anti-bacterial activity of 2,9-dmphen against Gram-negative bacteria was enhanced upon complexation with zinc valproate. On the other hand, complexes 1 and 3 showed weak inhibition activity against the tested species and complexes 4 and 5 didn't show any activity at all. Two methods were used for testing the inhibition of ferriprotoporphyrinIX bio-mineralization: a semi-quantitative micro-assay and a previously self-developed quantitative in-vitro method. Both were used to study the efficiency of these complexes in inhibiting the formation of the Malaria pigment which considered being the target of many known anti-malarial drugs such as Chloroquine and Amodiaquine. Results showed that the efficiency of complex 2 in preventing the formation of β-Hematin was 80%. The efficiency of Amodiaquine as a standard drug was reported to give 91%. PMID:24904962

  8. [Review on requirements of drug allergy or pseudoallergic reactions in pre-clinical evaluation].

    PubMed

    Han, Jia-yin; Yi, Yan; Liang, Ai-hua; Zhang, Yu-shi; Li, Chun-ying; Zhao, Yong; Wang, Lian-mei; Lu, Yu-ting; Li, Gui-qin

    2015-07-01

    Drug allergy and pseudoallergic reactions are main adverse drug reactions. Allergy is mainly induced by the immunogenicity of drug, drug metabolic products or drug additive. Pseudoallergic reactions may result from the irritation or activation of inflammatory material release. Pre-clinical evaluation of drug allergy and pseudoallergic reactions is included in immunotoxicity evaluation. Now there is no in vivo or in vitro method that could predict all kinds of allergy or pseudoallergic reactions due to the different mechanisms. In the past few years, FDA, SFDA OECD, ICH and WHO have published several guidelines on per-clinical immunotoxicity evaluation, however, no agreement has been reached on allergy and pseudoallergic reactions evaluation. This article reviews the requirements of allergy and pseudoallergic reactions in pre-clinical evaluation. PMID:26666009

  9. Comparative evaluation of humic substances in oral drug delivery.

    PubMed

    Mirza, Mohd Aamir; Ahmad, Niyaz; Agarwal, Suraj Prakash; Mahmood, Danish; Khalid Anwer, M; Iqbal, Z

    2011-05-01

    Major and biologically most explored components of natural organic matter (NOM) are humic acid (HA) and fulvic acid (FA). We have explored rock shilajit as a source of NOM. On the other hand carbamazepine (CBZ) is a well known anticonvulsant drug and has a limited accessibility to brain. Bioavailability and pharmacokinetic profiles of CBZ have been improved by complexation and different techniques also. Present study has assessed the comparative abilities of FA and HA as complexing agent for CBZ in order to enhance pharmacokinetic profile of CBZ and accessibility to the brain. These two complexing agents have been compared on various indices such as their abilities to cause complexation and enhance solubility, permeability and dissolution. The present study also compared pharmacodynamic and biochemical profiles after oral administration of complexes. With the help of various pharmaceutical techniques such as freeze drying, physical mixture, kneading and solvent evaporation, two molar ratios (1:1 and 1:2) were selected for complexation and evaluated for conformational analysis (molecular modeling). Complex formed was further characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), mass spectroscopy and X-ray diffraction (XRD). Preclinical study on rodents with CBZ-HA and CBZ-FA has yielded appreciable results in terms of their anticonvulsant and antioxidants activities. However, CBZ-HA (1:2) demonstrated better result than any other complex. PMID:25755978

  10. Comparative evaluation of humic substances in oral drug delivery

    PubMed Central

    Mirza, Mohd. Aamir; Ahmad, Niyaz; Agarwal, Suraj Prakash; Mahmood, Danish; Khalid Anwer, M.; Iqbal, Z.

    2011-01-01

    Major and biologically most explored components of natural organic matter (NOM) are humic acid (HA) and fulvic acid (FA). We have explored rock shilajit as a source of NOM. On the other hand carbamazepine (CBZ) is a well known anticonvulsant drug and has a limited accessibility to brain. Bioavailability and pharmacokinetic profiles of CBZ have been improved by complexation and different techniques also. Present study has assessed the comparative abilities of FA and HA as complexing agent for CBZ in order to enhance pharmacokinetic profile of CBZ and accessibility to the brain. These two complexing agents have been compared on various indices such as their abilities to cause complexation and enhance solubility, permeability and dissolution. The present study also compared pharmacodynamic and biochemical profiles after oral administration of complexes. With the help of various pharmaceutical techniques such as freeze drying, physical mixture, kneading and solvent evaporation, two molar ratios (1:1 and 1:2) were selected for complexation and evaluated for conformational analysis (molecular modeling). Complex formed was further characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), mass spectroscopy and X-ray diffraction (XRD). Preclinical study on rodents with CBZ–HA and CBZ–FA has yielded appreciable results in terms of their anticonvulsant and antioxidants activities. However, CBZ–HA (1:2) demonstrated better result than any other complex. PMID:25755978

