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Sample records for evaluate anti-malarial drug

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

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    Avinaba Mukherjee

    2016-03-01

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

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

    Science.gov (United States)

    Watsierah, Carren A; Jura, Walter G Z O; Oyugi, Henry; Abong'o, Benard; Ouma, Collins

    2010-10-26

    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. 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 cure. Mothers/caretakers provided information for children aged malaria care and decrease malaria-related morbidity and mortality by increasing drug affordability, ensuring that the recommended anti-malarial drugs are easily available in all government approved drug outlets and educates the local shopkeepers on the symptoms and appropriate treatment of malaria. Following a switch to ACT in national drug policy, education on awareness and behaviour change is recommended, since the efficacy of ACT alone is not sufficient to reduce morbidity and mortality due to malaria.

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

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    Abong'o Benard

    2010-10-01

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

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

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    Rusk Andria

    2012-08-01

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

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

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    Reeder John C

    2010-01-01

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

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

    Science.gov (United States)

    Marfurt, Jutta; Smith, Thomas A; Hastings, Ian M; Müller, Ivo; Sie, Albert; Oa, Olive; Baisor, Moses; Reeder, John C; Beck, Hans-Peter; Genton, Blaise

    2010-01-07

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

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

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    Kotaki Hajime

    2010-11-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform...... a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods: All drug shops selling...... practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug...

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

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    Dondorp Arjen M

    2008-11-01

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

  11. Determinants of price setting decisions on anti-malarial drugs at retail shops in Cambodia.

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    Patouillard, Edith; Hanson, Kara; Kleinschmidt, Immo; Palafox, Benjamin; Tougher, Sarah; Pok, Sochea; O'Connell, Kate; Goodman, Catherine

    2015-05-30

    In many low-income countries, the private commercial sector plays an important role in the provision of malaria treatment. However, the quality of care it provides is often poor, with artemisinin combination therapy (ACT) generally being too costly for consumers. Decreasing ACT prices is critical for improving private sector treatment outcomes and reducing the spread of artemisinin resistance. Yet limited evidence exists on the factors influencing retailers' pricing decisions. This study investigates the determinants of price mark-ups on anti-malarial drugs in retail outlets in Cambodia. Taking an economics perspective, the study tests the hypothesis that the structure of the anti-malarial market determines the way providers set their prices. Providers facing weak competition are hypothesized to apply high mark-ups and set prices above the competitive level. To analyse the relationship between market competition and provider pricing, the study used cross-sectional data from retail outlets selling anti-malarial drugs, including outlet characteristics data (e.g. outlet type, anti-malarial sales volumes), range of anti-malarial drugs stocked (e.g. dosage form, brand status) and purchase and selling prices. Market concentration, a measure of the level of market competition, was estimated using sales volume data. Market accessibility was defined based on travel time to the closest main commercial area. Percent mark-ups were calculated using price data. The relationship between mark-ups and market concentration was explored using regression analysis. The anti-malarial market was on average highly concentrated, suggesting weak competition. Higher concentration was positively associated with higher mark-ups in moderately accessible markets only, with no significant relationship or a negative relationship in other markets. Other determinants of pricing included anti-malarial brand status and generic type, with higher mark-ups on cheaper products. The results indicate that

  12. Malaria and anti-malarial drugs utilisation among adults in a rural ...

    African Journals Online (AJOL)

    ... two hundred thirty seven adult females were interviewed. Results: Prevalence of self-medication was found to be 44.2%, males being significantly more likely to take anti-malarial drugs without medical advice than females (52.2% vs. 38%). The level of education was found to be associated with pattern of self-medication.

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

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    Lee Sue J

    2009-11-01

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

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

    African Journals Online (AJOL)

    DR. AMINU

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

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

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    Chance Michael L

    2011-08-01

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

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

    Science.gov (United States)

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

    2011-08-21

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

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

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    McKenzie F Ellis

    2010-07-01

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

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

    Science.gov (United States)

    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

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

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    Giuseppe ePulice

    2016-03-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

    Shaukat, Ayesha M; Gilliams, Elizabeth A; Kenefic, Leo J; Laurens, Matthew B; Dzinjalamala, Fraction K; Nyirenda, Osward M; Thesing, Phillip C; Jacob, Christopher G; Molyneux, Malcolm E; Taylor, Terrie E; Plowe, Christopher V; Laufer, Miriam K

    2012-06-18

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

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

    Science.gov (United States)

    Nevin, Remington L; Croft, Ashley M

    2016-06-22

    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.

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

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    Antao Tiago

    2012-12-01

    Full Text Available Abstract 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.

  4. Social and cultural complexities of anti-malarial drug circulation: an ethnographic investigation in three rural remote communes of Cambodia.

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    Res, Phasy

    2017-10-25

    Anti-malarial medicine has a central role in malaria case management in Cambodia. It is, therefore, essential to study how anti-malarial drugs are distributed and consumed. This study aims to understand the socio-cultural complexity of anti-malarial drugs provision and usage practices. Semi-structured interviews and observation were conducted in Cambodia at the communal, provincial, and national levels from January 2014 to January 2015. Health ministers, non-governmental officers, anti-malarial medicines distributors, village malaria volunteers and malaria patients were interviewed. The findings show that artemisinin-based combination therapy (ACT) flows into unregulated outlets, and was sold without any diagnostic tests. Affordable Medicines Facility for malaria scheme (AMFm) cannot drive ineffective anti-malarial medicines out of the market because ACT is still more expensive due to price absortion by private and public providers. Malaria patients might not consume ACT because of patients' notions of 'Korp', and pharmaceutical and parasitic familiarity. The findings reflect that neither public nor private institutions have the capacity and resources to control the flow of ACT from going into the unlicensed sector. They do not have the ability to ensure that ACT is consumed after a positive rapid diagnostic test. With a weak regulation system and ailing public health infrastructure, pharmaceutical-neoliberal mechanism like AMFm is not an effective means to eradicate any forms of malaria. Therefore, horizontal programmes, such as public health infrastructure improvement, and population participation must be implemented. Ethnical responsibilities of medical practitioners must be enforced and be included into the national curriculum. The awareness of drug resistance must be implemented at all levels.

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

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

    2014-02-20

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

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

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    Pradines Bruno

    2011-10-01

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

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

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    Sylla Thiam

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

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

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

    2011-04-06

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

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

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    Dondorp Arjen M

    2009-10-01

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

  10. Evaluation of anti-malarial activity of Artemisia turcomanica and A. kopetdaghensis by cell-free β-hematin formation assay

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    M. Mojarrab

    2016-10-01

    Full Text Available Background and objectives:The plants of genus Artemisia (Asteraceae have been conventionally used for prevention and medication of a number of ailments. In the present research, ten extracts with different polarities from aerial parts of two Artemisia species, A. kopetdaghensis and A. turcomanica were evaluated for their potential anti-malarial properties. Methods: The plant materials were extracted successively with petroleum ether (PE, dichloromethane (DCM, ethyl acetate (EtOAC, ethanol, and ethanol-water (1:1 v/v  by cold maceration method. Cell free β-hematin formation assay were used for assessing anti-malarial activity of obtained extracts. Results: DCM extract of A. kopetdaghensis and PE extract of A. turcomanica showed remarkable anti-malarial activity with IC50 values of 1.04±0.02 mg/mL and 0.90±0.27 mg/mL, respectively, compared to positive control (chloroquine, IC50 0.04±0.01 mg/mL. Conclusion:  It seems that the anti-malarial activity of these extracts might be bound up with the presence of compounds with low or medium polarity; hence, this preliminary test indicated that these potent extracts could be considered for further investigations to find new sources of anti-malarial phytochemicals.