  11. Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing

    PubMed Central

    ZHANG, QI; WANG, SHANSHAN; YANG, DEXUAN; PAN, KEVIN; LI, LINNA; YUAN, SHOUJUN

    2016-01-01

    The established urinary antibiotic nitroxoline has recently regained considerable attention, due to its potent activities in inhibiting angiogenesis, inducing apoptosis and blocking cancer cell invasion. These features make nitroxoline an excellent candidate for anticancer drug repurposing. To rapidly advance nitroxoline repurposing into clinical trials, the present study performed systemic preclinical pharmacodynamic evaluation of its anticancer activity, including a methyl thiazolyl tetrazolium assay in vitro and an orthotopic urological tumor assay in vivo. The current study determined that nitroxoline exhibits dose-dependent anti-cancer activity in vitro and in urological tumor orthotopic mouse models. In addition, it was demonstrated that the routine nitroxoline administration regimen used for urinary tract infections was effective and sufficient for urological cancer treatment, and 2 to 4-fold higher doses resulted in obvious enhancement of anticancer efficacy without corresponding increases in toxicity. Furthermore, nitroxoline sulfate, one of the most common metabolites of nitroxoline in the urine, effectively inhibited cancer cell proliferation. This finding increases the feasibility of nitroxoline repurposing for urological cancer treatment. Due to the excellent anticancer activity demonstrated in the present study, and its well-known safety profile and pharmacokinetic properties, nitroxoline has been approved to enter into a phase II clinical trial in China for non-muscle invasive bladder cancer treatment (registration no. CTR20131716). PMID:27123101

  12. Use of PET Imaging to Evaluate Transporter-Mediated Drug-Drug Interactions.

    PubMed

    Langer, Oliver

    2016-07-01

    Several membrane transporters belonging to the adenosine triphosphate-binding cassette (ABC) and solute carrier (SLC) families can transport drugs and drug metabolites and thereby exert an effect on drug absorption, distribution, and excretion, which may potentially lead to transporter-mediated drug-drug interactions (DDIs). Some transporter-mediated DDIs may lead to changes in organ distribution of drugs (eg, brain, liver, kidneys) without affecting plasma concentrations. Positron emission tomography (PET) is a noninvasive imaging method that allows studying of the distribution of radiolabeled drugs to different organs and tissues and is therefore the method of choice to quantitatively assess transporter-mediated DDIs on a tissue level. There are 2 approaches to how PET can be used in transporter-mediated DDI studies. When the drug of interest is a potential perpetrator of DDIs, it may be administered in unlabeled form to assess its influence on tissue distribution of a generic transporter-specific PET tracer (probe substrate). When the drug of interest is a potential victim of DDIs, it may be radiolabeled with carbon-11 or fluorine-18 and used in combination with a prototypical transporter inhibitor (eg, rifampicin). PET has already been used both in preclinical species and in humans to assess the effects of transporter-mediated DDIs on drug disposition in different organ systems, such as brain, liver, and kidneys, for which examples are given in the present review article. Given the growing importance of membrane transporters with respect to drug safety and efficacy, PET is expected to play an increasingly important role in future drug development. PMID:27385172

  13. Quantitative evaluation of drug-drug interaction potentials by in vivo information- guided prediction approach.

    PubMed

    Chen, Feng; Hu, Zhe-Yi; Jia, Wei-Wei; Lu, Jing-Tao; Zhao, Yuan-Sheng

    2014-01-01

    Drug-drug interaction (DDI) is one important topic in drug discovery, drug development and clinical practice. Recently, a novel approach, in vivo information-guided prediction (IVIP), was introduced for predicting the magnitude of pharmacokinetic DDIs which are caused by changes in cytochrome P450 (CYP) activity. This approach utilizes two parameters, i.e. CR (the apparent contribution of the target metabolizing enzyme to the clearance of the substrate drug) and IX (the apparent effect of a perpetrator on the target CYP) to describe the magnitude of DDI between a perpetrator and a victim drug. The essential concept of this method assumes that at a given dose level, the IX for a given perpetrator remains constant whatever the victim drug is. Usually, this IVIP method is only based on information from clinical studies and does not need in vitro information. In this review, basic concept, application and extension, as well as pros and cons of the IVIP method were presented. How to apply this approach was also discussed. Thus far, this method displayed good performance in predicting DDIs associated with CYPs, and can be used to forecast the magnitude of a large number of possible DDIs, of which only a small portion have been investigated in clinical studies. The key concept of this static approach could even be implemented in dynamic modeling to assess risks of DDIs involving drug transporters. PMID:25705907