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

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    Ringsted Frank M

    2011-08-01

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

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

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    Van Erps Jan

    2011-03-01

    Full Text Available Abstract 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

  13. Multiple treatment comparisons in a series of anti-malarial trials with an ordinal primary outcome and repeated treatment evaluations

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    Youdom Solange

    2012-05-01

    Full Text Available Abstract Background Artemisinin-based combination therapies (ACT are widely used in African countries, including Cameroon. Between 2005 and 2007, five randomized studies comparing different treatment arms among artesunate-amodiaquine and other ACT were conducted in Cameroonian children aged two to 60 months who had uncomplicated Plasmodium falciparum malaria. In these studies, the categorical criterion proposed by the World Health Organization (WHO to assess the relative effectiveness of anti-malarial drugs was repeatedly evaluated on Days 14, 21 and 28 after treatment initiation. The aim of the present study was to compare the effects of different treatments on this repeated ordinal outcome, hence using the fully available information. Methods The quantitative synthesis was based on individual patient data. Due to the incomplete block design concerning treatment arms between different trials, a mixed treatment comparison (MTC meta-analysis approach was adopted. The repeated ordinal outcome was modelled through a latent variable, as a proportional odds mixed model with trial, period and treatment arms as covariates. The model was further complexified to account for the variance heterogeneity, and the individual log-residual variance was modelled as a linear mixed model, as well. The effects of individual covariates at inclusion, such as parasitaemia, fever, gender and weight, were also tested. Model parameters were estimated using a Bayesian approach via the WinBUGS software. After selecting the best model using Deviance Information Criterion (DIC, mixed treatment comparisons were based on the estimated treatment effects. Results Modeling the residual variance improved the model ability to adjust the data. The results showed that, compared to artesunate-amodiaquine (ASAQ, dihydroartemisinin-piperaquine (DHPP was significantly more efficacious. Artesunate-chlorproguanil-dapsone (ASCD was less efficacious than artesunate

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

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    Eberlin Marcos N

    2011-05-01

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

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

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

    2011-02-10

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

  16. Cellular engineering of Artemisia annua and Artemisia dubia with the rol ABC genes for enhanced production of potent anti-malarial drug artemisinin.

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    Kiani, Bushra Hafeez; Suberu, John; Mirza, Bushra

    2016-05-04

    Malaria is causing more than half of a million deaths and 214 million clinical cases annually. Despite tremendous efforts for the control of malaria, the global morbidity and mortality have not been significantly changed in the last 50 years. Artemisinin, extracted from the medicinal plant Artemisia sp. is an effective anti-malarial drug. In 2015, elucidation of the effectiveness of artemisinin as a potent anti-malarial drug was acknowledged with a Nobel prize. Owing to the tight market and low yield of artemisinin, an economical way to increase its production is to increase its content in Artemisia sp. through different biotechnological approaches including genetic transformation. Artemisia annua and Artemisia dubia were transformed with rol ABC genes through Agrobacterium tumefacienes and Agrobacterium rhizogenes methods. The artemisinin content was analysed and compared between transformed and untransformed plants with the help of LC-MS/MS. Expression of key genes [Cytochrome P450 (CYP71AV1), aldehyde dehydrogenase 1 (ALDH1), amorpha-4, 11 diene synthase (ADS)] in the biosynthetic pathway of artemisinin and gene for trichome development and sesquiterpenoid biosynthetic (TFAR1) were measured using Quantitative real time PCR (qRT-PCR). Trichome density was analysed using confocal microscope. Artemisinin content was significantly increased in transformed material of both Artemisia species when compared to un-transformed plants. The artemisinin content within leaves of transformed lines was increased by a factor of nine, indicating that the plant is capable of synthesizing much higher amounts than has been achieved so far through traditional breeding. Expression of all artemisinin biosynthesis genes was significantly increased, although variation between the genes was observed. CYP71AV1 and ALDH1 expression levels were higher than that of ADS. Levels of the TFAR1 expression were also increased in all transgenic lines. Trichome density was also significantly

  17. Detection of high levels of mutations involved in anti-malarial drug resistance in Plasmodium falciparum and Plasmodium vivax at a rural hospital in southern Ethiopia

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    González Vicenta

    2011-08-01

    Full Text Available Abstract Background In Ethiopia, malaria is caused by Plasmodium falciparum and Plasmodium vivax, and anti-malarial drug resistance is the most pressing problem confronting control of the disease. Since co-infection by both species of parasite is common and sulphadoxine-pyrimethamine (SP has been intensively used, resistance to these drugs has appeared in both P. falciparum and P. vivax populations. This study was conducted to assess the prevalence of anti-malarial drug resistance in P. falciparum and P. vivax isolates collected at a rural hospital in southern Ethiopia. Methods A total of 1,147 patients with suspected malaria were studied in different months across the period 2007-2009. Plasmodium falciparum dhfr and dhps mutations and P. vivax dhfr polymorphisms associated with resistance to SP, as well as P. falciparum pfcrt and pfmdr1 mutations conferring chloroquine resistance, were assessed. Results PCR-based diagnosis showed that 125 of the 1147 patients had malaria. Of these, 52.8% and 37.6% of cases were due to P. falciparum and P. vivax respectively. A total of 10 cases (8% showed co-infection by both species and two cases (1.6% were infected by Plasmodium ovale. Pfdhfr triple mutation and pfdhfr/pfdhps quintuple mutation occurred in 90.8% (95% confidence interval [CI]: 82.2%-95.5% and 82.9% (95% CI: 72.9%-89.7% of P. falciparum isolates, respectively. Pfcrt T76 was observed in all cases and pfmdr1 Y86 and pfmdr1 Y1246 in 32.9% (95% CI: 23.4%-44.15% and 17.1% (95% CI: 10.3-27.1%, respectively. The P. vivax dhfr core mutations, N117 and R58, were present in 98.2% (95% CI: 89.4-99.9% and 91.2% (95% CI: 80.0-96.7%, respectively. Conclusion Current molecular data show an extraordinarily high frequency of drug-resistance mutations in both P. falciparum and P. vivax in southern Ethiopia. Urgent surveillance of the emergence and spread of resistance is thus called for. The level of resistance indicates the need for implementation of entire

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

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    Masaninga Freddie

    2012-10-01

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

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

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    Ogunwande Isiaka A

    2011-08-01

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

  20. High prevalence of pfdhfr-pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine-pyrimethamine in combination with artesunate as first-line treatment in Iran.

    Science.gov (United States)

    Rouhani, Maryam; Zakeri, Sedigheh; Pirahmadi, Sakineh; Raeisi, Ahmad; Djadid, Navid Dinparast

    2015-04-01

    The spread of anti-malarial drug resistance will challenge any malaria control and elimination strategies, and routine monitoring of resistance-associated molecular markers of commonly used anti-malarial drugs is very important. Therefore, in the present investigation, the extent of mutations/haplotypes in dhfr and dhps genes of Plasmodium falciparum isolates (n=72) was analyzed seven years after the introduction of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) as first-line anti-malarial treatment in Iran using PCR-RFLP methods. The results showed that the majority of the patients (97.2%) carried both 59R and 108N mutations in pure form with wild-type genotype at positions N51 and I164. Additionally, a significant increase (Pdrug for treatment of falciparum patients in these malaria-endemic areas of Iran. However, no quintuple mutations associated with treatment failure were detected. In conclusion, the present results along with in vivo assays suggest that seven years after the adoption of SP-AS as the first-line treatment in Iran, this drug remains efficacious for treatment of uncomplicated falciparum malaria, as a partner drug with AS in these malaria-endemic areas. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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    Brasseur Philippe

    2012-12-01

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

  2. Assessment of molecular markers for anti-malarial drug resistance after the introduction and scale-up of malaria control interventions in western Kenya.

    Science.gov (United States)

    Shah, Monica; Omosun, Yusuf; Lal, Ashima; Odero, Christopher; Gatei, Wangeci; Otieno, Kephas; Gimnig, John E; ter Kuile, Feiko; Hawley, William A; Nahlen, Bernard; Kariuki, Simon; Walker, Edward; Slutsker, Laurence; Hamel, Mary; Shi, Ya Ping

    2015-02-14

    Although it is well known that drug pressure selects for drug-resistant parasites, the role of transmission reduction by insecticide-treated bed nets (ITNs) on drug resistance remains unclear. In this study, the drug resistance profile of current and previous first-line anti-malarials in Kenya was assessed within the context of drug policy change and scale-up of ITNs. National first-line treatment changed from chloroquine (CQ) to sulphadoxine-pyrimethamine (SP) in 1998 and to artemether-lumefantrine (AL) in 2004. ITN use was scaled-up in the Asembo, Gem and Karemo areas of western Kenya in 1997, 1999 and 2006, respectively. Smear-positive samples (N = 253) collected from a 2007 cross-sectional survey among children in Asembo, Gem and Karemo were genotyped for mutations in pfcrt and pfmdr1 (CQ), dhfr and dhps (SP), and at pfmdr-N86 and the gene copy number in pfmdr1 (lumefantrine). Results were compared among the three geographic areas in 2007 and to retrospective molecular data from children in Asembo in 2001. In 2007, 69 and 85% of samples harboured the pfmdr1-86Y mutation and dhfr/dhps quintuple mutant, respectively, with no significant differences by study area. However, the prevalence of the pfcrt-76T mutation differed significantly among areas (p dhps-436A, or dhps-613T. From 2001 to 2007, there were significant increases in the pfcrt-76T mutation from 82 to 94% (p dhps quintuple mutant from 62 to 82% (p drug pressure from the continued use of CQ, SP, and mechanistically similar drugs, such as amodiaquine and cotrimoxazole. There was no clear evidence that differences in transmission intensity, as a result of ITN scale-up, influenced the prevalence of drug resistance molecular markers.