  14. Evaluation of antitubercular drug-loaded surfactants as inhalable drug-delivery systems for pulmonary tuberculosis.

    PubMed

    Chimote, G; Banerjee, R

    2009-05-01

    Pulmonary tuberculosis is associated with a year-long chemotherapy, poor alveolar drug levels, drug-related systemic toxicity, and patient noncompliance. In this study, exogenous pulmonary surfactant is proposed as a drug carrier for antitubercular drugs. Dipalmitoylphosphatidylcholine (DPPC), the major lung-surfactant lipid, has been combined with antitubercular drugs isoniazid (INH), rifampicin (RFM), and ethambutol (ETH) in 1:1 ratio by weight, in which drugs had a ratio of 1:2:3 by weight. At 37 degrees C, the formulation had better surfactant function with quicker reduction of surface tension on adsorption (32.71 +/- 0.65 mN/m) than DPPC liposomes (44.67 +/- 0.57 mN/m) and maintained 100% airway patency in a capillary surfactometer. Drug-loaded surfactant liposomes were about 2 microm and had entrapment efficiency of 30.04% +/- 2.05%, 18.85% +/- 2.92%, and 61.47% +/- 3.32% for INH, RFM, and ETH, respectively. Sustained release of the drugs from surfactants was observed over 24 h. In vitro alveolar deposition efficiency using the twin impinger showed 12.06% +/- 1.87% of INH, 43.30% +/- 0.87% of RFM, and 22.07% +/- 2.02% of ETH deposited in the alveolar chamber upon nebulization for a minute using a jet nebulizer. The formulation was biocompatible and stable with physicochemical properties being retained even after storage for a month at 4 degrees C. Antitubercular drug-loaded surfactants developed could serve dual purposes of alveolar stabilization due to surfactant action and better reach of these drugs to the alveoli due to antiatelectatic effect of the surfactant. PMID:18431766

  15. Evaluating Drug Prices, Availability, Affordability, and Price Components: Implications for Access to Drugs in Malaysia

    PubMed Central

    Babar, Zaheer Ud Din; Ibrahim, Mohamed Izham Mohamed; Singh, Harpal; Bukahri, Nadeem Irfan; Creese, Andrew

    2007-01-01

    Background Malaysia's stable health care system is facing challenges with increasing medicine costs. To investigate these issues a survey was carried out to evaluate medicine prices, availability, affordability, and the structure of price components. Methods and Findings The methodology developed by the World Health Organization (WHO) and Health Action International (HAI) was used. Price and availability data for 48 medicines was collected from 20 public sector facilities, 32 private sector retail pharmacies and 20 dispensing doctors in four geographical regions of West Malaysia. Medicine prices were compared with international reference prices (IRPs) to obtain a median price ratio. The daily wage of the lowest paid unskilled government worker was used to gauge the affordability of medicines. Price component data were collected throughout the supply chain, and markups, taxes, and other distribution costs were identified. In private pharmacies, innovator brand (IB) prices were 16 times higher than the IRPs, while generics were 6.6 times higher. In dispensing doctor clinics, the figures were 15 times higher for innovator brands and 7.5 for generics. Dispensing doctors applied high markups of 50%–76% for IBs, and up to 316% for generics. Retail pharmacy markups were also high—25%–38% and 100%–140% for IBs and generics, respectively. In the public sector, where medicines are free, availability was low even for medicines on the National Essential Drugs List. For a month's treatment for peptic ulcer disease and hypertension people have to pay about a week's wages in the private sector. Conclusions The free market by definition does not control medicine prices, necessitating price monitoring and control mechanisms. Markups for generic products are greater than for IBs. Reducing the base price without controlling markups may increase profits for retailers and dispensing doctors without reducing the price paid by end users. To increase access and affordability

  16. Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis

    PubMed Central

    Papanikolaou, Xenofon; Johnson, Sarah; Garg, Tarun; Tian, Erming; Tytarenko, Ruslana; Zhang, Qing; Stein, Caleb; Barlogie, Bart; Epstein, Joshua; Heuck, Christoph

    2014-01-01

    Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naïve as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate's unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase–mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment. PMID:24948357

  17. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

    NASA Astrophysics Data System (ADS)

    Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

    2005-10-01

    In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

  18. Creating and evaluating genetic tests predictive of drug response

    PubMed Central

    Weiss, Scott T.; McLeod, Howard L.; Flockhart, David A.; Dolan, M. Eileen; Benowitz, Neal L.; Johnson, Julie A.; Ratain, Mark J.; Giacomini, Kathleen M.

    2009-01-01

    A key goal of pharmacogenetics — the use of genetic variation to elucidate inter-individual variation in drug treatment response — is to aid the development of predictive genetic tests that could maximize drug efficacy and minimize drug toxicity. The completion of the Human Genome Project and the associated HapMap Project, together with advances in technologies for investigating genetic variation, have greatly advanced the potential to develop such tests; however, many challenges remain. With the aim of helping to address some of these challenges, this article discusses the steps that are involved in the development of predictive tests for drug treatment response based on genetic variation, and factors that influence the development and performance of these tests. PMID:18587383

  19. A cardiomyocyte-based biosensor for antiarrhythmic drug evaluation by simultaneously monitoring cell growth and beating.

    PubMed

    Wang, Tianxing; Hu, Ning; Cao, Jiayue; Wu, Jieying; Su, Kaiqi; Wang, Ping

    2013-11-15

    Drug-induced cardiotoxicity greatly endangers the human health and results in resource waste. Also, it is a leading attribution to drug withdrawal and late-stage attrition in pharmaceutical industry. In the study, a dual function cardiomyocyte-based biosensor was introduced for rapid drug evaluation with xCELLigence RTCA Cardio system. The cardiomyocyte-based biosensor can monitor the cardiomyocyte growth and beating status simultaneously under the drug effects. Two typical cardiovascular drug, verapamil and flecainide were selected as treatment agents to test the performance of this biosensor. The experiment results showed that the performance of cardiomyocyte-based biosensor verified the basic drug effects by beating status and also tested the drug cytotoxicity by the cell index curves of cardiomyocyte growth. Based on the advanced sensor detection technology and cell culture technology, this cardiomyocyte-based biosensor will be a utility platform for the drug preclinical assessment. PMID:23708811

  20. A Comparative Evaluation of Hydroxycamptothecin Drug Nanorods With and Without Methotrexate Prodrug Functionalization for Drug Delivery.

    PubMed

    Guo, Fuqiang; Fan, Zhongxiong; Yang, Jinbin; Li, Yang; Wang, Yange; Zhao, Hai; Xie, Liya; Hou, Zhenqing

    2016-12-01

    We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells. PMID:27581601

  1. [The importance of clinical data management in improvement of drug evaluation].

    PubMed

    Huang, Qin; Wang, Jun

    2015-11-01

    Although the importance of clinical data is drawing more attention in drug development in China, the clinical data management is not good enough in the clinical trials right now. With the development of internet and progress of information technology, especially with the setup of the state innovation strategy for drug development, it is necessary and urgent to improve the clinical data quality. Good data quality is the primary basis of technical evaluation of drug at the marketing authorization. So Center for Drug Evaluation of CFDA has made some endeavors to enhance data management in the clinical trials in recent years. This article is focused on these aspects of data managment. PMID:26911033

  2. Perspectives on the drug court model across systems: a process evaluation.

    PubMed

    Wolfe, Ellen L; Guydish, Joseph; Woods, William; Tajima, Barbara

    2004-09-01

    Drug courts have been in existence since 1989, yet few process evaluations have appeared in the literature to help inform the discussion about their effectiveness. This article reports findings from a process evaluation of a drug court program in San Mateo, California. The evaluation was designed to document the history of the program, to examine program strengths and areas of improvement, to assess the roles and relationships among the various agencies involved and to describe the impact of the drug court on the justice and drug treatment systems. Methods included review of available drug court program documents, interviews with key stakeholders, and focus groups with drug court participants. The main findings were: support for the continuation of drug court, enhanced collaboration among all agencies, and an increased awareness of the needs of substance-using clients in the criminal justice system. Potential lessons for other drug courts include the importance of building strong collaborations and maintaining good communication, recognizing competing interests in developing procedures for drug court, and considering changes in eligibility criteria as experience with the drug court model expands. PMID:15559684

  3. Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions.

    PubMed

    Feng, Bo; Varma, Manthena V

    2016-07-01

    With numerous drugs cleared renally, inhibition of uptake transporters localized on the basolateral membrane of renal proximal tubule cells, eg, organic anion transporters (OATs) and organic cation transporters (OCTs), may lead to clinically meaningful drug-drug interactions (DDIs). Additionally, clinical evidence for the possible involvement of efflux transporters, such as P-glycoprotein (P-gp) and multidrug and toxin extrusion protein 1/2-K (MATE1/2-K), in the renal DDIs is emerging. Herein, we review recent progress regarding mechanistic understanding of transporter-mediated renal DDIs as well as the quantitative predictability of renal DDIs using static and physiologically based pharmacokinetic (PBPK) models. Generally, clinical DDI data suggest that the magnitude of plasma exposure changes attributable to renal DDIs is less than 2-fold, unlike the DDIs associated with inhibition of cytochrome P-450s and/or hepatic uptake transporters. It is concluded that although there is a need for risk assessment early in drug development, current available data imply that safety concerns related to the renal DDIs are generally low. Nevertheless, consideration must be given to the therapeutic index of the victim drug and potential risk in a specific patient population (eg, renal impairment). Finally, in vitro transporter data and clinical pharmacokinetic parameters obtained from the first-in-human studies have proven useful in support of quantitative prediction of DDIs associated with inhibition of renal secretory transporters, OATs or OCTs. PMID:27385169

  4. Evaluation of drug toxicity profiles based on the phenotypes of ascidian Ciona intestinalis.

    PubMed

    Mizotani, Yuji; Itoh, Shun; Hotta, Kohji; Tashiro, Etsu; Oka, Kotaro; Imoto, Masaya

    2015-08-01

    In vivo toxicity evaluation using model organisms is an important step for the development of new drugs. Here, we report that Ciona intestinalis, a chordate invertebrate, is beneficial to drug toxicity evaluation for the following reasons: rapid embryonic and larval development, resemblance to vertebrates, ease of management, low cost, transparent body, and low risk of ethical issues. The dynamic phenotypic change of Ciona larvae during metamorphosis prompted us to examine the effect of cytotoxic drugs on its development by quantifying six toxicity endpoints: degenerated tail size, ampulla length, rotation of body axis, stomach size, heart rate, and body size. As a result, mitochondrial respiratory inhibitors, tubulin polymerization/depolymerization inhibitors, or DNA/RNA synthesis inhibitors showed distinct toxicity profiles against these six endpoints, but drugs with the same targets showed a similar toxicity profile in Ciona. Our results suggest Ciona is an effective animal model for profiling drug toxicity and exploring the mechanisms of drugs with unknown targets. PMID:26043689