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

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    Lall Varinder K

    2012-12-01

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

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

    Science.gov (United States)

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

    2015-03-26

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

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

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    Antia R

    2003-02-01

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

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

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    Akter Jasmin

    2012-11-01

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

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

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    Sow Diarietou

    2009-06-01

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

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

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    Ronn Anita

    2011-08-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

    Duffy, Sandra; Avery, Vicky M

    2017-12-01

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

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

    OpenAIRE

    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 trimethopri...

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

    Science.gov (United States)

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

    2014-12-13

    Little is known about how people living with human immunodeficiency virus (HIV) experience malaria and the concomitant use of anti-malarial treatments with anti-retrovirals (ARVs). An understanding of how patients make sense of these experiences is important to consider in planning and supporting the clinical management and treatment for co-infected individuals. A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and malaria co-infection. Focus group discussions were held with people receiving treatment for HIV and/or malaria, and in-depth interviews with health workers responsible for HIV care and members of the clinical trial team. Data were analysed inductively to identify themes and develop theoretical narratives. Results suggest that people living with HIV perceived malaria to be more harmful to them due to their compromised immune status but saw the disease as unavoidable. For those enrolled in the clinical controlled study, taking anti-malarials together with ARVs was largely seen as unproblematic, with health workers' advice and endorsement of concomitant drug taking influential in reported adherence. However, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes. In the context of a trial concerned with both diseases, patients experienced the support of clinicians in guiding and reassuring them about when and how to take drugs concomitantly. This points towards the need to continue to strive for integrated care for patients with HIV.

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2016-02-13

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

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

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    Littrell Megan

    2011-10-01

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

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

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    Wells Timothy NC

    2011-03-01

    medicinal products already 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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

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    Chapman Steven

    2011-10-01

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

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

    Science.gov (United States)

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

    2013-10-30

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

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

    Science.gov (United States)

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

    2017-03-03

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

  1. Immunity as a predictor of anti-malarial treatment failure: a systematic review.

    Science.gov (United States)

    O'Flaherty, Katherine; Maguire, Julia; Simpson, Julie A; Fowkes, Freya J I

    2017-04-20

    Naturally acquired immunity can reduce parasitaemia and potentially influence anti-malarial treatment outcomes; however, evidence for this in the current literature provides conflicted results. The available evidence was synthesized to determine and quantify the association between host immunity and anti-malarial treatment failure. Four databases were searched to identify studies investigating malaria antibody levels in patients receiving anti-malarial treatment for symptomatic malaria with treatment failure recorded according to the World Health Organization classification. Odds ratios or hazard ratios were extracted or calculated to quantify the association between malarial antibody levels and treatment failure, and findings from different studies were visualized using forest plots. Eight studies, including patients with falciparum malaria treated with mono- and combination therapy of artemisinin derivatives, sulfadoxine, pyrimethamine and chloroquine, were identified. Reported and calculated effect estimates varied greatly between studies, even those assessing the same antigens and treatments. An association between blood-stage IgG responses and treatment efficacy was observed. The greatest magnitudes of effect were observed for artemisinin [OR/HR (95% CI) range 0.02 (0.00, 0.45)-1.08 (0.57, 2.06)] and chloroquine [0.24 (0.04, 1.37)-0.32 (0.05, 1.96)] treatments, and larger magnitudes of effect were observed for variant surface antigen responses [0.02 (0.00, 0.45)-1.92 (0.94, 3.91)] when compared with merozoite specific responses [0.24 (0.04, 1.37)-2.83 (1.13, 7.09)]. Naturally acquired malarial immunity is associated with reduced anti-malarial treatment failure in malaria endemic populations. Anti-malarial IgG effects treatment outcome differently for different anti-malarial drugs and antigen targets, and had the greatest impact during treatment with the current first-line treatments, the artemisinins. This has implications for the assessment of the therapeutic

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

    Directory of Open Access Journals (Sweden)

    Gwét Henri

    2010-06-01

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

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

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    Nambei W.S.

    2005-03-01

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

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

    OpenAIRE

    Mangesho, PE; Reynolds, J.; Lemnge, M; Vestergaard, LS; Chandler, CIR

    2014-01-01

    Background Little is known about how people living with human immunodeficiency virus (HIV) experience malaria and the concomitant use of anti-malarial treatments with anti-retrovirals (ARVs). An understanding of how patients make sense of these experiences is important to consider in planning and supporting the clinical management and treatment for co-infected individuals. Methods A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and mal...

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

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    Ladda Kajeechiwa

    2016-09-01

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

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

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    Simiyu Chrispinus

    2011-10-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

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

    Science.gov (United States)

    Karunamoorthi, Kaliyaperumal

    2014-06-02

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

  9. Poisoning by anti-malarial drugs

    African Journals Online (AJOL)

    may result from stimulation of the pancreatic islet beta-cells. This is more common in pregnancy and infants. The risk is reduced by administering the quinine with glucose. However the nursing and medical staff must be aware constantly of the probability of hypoglycaemia. Thrombocytopenia. • may result from an immune.

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

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    Diakite Chiaka

    2011-03-01

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

  11. In silico prediction of anti-malarial hit molecules based on machine learning methods.

    Science.gov (United States)

    Kumari, Madhulata; Chandra, Subhash

    2015-01-01

    Machine learning techniques have been widely used in drug discovery and development in the areas of cheminformatics. Aspartyl aminopeptidase (M18AAP) of Plasmodium falciparum is crucial for survival of malaria parasite. We have created predictive models using weka and evaluated their performance based on various statistical parameters. Random Forest based model was found to be the most specificity (97.94%), with best accuracy (97.3%), MCC (0.306) as well as ROC (86.1%). The accuracy and MCC of these models indicated that they could be used to classify huge dataset of unknown compounds to predict their antimalarial compounds to develop effective drugs. Further, we deployed best predictive model on NCI diversity set IV. As result we found 59 bioactive anti-malarial molecules inhibiting M18AAP. Further, we obtained 18 non-toxic hit molecules out of 59 bioactive compounds. We suggest that such machine learning approaches could be applied to reduce the cost and length of time of drug discovery.

  12. Evidence on anti-malarial and diagnostic markets in Cambodia to guide malaria elimination strategies and policies.

    Science.gov (United States)

    Phok, Sochea; Lek, Dysoley

    2017-04-25

    Understanding Cambodia's anti-malarial and diagnostic landscape in 2015 is critical for informing and monitoring strategies and policies as Cambodia moves forward with national efforts to eliminate malaria. The aim of this paper is to present timely and key findings on the public and private sector anti-malarial and diagnostic landscape in Cambodia. This evidence can serve as a baseline benchmark for guiding implementation of national strategies as well as other regional initiatives to address malaria elimination activities. From August 17th to October 1st, 2015, a cross sectional, nationally-representative malaria outlet survey was conducted in Cambodia. A census of all public and private outlets with potential to distribute malaria testing and/or treatment was conducted among 180 communes. An audit was completed for all anti-malarials, malaria rapid diagnostic tests (RDT) and microscopy. A total of 26,664 outlets were screened, and 1303 outlets were eligible and interviewed. Among all screened outlets in the public sector, 75.9% of public health facilities and 67.7% of community health workers stocked both malaria diagnostic testing and a first-line artemisinin-based combination therapy (ACT). Among anti-malarial-stocking private sector outlets, 64.7% had malaria blood testing available, and 70.9% were stocking a first-line ACT. Market share data illustrate that most of the anti-malarials were sold or distributed through the private sector (58.4%), including itinerant drug vendors (23.4%). First-line ACT accounted for the majority of the market share across the public and private sectors (90.3%). Among private sector outlets stocking any anti-malarial, the proportion of outlets with a first-line ACT or RDT was higher among outlets that had reportedly received one or more forms of 'support' (e.g. reportedly received training in the previous year on malaria diagnosis [RDT and/or microscopy] and/or the national treatment guidelines for malaria) compared to outlets

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

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    Khodakarim Nastaran

    2010-05-01

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

  14. A framework for assessing the risk of resistance for anti-malarials in development

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    Ding Xavier C

    2012-08-01

    Full Text Available Abstract Resistance is a constant challenge for anti-infective drug development. Since they kill sensitive organisms, anti-infective agents are bound to exert an evolutionary pressure toward the emergence and spread of resistance mechanisms, if such resistance can arise by stochastic mutation events. New classes of medicines under development must be designed or selected to stay ahead in this vicious circle of resistance control. This involves both circumventing existing resistance mechanisms and selecting molecules which are resilient against the development and spread of resistance. Cell-based screening methods have led to a renaissance of new classes of anti-malarial medicines, offering us the potential to select and modify molecules based on their resistance potential. To that end, a standardized in vitro methodology to assess quantitatively these characteristics in Plasmodium falciparum during the early phases of the drug development process has been developed and is presented here. It allows the identification of anti-malarial compounds with overt resistance risks and the prioritization of the most robust ones. The integration of this strategy in later stages of development, registration, and deployment is also discussed.