  5. Cluster-randomized study of intermittent preventive treatment for malaria in infants (IPTi) in southern Tanzania: evaluation of impact on survival

    PubMed Central

    2011-01-01

    Background Intermittent Preventive Treatment for malaria control in infants (IPTi) consists of the administration of a treatment dose of an anti-malarial drug, usually sulphadoxine-pyrimethamine, at scheduled intervals, regardless of the presence of Plasmodium falciparum infection. A pooled analysis of individually randomized trials reported that IPTi reduced clinical episodes by 30%. This study evaluated the effect of IPTi on child survival in the context of a five-district implementation project in southern Tanzania. [Trial registration: clinical trials.gov NCT00152204]. Methods After baseline household and health facility surveys in 2004, five districts comprising 24 divisions were randomly assigned either to receive IPTi (n = 12) or not (n = 12). Implementation started in March 2005, led by routine health services with support from the research team. In 2007, a large household survey was undertaken to assess the impact of IPTi on survival in infants aged two-11 months through birth history interviews with all women aged 13-49 years. The analysis is based on an "intention-to-treat" ecological design, with survival outcomes analysed according to the cluster in which the mothers lived. Results Survival in infants aged two-11 months was comparable in IPTi and comparison areas at baseline. In intervention areas in 2007, 48% of children aged 12-23 months had documented evidence of receiving three doses of IPTi, compared to 2% in comparison areas (P < 0.0001). Over the three years of the study there was a marked improvement in survival in both groups. Between 2001-4 and 2005-7, mortality rates in two-11 month olds fell from 34.1 to 23.6 per 1,000 person-years in intervention areas and from 32.3 to 20.7 in comparison areas. In 2007, divisions implementing IPTi had a 14% (95% CI -12%, 49%) higher mortality rate in two-11 month olds in comparison with non-implementing divisions (P = 0.31). Conclusion The lack of evidence of an effect of IPTi on survival could be a false

  6. Evaluation of an AIDS education model for women drug users in jail.

    PubMed

    Magura, S; Kang, S Y; Shapiro, J L; O'Day, J

    1995-02-01

    This paper reports outcome evaluation results of an AIDS education program for drug-using women in jail, of whom the majority were current drug injectors, had high-risk sexual partners, and never used condoms for insertive sex. The women participated in four small-group health/HIV education sessions. Education participants and controls were followed-up 7 months after their release from jail; the two groups did not differ significantly on drug- or sex-related HIV risk behaviors at follow-up. However, being in drug dependency treatment (primarily methadone maintenance) at follow-up was associated with reduced heroin use, crack use, drug dealing, and criminal activity. Although improved HIV education in jail is important, better networks of community resources, including more accessible community drug dependency treatment, also must be developed to support drug-dependent women after their release from jail. PMID:7790127

  7. An Impact Evaluation of a Rural Youth Drug Education Program.

    ERIC Educational Resources Information Center

    Sarvela, Paul D.; McClendon, E. J.

    1987-01-01

    Examined effects of mixed affective-cognitive drug education program on rural northern Michigan and northeastern Wisconsin sixth and seventh graders' (N=265) substance use health beliefs and behaviors. Alcohol use in this population was determined to be much higher than national average for similar age groups while marijuana, cigarette, and…

  8. Likelihood approach for evaluating bioequivalence of highly variable drugs

    PubMed Central

    Du, Liping; Choi, Leena

    2015-01-01

    Bioequivalence (BE) is required for approving a generic drug. The Two-One-Sided-Test (TOST, or the 90% confidence interval approach) has been used as the mainstream methodology to test average BE (ABE) on pharmacokinetic parameters such as the area under the blood concentration-time curve and the peak concentration. However, for highly variable drugs (%CV > 30%), it is difficult to demonstrate ABE in a standard cross-over study with the typical number of subjects using the TOST due to lack of power. Recently, the US Food and Drug Administration and the European Medicines Agency recommended similar but not identical reference scaled average bioequivalence (RSABE) approaches to address this issue. Although the power is improved, the new approaches may not guarantee a high level of confidence for the true difference between two drugs at the ABE boundaries. It is also difficult for these approaches to address the issues of population BE (PBE) and individual BE (IBE). We advocate the use of a likelihood approach for representing and interpreting BE data as evidence. Using example data from a full replicate 2 × 4 cross-over study, we demonstrate how to present evidence using the profile likelihoods for the mean difference and standard deviation ratios of the two drugs for the pharmacokinetic parameters. With this approach, we present evidence for PBE and IBE as well as ABE within a unified framework. Our simulations show that the operating characteristics of the proposed likelihood approach are comparable with the RSABE approaches when the same criteria are applied. PMID:25408492

  9. 76 FR 44593 - Identifying the Center for Drug Evaluation and Research's Science and Research Needs...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-26

    ...The Food and Drug Administration (FDA) is announcing the availability of a draft report entitled ``Identifying CDER's Science and Research Needs.'' This document identifies current priorities in regulatory science related to the mission of the Center for Drug Evaluation and Research (CDER), and will guide strategic planning of internal research efforts. Through external communication of the......

  10. Evaluation of a Court-Ordered MADD Presentation for Juvenile Alcohol and Drug Offenders

    ERIC Educational Resources Information Center

    Theriot, Matthew T.

    2006-01-01

    This study evaluates the effectiveness of a court-ordered Mothers Against Drunk Driving (MADD) presentation to prevent alcohol or drug-related recidivism among 247 juvenile alcohol and drug offenders. The presentation, which incorporates educational components with a victim awareness program, seeks to increase offenders' empathy and knowledge…

  11. Current Status of the Matson Evaluation of Drug Side Effects (MEDS)

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Cervantes, Paige E.

    2013-01-01

    The Matson Evaluation of Drug Side Effects (MEDS) is currently the best established and most researched measure of drug side effects in the intellectual disability (ID) literature. Initial research was conducted on its psychometric properties such as reliability and validity. More recent research studies have used the measure to determine the…

  12. 76 FR 72422 - Draft Guidance for Industry on Evaluating the Effectiveness of Anticoccidial Drugs in Food...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ...The Food and Drug Administration (FDA) is announcing the availability of draft guidance for industry 217 entitled ``Evaluating the Effectiveness of Anticoccidial Drugs in Food-Producing Animals.'' The draft guidance, when finalized, is intended to provide guidance to industry for designing and conducting clinical effectiveness studies, and describes criteria that the Center for......

  13. Evaluating Technical Assistance to Drug-Free Schools Programs: Three Complementary Approaches.

    ERIC Educational Resources Information Center

    Gabriel, Roy M.; Salmon, Jennifer R.

    With the passage of the Drug-Free Schools and Communities Act in 1986 a regional technical assistance center program was expanded to train school teams, assist state educational agencies, assist local educational agencies and institutions of higher education, and evaluate and disseminate information on effective drug and alcohol abuse education…

  14. Drug Treatment in Adult Probation: An Evaluation of an Outpatient and Acupuncture Program.

    ERIC Educational Resources Information Center

    Moon, Melissa M.; Latessa, Edward J.

    1994-01-01

    The effectiveness of an innovative outpatient drug-free treatment facility serving felony drug offenders who are placed on probation is evaluated. Treatment included educational and group therapy as well as acupuncture. Background characteristics, levels of treatment, and selected outcomes are described. Principles of successful interventions are…

  15. Formulation, Evaluation and Optimization of Pectin- Bora Rice Beads for Colon Targeted Drug Delivery System

    PubMed Central

    Ramteke, Kuldeep Hemraj; Nath, Lilakant

    2014-01-01

    Purpose: The purpose of this research was to established new polysaccharide for the colon targeted drug delivery system, its formulation and in vitro and in vivo evaluation. Methods: Microspheres containing pectin and bora rice were prepared by ionotropic gelation technique using zinc acetate as cross linking agent and model drug used was glipizide. A 32 full factorial design was employed to study the effect of independent variables, polymer to drug ratio (A), and concentration of cross linking agent (B) on dependent variables, particle size, swelling index, drug entrapment efficiency and percentage drug release. Results: Results of trial batches indicated that polymer to drug ratio and concentration of cross linking agent affects characteristics of beads. Beads were discrete, spherical and free flowing. Beads exhibited small particle size and showed higher percentage of drug entrapment efficiency. The optimized batch P2 exhibited satisfactory drug entrapment efficiency 68% and drug release was also controlled for more than 24 hours. The polymer to drug ratio had a more significant effect on the dependent variables. In vivo gamma scintigraphy study of optimized pectin-bora rice beads demonstrated degradation of beads whenever they reached to the colon. Conclusion: Bora rice is potential polysaccharide for colon targeted drug delivery system. PMID:24511481

  16. Drugs' rapid payoffs distort evaluation of their instrumental uses.

    PubMed

    Ainslie, George

    2011-12-01

    Science has needed a dispassionate valuation of psychoactive drugs, but a motivational analysis should be conducted with respect to long-term reward rather than reproductive fitness. Because of hyperbolic overvaluation of short-term rewards, an individual's valuation depends on the time she forms it and the times she will revisit it, sometimes making her best long-term interest lie in total abstinence. PMID:22074964

  17. [Drug evaluation in healthy volunteers. Legislative and ethical aspects].

    PubMed

    Warot, D

    1991-01-01

    Studies in healthy volunteers have been legalized since December 20th 1988 in France. The healthy volunteer is employed for a variety of studies in phases I and IV of drug development. This type of research can equally be called nontherapeutic in nature. Every experiment involving healthy volunteers should be approved by the Ethics Committee. Using volunteers within the department, company or other organisation, while offering advantages for the investigator should be prohibited as freedom of concept might not be safeguarded. As well, financial incentives may over-persuade individuals, including students, who have low incomes and promote the "professional volunteer". To avoid this problem, French law planned a national register. The potential benefits of such a disposition are still unknown. Having been given appropriate information concerning the drug trial, his obligations and rights, the healthy volunteer gives his written consent. Specific recommendations for nontherapeutic assessments of drug effects are given concerning prisoners, the mentally handicapped, women with a risk of frequency, children. Ethical considerations concerning research on a healthy population must go beyond the law recently promulgated in France. PMID:2050001

  18. Application of Physiologically Based Absorption Modeling for Amphetamine Salts Drug Products in Generic Drug Evaluation.