  15. Fusaripeptide A: new antifungal and anti-malarial cyclodepsipeptide from the endophytic fungus Fusarium sp.

    Science.gov (United States)

    Ibrahim, Sabrin R M; Abdallah, Hossam M; Elkhayat, Ehab S; Al Musayeib, Nawal M; Asfour, Hani Z; Zayed, Mohamed F; Mohamed, Gamal A

    2018-01-01

    From the culture of the endophytic fungus Fusarium sp. isolated from the roots of Mentha longifolia L. (Labiatae) growing in Saudi Arabia, a new cyclodepsipeptide, namely fusaripeptide A (1), along with three known compounds adenosine (2), 2[(2-hydroxypropionyl)amino]benzamide (3), and cyclopentanol (4), have been isolated. Their structures were determined, using extensive 1D and 2D NMR and HRESI and GC mass spectral data. That is the first report for the isolation of compound 4 from natural source. In addition, compounds 2 and 3 are reported here for the first time from Fusarium sp. The absolute configuration of the amino acid residues of 1 was assigned by chiral GCMS and Marfey's analysis after acid hydrolysis. Fusaripeptide A differs from the reported ones from Fusarium sp. in the length of fatty acidic alkyl chain. Compound 1 was evaluated for its antifungal, anti-malarial, and cytotoxic activities. It exhibited potent antifungal activity toward C. albicans, C. glabrata, C. krusei, and A. fumigates with IC 50 values of 0.11, 0.24, 0.19, and 0.14 μM, respectively. Furthermore, it had significant anti-malarial activity toward P. falciparum (D6 clone) with IC 50 value of 0.34 μM. However, it showed cytotoxic activity toward the tested cell lines.

  16. In silico analysis reveals the anti-malarial potential of quinolinyl chalcone derivatives.

    Science.gov (United States)

    Thillainayagam, Mahalakshmi; Pandian, Lavanya; Murugan, Kumar Kalavathy; Vijayaparthasarathi, Vijayakumar; Sundaramoorthy, Sarveswari; Anbarasu, Anand; Ramaiah, Sudha

    2015-01-01

    In this study, the correlation between chemical structures and various parameters such as steric effects and electrostatic interactions to the inhibitory activities of quinolinyl chalcone derivatives is derived to identify the key structural elements required in the rational design of potent and novel anti-malarial compounds. The molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are carried out on 38 chalcones derivatives using Plasmodium falciparum lactate dehydrogenase (PfLDH) as potential target. Surflex-dock is used to determine the probable binding conformations of all the compounds at the active site of pfLDH and to identify the hydrogen bonding interactions which could be used to alter the inhibitory activities. The CoMFA model has provided statistically significant results with the cross-validated correlation coefficient (q(2)) of .850 and the non-cross-validated correlation coefficient (r(2)) of .912. Standard error of estimation (SEE) is .280 and the optimum number of component is five. The predictive ability of the resultant model is evaluated using a test set comprising of 13 molecules and the predicted r(2) value is .885. The results provide valuable insight for optimization of quinolinyl chalcone derivatives for better anti-malarial therapy.

  17. Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii

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    Mout Rubul

    2012-02-01

    Full Text Available Abstract Background Geldanamycin (GA, a benzoquinone ansamycin antibiotic has been shown in vitro to possess anti-plasmodial activity. Pharmacological activity of this drug is attributed to its ability to inhibit PfHSP90. The parasite growth arrest has been shown to be due to drug-induced blockage of the transition from ring to trophozoite stage. To further evaluate the consequences of this pharmacodyamic feature, the anti-malarial activity of GA analogs with enhanced drug properties in a Plasmodium-infected animal model have been evaluated for their capacity to induce clearance of the parasite. In the process, a hypothesis was subsequently tested regarding the susceptibility of the cured animals to malaria reflected in an attenuated parasite load that may be evoked by a protective immune response in the host. Methods Six weeks old Swiss mice were infected with a lethal Plasmodium yoelii (17XL strain. On appearance of clinical symptoms of malaria, these animals were treated with two different GA derivatives and the parasite load was monitored over 15-16 days. Drug-treated animals cured of the parasite were then re-challenged with a lethal dose of P. yoelii 17XL. Serum samples from GA cured mice that were re-challenged with P. yoelii 17XL were examined for the presence of antibodies against the parasite proteins using western blot analysis. Results Treatment of P. yoelii 17XL infected mice with GA derivatives showed slow recovery from clinical symptoms of the disease. Blood smears from drug treated mice indicated a dominance of ring stage parasites when compared to controls. Although, P. yoelii preferentially invades normocytes (mature rbcs, in drug-treated animals there was an increased invasion of reticulocytes. Cured animals exhibited robust protection against subsequent infection and serum samples from these animals showed antibodies against a vast majority of parasite proteins. Conclusions Treatment with GA derivatives blocked the transition

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

    Science.gov (United States)

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

    2009-04-28

    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. To understand the wider context in which national malaria treatment guidelines were formulated in a specific country (Peru). 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. 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. 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 political will to their favor, approved the policy, and

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

    OpenAIRE

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Tonlong WANGPAN

    2016-03-01

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

  1. Comparison of electrospray ionisation, atmospheric pressure chemical ionisation and atmospheric pressure photoionisation for the identification of metabolites from labile artemisinin-based anti-malarial drugs using a QTRAP® mass spectrometer.

    Science.gov (United States)

    Louw, Stefan; Njoroge, Mathew; Chigorimbo-Murefu, Nyaradzo; Chibale, Kelly

    2012-10-30

    Artemisinin-based drugs and their metabolites are prone to in-source fragmentation under atmospheric pressure ionisation mass spectrometry (API-MS) conditions. To facilitate correct and efficient identification of all possible drug metabolites using full scan MS analyzer methods, stable [M + NH(4) ](+) ions should be produced in the MS source. Using a high-performance liquid chromatography (HPLC) hybrid triple quadrupole linear ion trap MS system, electrospray ionisation (ESI), atmospheric pressure chemical ionisation (APCI) and atmospheric pressure photoionisation (APPI) methods were developed for the detection of [M + NH(4) ](+) ions of the test compounds dihydroartemisinin, artemisinin, artemether and artesunic acid. The optimised methods employed ammonium formate buffered HPLC mobile phase in combination with moderate source temperatures (100-200 °C) and showed satisfactorily reduced in-source fragmentation. With a full scan MS analyser method for the detection of the in vitro metabolites of the test compounds, the respective performance of the ESI and APCI methods was found to be comparable. ESI generally resulted in less in-source fragmentation. Incorrect assignment of metabolites resulted from strong in-source fragmentation of artemether using the APPI method. The most number of metabolites could be detected using ESI in combination with a selective MS analyser method. ESI and APCI full scan methods proved to be capable of detecting any drug metabolites present in reasonable concentrations, and are useful when employed in addition to selective scan methods that target low level expected metabolites. APPI can be a valuable alternative for detecting expected metabolites due to good signal-to-noise (S/N) ratio. Copyright © 2012 John Wiley & Sons, Ltd.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    ABSTRACT: BACKGROUND: Sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been used in treatment of falciparum and vivax malaria in Nepal. Recently, resistance to both drugs have necessitated a change towards artemisinin combination therapy (ACT) against Plasmodium falciparum in highly...... if high levels of in vivo resistance are reflected at molecular level as well. METHODS: Finger prick blood samples (n=189) were collected from malaria positive patients from two high endemic districts and analysed for single nucleotide polymorphisms (SNPs) in the resistance related genes of P. falciparum...... and P. vivax for CQ (Pfcrt, Pfmdr1, Pvmdr1) and SP (Pfdhfr, Pfdhps, Pvdhfr), using various PCR-based methods. RESULTS AND DISCUSSION: Positive P. vivax and P. falciparum infections were identified by PCR in 92 and 41 samples respectively. However, some of these were negative in subsequent PCRs. Based...