    PubMed

    Babiskin, Andrew H; Zhang, Xinyuan

    2015-09-01

    Amphetamine (AMP) salts-based extended-release (ER) drug products are widely used for the treatment of attention deficit hyperactivity disorder. We developed physiologically based absorption models for mixed AMP salts ER capsules and dextroamphetamine sulfate ER capsules to address specific questions raised during generic drug postmarketing surveillance and bioequivalence (BE) guidance development. The models were verified against several data sets. Virtual BE simulations were conducted to assess BE in various populations other than normal healthy subjects where BE studies are generally conducted for approval. The models were also used to predict pharmacokinetics (PK) for hypothetical formulations having dissolution profiles falling within specification after the development of in vitro-in vivo relation. Finally, we demonstrated how to use the models to test sensitivity of PK metrics to the changes in formulation variables. PMID:25973928

  19. An Evaluation of Immediate Outcomes and Fidelity of a Drug Abuse Prevention Program in Continuation High Schools: Project towards No Drug Abuse (TND)

    ERIC Educational Resources Information Center

    Lisha, Nadra E.; Sun, Ping; Rohrbach, Louise A.; Spruijt-Metz, Donna; Unger, Jennifer B.; Sussman, Steve

    2012-01-01

    The present study provides an implementation fidelity, process, and immediate outcomes evaluation of Project Towards No Drug Abuse (TND), a drug prevention program targeting continuation high school youth (n = 1426) at risk for drug abuse. A total of 24 schools participated in three randomized conditions: TND Only, TND and motivational…

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

    SciTech Connect

    Li, Xiaoguang; Qian, Hua; Miyamoto, Fusako; Kawaji, Kumi; Hattori, Toshio; Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka; and others

    2012-07-27

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

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

    PubMed Central

    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

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

    PubMed

    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; Renia, Laurent

    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

  3. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism.

    PubMed

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik; Olsson, Roger

    2016-05-18

    The metabolism of drugs in the brain is difficult to study in most species because of enzymatic instability in vitro and interference from peripheral metabolism in vivo. A locust ex vivo model that combines brain barrier penetration, efflux, metabolism, and analysis of the unbound fraction in intact brains was evaluated using known drugs. Clozapine was analyzed, and its major metabolites, clozapine N-oxide (CNO) and N-desmethylclozapine (NDMC), were identified and quantified. The back-transformation of CNO into clozapine observed in humans was also observed in locusts. In addition, risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data in the literature for mammals except for the stated fact that CNO is a highly blood-brain barrier permeant compound. Overall, the experiments indicated that invertebrates might be useful for screening of blood-brain barrier permeation, efflux, metabolism, and analysis of the unbound fraction of drugs in the brain in early drug discovery. PMID:26930271

  4. Evaluation of a procedure to assess the adverse effects of illicit drugs.

    PubMed

    van Amsterdam, J G C; Best, W; Opperhuizen, A; de Wolff, F A

    2004-02-01

    The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medical, health, legal, and criminalistic issues of the drugs. After this face-to-face discussion the drugs were scored again. Taking the assessment of ketamine as an example, it appeared that each expert used its own scale to score, and that policymakers do not score deviant from experts trained in the medical-biological field. Of the five drugs evaluated by the panel, p-methoxy-metamphetamine (PMMA), gamma-hydroxybutyric acid (GHB), and 4-methylthio-amphetamine (MTA) were assessed as more adverse than ketamine and psilocine and psilocybine-containing mushrooms. Whereas some experts slightly adjusted during the assessment procedure their opinion on ketamine and PMMA, the opinion on mushrooms was not affected by the discussion held between the two scoring rounds. All experts rank the five drugs in a similar way on the adverse effect scale i.e., concordance scale of the Electre model, indicating unanimity in the expert panel with respect to the risk classification of these abused drugs. PMID:14746774

  5. The future of artemisinins: natural, synthetic or recombinant?

    PubMed Central

    Hommel, Marcel

    2008-01-01

    Artemisinins are the most important anti-malarial drugs in use today, but are more costly than previous anti-malarials and production and price tend to fluctuate. Alternative ways of producing artemisinins are discussed here in the light of a recent paper in BMC Biotechnology on improving the yield of the precursor, artemisinic acid, in genetically engineered yeast. PMID:19090980

  6. Preparation and Evaluation of Transdermal Drug Delivery System of Etoricoxib Using Modified Chitosan

    PubMed Central

    Wahid, A.; Sridhar, B. K.; Shivakumar, S.