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

    Directory of Open Access Journals (Sweden)

    Kaludov Nikola

    2011-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Vincent-Mark Arlene

    2009-04-01

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

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

    Science.gov (United States)

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

    2015-11-04

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

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

    Science.gov (United States)

    O'Meara, Wendy Prudhomme; Obala, Andrew; Thirumurthy, Harsha; Khwa-Otsyula, Barasa

    2013-06-05

    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. 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). 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. 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 role in greater adoption of AL.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Sebbag Robert

    2011-05-01

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

  9. Effects of anti-malarial alkaloids on the sperm properties and blood ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-10-06

    Oct 6, 2008 ... Key words: Anti-malarial alkaloids, quinine, chloroquine, sperm properties, reproductive hormones, adult men. INTRODUCTION. Malaria is caused by any of the four protozoan species of the genus plasmodium. Plasmodium falciparum is the deadliest of all the species and is the most common cause of ...

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

    NARCIS (Netherlands)

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

    2017-01-01

    Background: Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that

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

    NARCIS (Netherlands)

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

    2017-01-01

    Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass

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

    Science.gov (United States)

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

    2017-05-19

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

  13. OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimens.

    Science.gov (United States)

    Aljayyoussi, Ghaith; Kay, Katherine; Ward, Stephen A; Biagini, Giancarlo A

    2016-07-07

    The search for highly effective anti-malarial therapies has gathered pace and recent years have seen a number of promising single and combined therapies reach the late stages of development. A key drug development challenge is the need for early assessment of the clinical utility of new drug leads as it is often unclear for developers whether efforts should be focused on efficacy or metabolic stability/exposure or indeed whether the continuation of iterative QSAR (quantitative structure-activity and relationships) cycles of medicinal chemistry and biological testing will translate to improved clinical efficacy. Pharmacokinetic and pharmacodynamic (PK/PD)-based measurements available from in vitro studies can be used for such clinical predictions. However, these predictions often require bespoke mathematical PK/PD modelling expertise and are normally performed after candidate development and, therefore, not during the pre-clinical development phase when such decisions need to be made. An internet-based tool has been developed using STELLA(®) software. The tool simulates multiple differential equations that describe anti-malarial PK/PD relationships where the user can easily input PK/PD parameters. The tool utilizes a simple stop-light system to indicate the efficacy of each combination of parameters. This tool, called OptiMal-PK, additionally allows for the investigation of the effect of drug combinations with known or custom compounds. The results of simulations obtained from OptiMal-PK were compared to a previously published and validated mathematical model on which this tool is based. The tool has also been used to simulate the PK/PD relationship for a number of existing anti-malarial drugs in single or combined treatment. Simulations were predictive of the published clinical parasitological clearance activities for these existing therapies. OptiMal-PK is designed to be implemented by medicinal chemists and pharmacologists during the pre-clinical anti-malarial

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

    Directory of Open Access Journals (Sweden)

    Wahajuddin

    2011-10-01

    Full Text Available Abstract 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

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

    Science.gov (United States)

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

    2015-03-25

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

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

    Science.gov (United States)

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

    2015-07-14

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

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

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

    A PubMed search of about 127 papers on anti‑cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. Experimental evidences suggest that artemisinin compounds may be a therapeutic alternative in highly ...

  19. In vivo anti-malarial activity of hydroalcoholic extracts from ...

    African Journals Online (AJOL)

    Administrator

    administration is about 100 times less toxic than intraperitoneal (30). However, the hydro alcoholic extracts showed no lethality to mice at 5,000 mg/kg, which is 25 ... leadership of EHNRI for providing assistance. Reference. 1. Hardman J.G and Limbird L.E. Drugs used in the chemotherapy of malaria. In: Mc Graw-Hill eds.

  20. In vivo anti-malarial activity of hydroalcoholic extracts from ...

    African Journals Online (AJOL)

    Administrator

    leadership of EHNRI for providing assistance. Reference. 1. Hardman J.G and Limbird L.E. Drugs used in the chemotherapy of malaria. In: Mc Graw-Hill eds. .... eurycomalactone and Eurycoma longifolia Jack extracts in mice. Thai. J. Phytopharmacy.1998;5(2):14-27. 31. Abebe D, Debella A., and Urga K. Medicinal plants.

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

    Science.gov (United States)

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

    2011-12-15

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

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

    Science.gov (United States)

    O'Connell, Kathryn A; Poyer, Stephen; Solomon, Tsione; Munroe, Erik; Patouillard, Edith; Njogu, Julius; Evance, Illah; Hanson, Kara; Shewchuk, Tanya; Goodman, Catherine

    2013-02-05

    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. 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. 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, including questionnaire design, field worker

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

    Directory of Open Access Journals (Sweden)

    Evans Lawrence

    2012-06-01

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

  4. Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

    Science.gov (United States)

    Shelton, Jennifer M G; Corran, Patrick; Risley, Paul; Silva, Nilupa; Hubbart, Christina; Jeffreys, Anna; Rowlands, Kate; Craik, Rachel; Cornelius, Victoria; Hensmann, Meike; Molloy, Sile; Sepulveda, Nuno; Clark, Taane G; Band, Gavin; Clarke, Geraldine M; Spencer, Christopher C A; Kerasidou, Angeliki; Campino, Susana; Auburn, Sarah; Tall, Adama; Ly, Alioune Badara; Mercereau-Puijalon, Odile; Sakuntabhai, Anavaj; Djimdé, Abdoulaye; Maiga, Boubacar; Touré, Ousmane; Doumbo, Ogobara K; Dolo, Amagana; Troye-Blomberg, Marita; Mangano, Valentina D; Verra, Frederica; Modiano, David; Bougouma, Edith; Sirima, Sodiomon B; Ibrahim, Muntaser; Hussain, Ayman; Eid, Nahid; Elzein, Abier; Mohammed, Hiba; Elhassan, Ahmed; Elhassan, Ibrahim; Williams, Thomas N; Ndila, Carolyne; Macharia, Alexander; Marsh, Kevin; Manjurano, Alphaxard; Reyburn, Hugh; Lemnge, Martha; Ishengoma, Deus; Carter, Richard; Karunaweera, Nadira; Fernando, Deepika; Dewasurendra, Rajika; Drakeley, Christopher J; Riley, Eleanor M; Kwiatkowski, Dominic P; Rockett, Kirk A

    2015-08-28

    Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of

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

    Science.gov (United States)

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

    2013-01-01

    Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of “autophagy addiction” because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

  6. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with anti-malarial activity in mice

    Science.gov (United States)

    Gujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah; White, John; White, Karen L.; Creason, Sharon; Shackleford, David M.; Baldwin, Jeffrey; Charman, William N.; Buckner, Frederick S; Charman, Susan; Rathod, Pradipsinh K.; Phillips, Margaret A.

    2009-01-01

    Plasmodium faliciparum causes 1–2 million deaths annually, yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro, however they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure, and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for anti-malarial chemotherapy. PMID:19296651

  7. Several Human Cyclin-Dependent Kinase Inhibitors, Structurally Related to Roscovitine, As New Anti-Malarial Agents

    Directory of Open Access Journals (Sweden)

    Sandrine Houzé

    2014-09-01

    Full Text Available In Africa, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs. Among newly proposed anti-malaria targets, are the P. falciparum cyclin-dependent kinases (PfCDKs. There are involved in different stages of the protozoan growth and development but share high sequence homology with human cyclin-dependent kinases (CDKs. We previously reported the synthesis of CDKs inhibitors that are structurally-related to (R-roscovitine, a 2,6,9-trisubstituted purine, and they showed activity against neuronal diseases and cancers. In this report, we describe the synthesis and the characterization of new CDK inhibitors, active in reducing the in vitro growth of P. falciparum (3D7 and 7G8 strains. Six compounds are more potent inhibitors than roscovitine, and three exhibited IC50 values close to 1 µM for both 3D7 and 7G8 strains. Although, such molecules do inhibit P. falciparum growth, they require further studies to improve their selectivity for PfCDKs.

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

    Science.gov (United States)

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

    2014-07-03

    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. 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. 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. 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 services, particularly at primary health

  9. Anti-malarial synergy of secondary metabolites from Morinda lucida Benth.

    Science.gov (United States)

    Chithambo, Bertha; Noundou, Xavier Siwe; Krause, Rui W M

    2017-03-06

    The roots, stem and leaves of Morinda lucida are used in some African countries as treatment against different types of fevers including yellow fever, malaria, trypanosomiasis and feverish conditions during child birth. To determine the in vitro cell toxicity and anti-malarial activity of the extracts of stem bark of M. lucida and to identify the secondary metabolites in the extract that may be responsible for this activity. The cell toxicity studies of crude extract [dichloromethane (DCM): Methanol (MeOH) in a ratio of1:1 (v/v)] as well as compounds isolated from the same extract were carried out using human cervix adenocarcinoma cells (HeLa cells); while the anti-malarial activities of the same samples were performed against Plasmodium falciparum strain 3D7 using the parasite lactate dehydrogenase (pLDH) assay. The isolation of the active compounds was carried out using chromatographic techniques (column and thin layer chromatography) where as mass spectrometry (MS), Fourier transform infrared spectroscopy (FTIR) as well as 1D- and 2D- nuclear magnetic resonance (NMR) analyses were employed in the characterisation and identification of the isolated secondary metabolites. The pLDH and cell toxicity assays for the crude extract and the fractions of M. lucida indicated that some fractions reduced the malaria parasite viability by approximately 50% at 100μg/mL and they were not significantly cytotoxic. An IC50 done on the crude extract gave a value of 25μg/mL. The % cell viability for the crude extract in cell toxicity assay remained at 100%. Seven chemical constituents i.e. asperuloside (1), asperulosidic acid (2), stigmasterol (3a), β-sitosterol (3b), cycloartenol (3c), campesterol (3d) and 5,15-O-dimethylmorindol (4) were isolated from the DCM-MeOH extract of stem bark. The isolated compounds tested were not that active by themselves individually at 20μM but their activities were increased when the isolated compounds were combined. As seen when compounds 2, 3

  10. Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model.

    Science.gov (United States)

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

    2010-10-22

    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(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-11-22

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

  12. Plasmodium serine hydroxymethyltransferase as a potential anti-malarial target: inhibition studies using improved methods for enzyme production and assay

    Directory of Open Access Journals (Sweden)

    Sopitthummakhun Kittipat

    2012-06-01

    Full Text Available Abstract Background There is an urgent need for the discovery of new anti-malarial drugs. Thus, it is essential to explore different potential new targets that are unique to the parasite or that are required for its viability in order to develop new interventions for treating the disease. Plasmodium serine hydroxymethyltransferase (SHMT, an enzyme in the dTMP synthesis cycle, is a potential target for such new drugs, but convenient methods for producing and assaying the enzyme are still lacking, hampering the ability to screen inhibitors. Methods Production of recombinant Plasmodium falciparum SHMT (PfSHMT and Plasmodium vivax SHMT (PvSHMT, using auto-induction media, were compared to those using the conventional Luria Bertani medium with isopropyl thio-β-D-galactoside (LB-IPTG induction media. Plasmodium SHMT activity, kinetic parameters, and response to inhibitors were measured spectrophotometrically by coupling the reaction to that of 5,10-methylenetetrahydrofolate dehydrogenase (MTHFD. The identity of the intermediate formed upon inactivation of Plasmodium SHMTs by thiosemicarbazide was investigated by spectrophotometry, high performance liquid chromatography (HPLC, and liquid chromatography-mass spectrometry (LC-MS. The active site environment of Plasmodium SHMT was probed based on changes in the fluorescence emission spectrum upon addition of amino acids and folate. Results Auto-induction media resulted in a two to three-fold higher yield of Pf- and PvSHMT (7.38 and 29.29 mg/L compared to that produced in cells induced in LB-IPTG media. A convenient spectrophotometric activity assay coupling Plasmodium SHMT and MTHFD gave similar kinetic parameters to those previously obtained from the anaerobic assay coupling SHMT and 5,10-methylenetetrahydrofolate reductase (MTHFR; thus demonstrating the validity of the new assay procedure. The improved method was adopted to screen for Plasmodium SHMT inhibitors, of which some were originally designed

  13. Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action

    OpenAIRE

    de Souza, Nicolli B; Carmo, Arturene ML; da Silva, Adilson D; França, Tanos CC; Krettli, Antoniana U

    2014-01-01

    Background Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Methods Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytoto...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-01

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

  15. Assessment of the effectiveness of the CD3+ tool to detect counterfeit and substandard anti-malarials.

    Science.gov (United States)

    Batson, JaCinta S; Bempong, Daniel K; Lukulay, Patrick H; Ranieri, Nicola; Satzger, R Duane; Verbois, Leigh

    2016-02-25

    The US FDA recently developed CD3+, a counterfeit detection tool that is based on sample illumination at specific wavelengths of light and visual comparison of suspect sample and packaging materials to an authentic sample. To test performance of the CD3+ in field conditions, a study was conducted in Ghana which compared the CD3+ side-by-side with two existing medicine quality screening technologies-TruScan™ Portable Raman spectrometer and GPHF Minilab(®). A total of 84 anti-malarial test samples comprising artemether-lumefantrine tablets and artesunate-amodiaquine tablets were used. The technologies were evaluated for sensitivity in determining counterfeit/substandard (The term counterfeit or falsified is used in this article to refer to medicines that carry a false representation of identity or source or both. The term substandard is used to refer to medicines that do not meet the quality specifications given in the accepted pharmacopeia.) medicines, specificity in determining authentic products, and reliability of the results. Authentic samples obtained from manufacturers were used as reference standards. HPLC analysis data was used as the "gold standard" for decisions regarding a sample being authentic or substandard/counterfeit. CD3+ had a sensitivity of 1.00 in detecting counterfeit/substandard products compared to Minilab (0.79) and TruScan (0.79). CD3+ had a lower specificity (0.53) in determining authentic products compared to the specificities reached by Minilab (0.99) and TruScan (1.00). High sensitivity in this context means that the technology is effective in identifying substandard/counterfeit products whereas the low specificity means that the technique can sometimes mischaracterize good products as substandard/counterfeit. Examination of dosage units only (and not packaging) using CD3+ yielded improved specificity 0.64. When only assessment of sample identification was done, the TruScan provided sensitivity (1.00) and specificity (0.99); and the

  16. Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents

    OpenAIRE

    Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

    2017-01-01

    The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure...

  17. Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents

    Directory of Open Access Journals (Sweden)

    Nafees Ahmed

    2017-06-01

    Full Text Available The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

  18. Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K as anti-malarial agents

    Science.gov (United States)

    Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

    2017-06-01

    The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

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

    Directory of Open Access Journals (Sweden)

    Swai Ndeniria

    2011-04-01

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

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

    African Journals Online (AJOL)

    Vihar

    malaria while gender, level of formal education and individual's occupation are factors that influence self-medication. INTRODUCTION. Malaria is the commonest cause of fever and morbidity in the tropics [1] and a significant source of mortality, especially among infants and young children. Every year, malaria causes ...

  1. Anti-malarial medicine quality field studies and surveys: a systematic review of screening technologies used and reporting of findings.

    Science.gov (United States)

    Lalani, Mirza; Kitutu, Freddy Eric; Clarke, Siân E; Kaur, Harparkash

    2017-05-15

    Assessing the quality of medicines in low-middle income countries (LMICs) relies primarily on human inspection and screening technologies, where available. Field studies and surveys have frequently utilized screening tests to analyse medicines sampled at the point of care, such as health care facilities and medicine outlets, to provide a snap shot of medicine quality in a specific geographical area. This review presents an overview of the screening tests typically employed in surveys to assess anti-malarial medicine quality, summarizes the analytical methods used, how findings have been reported and proposes a reporting template for future studies. A systematic search of the peer-reviewed and grey literature available in the public domain (including national and multi-national medicine quality surveys) covering the period 1990-2016 was undertaken. Studies were included if they had used screening techniques to assess the quality of anti-malarial medicines. As no standardized set of guidelines for the methodology and reporting of medicine quality surveys exist, the included studies were assessed for their standard against a newly proposed list of criteria. The titles and abstracts of 4621 records were screened and only 39 were found to meet the eligibility criteria. These 39 studies utilized visual inspection, disintegration, colorimetry and Thin Layer Chromatography (TLC) either as components of the Global Pharma Health Fund (GPHF) MiniLab® or as individual tests. Overall, 30/39 studies reported employing confirmatory testing described in international pharmacopeia to verify the quality of anti-malarials post assessment by a screening test. The authors assigned scores for the 23 criteria for the standard of reporting of each study. There is considerable heterogeneity in study design and inconsistency in reporting of field surveys of medicine quality. A lack of standardization in the design and reporting of studies of medicine quality increases the risk of bias and

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

    Directory of Open Access Journals (Sweden)

    O'Connell Kathryn A

    2011-10-01

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

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

    Science.gov (United States)

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

    2017-01-28

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

  4. Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration.