    2008-01-01

    In the present investigation chitosan has been chemically modified by treating with two different aldehydes like acetaldehyde and propionaldehyde to form Schiff’s bases. Schiff’s bases of chitosan with acetaldehyde and propionaldehyde were named as polymer A and polymer B, respectively. Fourier Transform Infra Red (FTIR) spectral data have confirmed the reaction carried out on chitosan. Drug free polymeric films of chitosan, chemically modified chitosan and chitosan/hydroxypropylmethylcellulose blend were prepared and evaluated for various physicochemical characters. Further, the films were incorporated with anti-inflammatory drug, etoricoxib using glycerol as plasticizer. The drug loaded films were cross-linked with sodium citrate and studied for permeation characteristics across dialysis membrane and rat skin. All the films were evaluated for bursting strength, swelling index, moisture uptake, thickness uniformity, drug content uniformity, tensile strength, percent elongation at break, percent flatness, water vapour transmission rate and in vitro drug permeation study. PMID:20046770

  7. In vivo evaluation of drug delivery after ultrasound application: A new use for the photoacoustic technique

    NASA Astrophysics Data System (ADS)

    Barja, P. R.; Acosta-Avalos, D.; Rompe, P. C. B.; Dos Anjos, F. H.; Marciano, F. R.; da Silva, M. D.

    2005-06-01

    Ultrasound application is a therapeutical resource widely employed in physiotherapy. One of its applications is the phonophoresis, a technique in which the ultrasound radiation is utilized to deliver drugs through the skin to soft tissues. The proposal of our study was to employ the Photoacoustic Technique to evaluate the efficacy of such treatment, analyzing if phonophoresis could enhance drug delivery through skin when compared to the more traditional method of manual massage. The configuration of the system employed was such that it was possible to perform in vivo measurements, which is a pre-requisite for this kind of study. The changes observed in the photoacoustic signal amplitude after each form of drug application were attributed to changes in the thermal effusivity of the system, due to penetration of the drug. The technique was able to detect differences in drug delivery between the specified physiotherapy treatments, indicating that phonophoresis enhances drug absorption by tissue.

  8. Evaluation of food-drug interaction of guava leaf tea.

    PubMed

    Kaneko, Kimiyuki; Suzuki, Katsuya; Iwadate-Iwata, Emi; Kato, Ikuo; Uchida, Kazumi; Onoue, Masaharu

    2013-02-01

    Guava leaf tea (GLT) contains guava leaf polyphenol (Gvpp), which regulates the absorption of dietary carbohydrate from the intestines. Borderline diabetics, who are at high risk of development of diabetes, take GLT to suppress a rapid increase of blood sugar level after meals. However, patients with diabetes in whom diabetic drugs or warfarin as a blood thinner are prescribed also take GLT with the expectation of glycemic control. Therefore, we studied whether GLT had potential for inhibition or induction of cytochrome P450 (CYP) and an influence on the action of warfarin. Extract of guava leaf (GvEx) consists of carbohydrate and polyphenols, which are Gvpp, quercetin, and ellagic acid. These polyphenols, but not GvEx, showed a certain level of inhibition of human-cDNA-expressed CYPs. In a comparison of GLT and grapefruit juice, GLT showed weaker inhibition of CYP activities and of midazolam 1'-hydroxylation than grapefruit juice. Furthermore, neither liver weight nor CYP3A expression in the liver was changed in rats that received GvEx for 90 days compared with the control group. When rats were concomitantly treated with GLT and warfarin, the prolongation of clotting time of blood by warfarin was not influenced. These data suggest that GLT is unlikely to interact with drugs. PMID:22566187

  9. Predicting drug metabolism--an evaluation of the expert system METEOR.

    PubMed

    Testa, Bernard; Balmat, Anne-Loyse; Long, Anthony; Judson, Philip

    2005-07-01

    The paper begins with a discussion of the goals of metabolic predictions in early drug research, and some difficulties toward this objective, mainly the various substrate and product selectivities characteristic of drug metabolism. The major in silico approaches to predict drug metabolism are then classified and summarized. A discrimination is, thus, made between 'local' and 'global' systems. In its second part, an evaluation of METEOR, a rule-based expert system used to predict the metabolism of drugs and other xenobiotics, is reported. The published metabolic data of ten substrates were used in this evaluation, the overall results being discussed in terms of correct vs. disputable (i.e., false-positive and false-negative) predictions. The predictions for four representative substrates are presented in detail (Figs. 1-4), illustrating the interest of such an evaluation in identifying where and how predictive rules can be improved. PMID:17193178

  10. Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs.

    PubMed

    Hayakawa, Yoshihiro; Kawada, Manabu; Nishikawa, Hiroyoshi; Ochiya, Takahiro; Saya, Hideyuki; Seimiya, Hiroyuki; Yao, Ryoji; Hayashi, Masahiro; Kai, Chieko; Matsuda, Akira; Naoe, Tomoki; Ohtsu, Atsushi; Okazaki, Taku; Saji, Hideo; Sata, Masataka; Sugimura, Haruhiko; Sugiyama, Yuichi; Toi, Masakazu; Irimura, Tatsuro

    2016-02-01

    Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs. PMID:26919617