    Science.gov (United States)

    Srimuang, Krongkan; Miotto, Olivo; Lim, Pharath; Fairhurst, Rick M; Kwiatkowski, Dominic P; Woodrow, Charles J; Imwong, Mallika

    2016-11-08

    Declining anti-malarial efficacy of artemisinin-based combination therapy, and reduced Plasmodium falciparum susceptibility to individual anti-malarials are being documented across an expanding area of Southeast Asia (SEA). Genotypic markers complement phenotypic studies in assessing the efficacy of individual anti-malarials. The markers pfmdr1 and pfcrt were genotyped in parasite samples obtained in 2011-2014 at 14 TRAC (Tracking Resistance to Artemisinin Collaboration) sites in mainland Southeast Asia using a combination of PCR and next-generation sequencing methods. Pfmdr1 amplification, a marker of mefloquine and lumefantrine resistance, was highly prevalent at Mae Sot on the Thailand-Myanmar border (59.8% of isolates) and common (more than 10%) at sites in central Myanmar, eastern Thailand and western Cambodia; however, its prevalence was lower than previously documented in Pailin, western Cambodia. The pfmdr1 Y184F mutation was common, particularly in and around Cambodia, and the F1226Y mutation was found in about half of samples in Mae Sot. The functional significance of these two mutations remains unclear. Other previously documented pfmdr1 mutations were absent or very rare in the region. The pfcrt mutation K76T associated with chloroquine resistance was found in 98.2% of isolates. The CVIET haplotype made up 95% or more of isolates in western SEA while the CVIDT haplotype was common (30-40% of isolates) in north and northeastern Cambodia, southern Laos, and southern Vietnam. These findings generate cause for concern regarding the mid-term efficacy of artemether-lumefantrine in Myanmar, while the absence of resistance-conferring pfmdr1 mutations and SVMNT pfcrt haplotypes suggests that amodiaquine could be an efficacious component of anti-malarial regimens in SEA.

  5. Anti-malarial prescriptions in three health care facilities after the emergence of chloroquine resistance in Niakhar, Senegal (1992–2004

    Directory of Open Access Journals (Sweden)

    Arduin Pascal

    2009-04-01

    Full Text Available Abstract Background In the rural zone of Niakhar in Senegal, the first therapeutic failures for chloroquine (CQ were observed in 1992. In 2003, the national policy regarding first-line treatment of uncomplicated malaria was modified, replacing CQ by a transitory bi-therapy amodiaquine/sulphadoxine-pyrimethamine (AQ/SP, before the implementation of artemisinin-based combination therapy (ACT in 2006. The aims of the study were to assess the evolution of anti-malarial prescriptions in three health care facilities between 1992 and 2004, in parallel with increasing CQ resistance in the region. Methods The study was conducted in the area of Niakhar, a demographic surveillance site located in a sahelo-sudanese region of Senegal, with mesoendemic and seasonal malaria transmission. Health records of two public health centres and a private catholic dispensary were collected retrospectively to cover the period 1992–2004. Results Records included 110,093 consultations and 292,965 prescribed treatments. Twenty-five percent of treatments were anti-malarials, prescribed to 49% of patients. They were delivered all year long, but especially during the rainy season, and 20% of patients with no clinical malaria diagnosis received anti-malarials. Chloroquine and quinine represented respectively 55.7% and 34.6% of prescribed anti-malarials. Overall, chloroquine prescriptions rose from 1992 to 2000, in parallel with clinical malaria; then the CQ prescription rate decreased from 2000 and was concomitant with the rise of SP and the persistence of quinine use. AQ and SP were mainly used as bi-therapy after 2003, at the time of national treatment policy change. Conclusion The results show the overall level of anti-malarial prescription in the study area for a considerable number of patients over a large period of time. Even though resistance to CQ rapidly increased from 1992 to 2001, no change in CQ prescription was observed until the early 2000s, possibly due to the

  6. Anti-malarial prescriptions in three health care facilities after the emergence of chloroquine resistance in Niakhar, Senegal (1992-2004).

    Science.gov (United States)

    Munier, Aline; Diallo, Aldiouma; Cot, Michel; Ndiaye, Ousmane; Arduin, Pascal; Chippaux, Jean-Philippe

    2009-04-27

    In the rural zone of Niakhar in Senegal, the first therapeutic failures for chloroquine (CQ) were observed in 1992. In 2003, the national policy regarding first-line treatment of uncomplicated malaria was modified, replacing CQ by a transitory bi-therapy amodiaquine/sulphadoxine-pyrimethamine (AQ/SP), before the implementation of artemisinin-based combination therapy (ACT) in 2006. The aims of the study were to assess the evolution of anti-malarial prescriptions in three health care facilities between 1992 and 2004, in parallel with increasing CQ resistance in the region. The study was conducted in the area of Niakhar, a demographic surveillance site located in a sahelo-sudanese region of Senegal, with mesoendemic and seasonal malaria transmission. Health records of two public health centres and a private catholic dispensary were collected retrospectively to cover the period 1992-2004. Records included 110,093 consultations and 292,965 prescribed treatments. Twenty-five percent of treatments were anti-malarials, prescribed to 49% of patients. They were delivered all year long, but especially during the rainy season, and 20% of patients with no clinical malaria diagnosis received anti-malarials. Chloroquine and quinine represented respectively 55.7% and 34.6% of prescribed anti-malarials. Overall, chloroquine prescriptions rose from 1992 to 2000, in parallel with clinical malaria; then the CQ prescription rate decreased from 2000 and was concomitant with the rise of SP and the persistence of quinine use. AQ and SP were mainly used as bi-therapy after 2003, at the time of national treatment policy change. The results show the overall level of anti-malarial prescription in the study area for a considerable number of patients over a large period of time. Even though resistance to CQ rapidly increased from 1992 to 2001, no change in CQ prescription was observed until the early 2000s, possibly due to the absence of an obvious decrease in CQ effectiveness, a lack of

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

    Science.gov (United States)

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

    2011-10-31

    Artemisinin-based combination therapy (ACT) is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia. Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets) as compared to first-line quality-assured ACT (public/not-for-profit sector, first-line quality-assured ACT was available for free in all countries except Benin and the DRC (US$1.29 [Inter Quartile Range (IQR): $1.29-$1.29] and $0.52[IQR: $0.00-$1.29] per adult equivalent dose respectively). In the private sector, first-line quality-assured ACT was 5-24 times more expensive than non-artemisinin therapies. The exception was Madagascar where, due to national social marketing of subsidized ACT, the price of first-line quality-assured ACT ($0.14 [IQR: $0.10, $0.57]) was significantly lower than the most popular treatment (chloroquine, $0.36 [IQR: $0.36, $0.36]). Quality-assured ACT accounted for less than 25% of total anti-malarial volumes; private-sector quality-assured ACT volumes represented less than 6% of the total market share. Most anti-malarials were distributed

  8. Donor support for quality assurance and pharmacovigilance of anti-malarials in malaria-endemic countries.

    Science.gov (United States)

    Kovacs, Stephanie D; Mills, Brianna M; Stergachis, Andy

    2017-07-11

    Malaria control efforts have been strengthened by funding from donor groups and government agencies. The Global Fund to Fight AIDS, Tuberculosis and the Malaria (Global Fund), the US President's Malaria Initiative (PMI) account for the majority of donor support for malaria control and prevention efforts. Pharmacovigilance (PV), which encompasses all activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem, is a necessary part of efforts to reduce drug resistance and improve treatment outcomes. This paper reports on an analysis of PV plans in the Global Fund and PMI and World Bank's grants for malaria prevention and control. All active malaria grants as of September 2015 funded by the Global Fund and World Bank, and fiscal year 2015 and 2016 PMI Malaria Operational Plans (MOP) were identified. The total amount awarded for PV-related activities and drug quality assurance was abstracted. A Key-Word-in-Context (KWIC) analysis was conducted for the content of each grant. Specific search terms consisted of pharmacovigilance, pregn*, registry, safety, adverse drug, mass drug administration, primaquine, counterfeit, sub-standard, and falsified. Grants that mentioned PV activities identified in the KWIC search, listed PV in their budgets, or included the keywords: counterfeit, sub-standard, falsified, mass drug administration, or adverse event were thematically coded using Dedoose software version 7.0. The search identified 159 active malaria grants including 107 Global Fund grants, 39 fiscal year 2015 and 2016 PMI grants and 13 World Bank grants. These grants were primarily awarded to low-income countries (57.2%) and in sub-Saharan Africa (SSA) (70.4%). Thirty-seven (23.3%) grants included a budget line for PV- or drug quality assurance-related activities, including 21 PMI grants and 16 Global Fund grants. Only 23 (14.5%) grants directly mentioned PV. The primary focus area was improving drug

  9. Community participation during two mass anti-malarial administrations in Cambodia: lessons from a joint workshop

    NARCIS (Netherlands)

    Peto, Thomas J.; Debackere, Mark; Etienne, William; Vernaeve, Lieven; Tripura, Rupam; Falq, Gregoire; Davoeung, Chan; Nguon, Chea; Rekol, Huy; von Seidlein, Lorenz; Dondorp, Arjen M.; Sanann, Nou; Cheah, Phaik Yeong; de Smet, Martin; Pell, Christopher; Kindermans, Jean-Marie

    2018-01-01

    Two mass drug administrations (MDA) against falciparum malaria were conducted in 2015-16, one as operational research in northern Cambodia, and the other as a clinical trial in western Cambodia. During an April 2017 workshop in Phnom Penh the field teams from Medecins Sans Frontieres and the

  10. Effects of anti-malarial alkaloids on the sperm properties and blood ...

    African Journals Online (AJOL)

    pre-treatment results were compared with post-treatment and 65th day results as well as when results of quinine and chloroquine treated groups were compared with those of control group. The suggestion by disparate in vivo animal and in vitro studies that the short term use of these drugs to treat malaria may be associated ...

  11. [Development of anti-malarial vaccines and need for clinical trials in accordance with international standards in South Africa].

    Science.gov (United States)

    Doumbo, O K; Djimdé, A A; Théra, M A

    2008-06-01

    In the 20th century malaria remains a major problem of public health in sub-Saharan Africa. This haemosporidium discovered in Africa by Laveran in 1880, kills one child every 30 seconds which amounts to three "tsunami" flowing each year into the African continent. The current international solidarity raises new hopes as regards the possibility to suppress the morbidity effects on the population's health condition. In order to be efficient, today's strategies (impregnated mosquito nets, intermittent preventive treatments, artemisinin based combination therapy) should reach at least 80% of the targeted population (pregnant women and children). By 2025, the uncontrolled urbanization of the African population and the social disorders will make a new population a target for malaria. The new data of functional genomics and proteonics open new avenues of research for new mechanisms, new therapeutics and vaccine targets and new tools of diagnosis and prognosis. The current candidate vaccines of the first generation have allowed the development of African competences in clinical trials of international standard. Although they represent scientific advances they will not resolve the problem of public health. Research on candidate vaccines of 2nd and 3rd generation remains a challenge for the international scientific community. Africa should play a determining role in this process. Scientific information on the field remains essential for these generations of new anti-malarial vaccines. The ethical aspects regarding those clinical trials and actions of public health and research remain an universal necessity Deontology and ethics are two complementary approaches for the good practice of medicine and research of a good practitioner. For the protection and advantages of the patient and/or volunteer of the research are the cornerstones of the ethical approach. The scientific quality of a research protocol submitted to an independent research ethics committee and the volunteer 's

  12. Human saliva as a source of anti-malarial antibodies to examine population exposure to Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    West Sheila

    2011-04-01

    Full Text Available Abstract Background Antibody responses to malaria antigens reflect exposure to parasites, and seroprevalence correlates with malaria transmission intensity. Antibodies are routinely measured in sera or on dried blood spots but a non-invasive method would provide extra utility in sampling general populations. Saliva is already in use in the detection of plasma-derived IgM and IgG to viral infections. In this study, antibodies to Plasmodium falciparum merozoite antigens were compared between blood and saliva samples from the same individuals in unlinked surveys conducted in Tanzania and The Gambia. Methods In Tanzania, 53 individuals provided paired fingerprick blood and saliva sample using two commercially available sampling devices. In the Gambia, archived plasma and saliva samples collected from 200 children in the Farafenni area in a cross-sectional survey were analyzed. IgG antibodies against P. falciparum antigens, Merozoite Surface Protein-1 (MSP-119 and Apical membrane Antigen (AMA-1 were measured by ELISA in paired saliva and blood samples from both sites. Antibody levels were compared as continuous optical density (OD values and by sero-positivity. Results Significant correlations between saliva and plasma antibody levels were seen in Tanzania for both antigens, AMA-1(r2 range 0.93 to 0.89, p 19 (r2 range 0.93 to 0.75, p 2range 0.64 to 0.63, p 19 (sensitivity range 64-77% and specificity range 91-100% & 47-67% and 90-97% respectively over the different sample sets. Conclusions These data demonstrate anti-malarial antibodies can be detected in saliva and correlate strongly with levels in plasma. This non-invasive relatively simple collection method will be potentially useful for general population surveys, and particularly in migratory populations or those with infrequent contact with health services or opposed to blood withdrawal. Further studies will be needed to optimize collection methods, standardize volumes and content and develop

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

    Science.gov (United States)

    Khatib, Rashid A; Selemani, Majige; Mrisho, Gumi A; Masanja, Irene M; Amuri, Mbaraka; Njozi, Mustafa H; Kajungu, Dan; Kuepfer, Irene; Abdulla, Salim M; de Savigny, Don

    2013-05-07

    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. From October 2009 to June 2011 we 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. 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. 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.

  14. Patterns of selection in anti-malarial immune genes in malaria vectors: evidence for adaptive evolution in LRIM1 in Anopheles arabiensis.

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    Michel A Slotman

    2007-08-01

    Full Text Available Co-evolution between Plasmodium species and its vectors may result in adaptive changes in genes that are crucial components of the vector's defense against the pathogen. By analyzing which genes show evidence of positive selection in malaria vectors, but not in closely related non-vectors, we can identify genes that are crucial for the mosquito's resistance against Plasmodium.We investigated genetic variation of three anti-malarial genes; CEC1, GNBP-B1 and LRIM1, in both vector and non-vector species of the Anopheles gambiae complex. Whereas little protein differentiation was observed between species in CEC1 and GNBP-B1, McDonald-Kreitman and maximum likelihood tests of positive selection show that LRIM1 underwent adaptive evolution in a primary malaria vector; An. arabiensis. In particular, two adjacent codons show clear signs of adaptation by having accumulated three out of four replacement substitutions. Furthermore, our data indicate that this LRIM1 allele has introgressed from An. arabiensis into the other main malaria vector An. gambiae.Although no evidence exists to link the adaptation of LRIM1 to P. falciparum infection, an adaptive response of a known anti-malarial gene in a primary malaria vector is intriguing, and may suggest that this gene could play a role in Plasmodium resistance in An. arabiensis. If so, our data also predicts that LRIM1 alleles in An. gambiae vary in their level of resistance against P. falciparum.

  15. Effect of anti-malarial interventions on trends of malaria cases, hospital admissions and deaths, 2005-2015, Ghana.

    Science.gov (United States)

    Aregawi, Maru; Malm, Keziah L; Wahjib, Mohammed; Kofi, Osae; Allotey, Naa-Korkor; Yaw, Peprah Nana; Abba-Baffoe, Wilmot; Segbaya, Sylvester; Owusu-Antwi, Felicia; Kharchi, Abderahmane T; Williams, Ryan O; Saalfeld, Mark; Workneh, Nibretie; Shargie, Estifanos Biru; Noor, Abdisalan M; Bart-Plange, Constance

    2017-04-26

    indicators were observed in the three epidemiological strata (coastal, forest, savannah). All-cause admissions increased significantly in patients covered by the National Health Insurance Scheme (NHIS) compared to the non-insured. The non-malaria cases and non-malaria deaths increased or remained unchanged during the same period. All-cause mortality for children under 5 years old in household surveys, similar to those observed in the hospitals, declined by 43% between 2008 and 2014. The data provide compelling evidence of impact following LLIN mass campaigns targeting all ages since 2011, while maintaining other anti-malarial interventions. Malaria cases and deaths decreased by over 50 and 65%, respectively. The declines were stronger in children under five. Test positivity rate in all ages decreased by >40%. The decrease in malaria deaths was against a backdrop of increased admissions owing to free access to hospitalization through the NHIS. The study demonstrated that retrospective health facility-based data minimize reporting biases to assess effect of interventions. Malaria control in Ghana is dependent on sustained coverage of effective interventions and strengthened surveillance is vital to monitor progress of these investments.

  16. A validated HPLC method for determining residues of a dual active ingredient anti-malarial drug on manufacturing equipment surfaces.

    Science.gov (United States)

    Boca, Madalina Brindusa; Apostolides, Zeno; Pretorius, Etheresia

    2005-03-09

    Analytical method validation, determining the recovery rate from the equipment surface and the stability of a potential contaminant are important steps of a cleaning validation process. A rapid, sensitive and reproducible reversed-phase high-performance liquid chromatographic method was developed for the determination of pyrimethamine (PYR) and sulfadoxine (SUL) in cleaning validation swab samples. The active compounds can be selectively quantified in a sample matrix containing detergent and swab material as low as 0.12 microg/ml. The swabbing procedure used on stainless steel coupons was validated and the stability of PYR and SUL in the swab samples was assessed. The calculated limit of contamination values for PYR (4.99 microg/cm2) and SUL (19.14 microg/cm2) were not exceeded during four consecutive equipment cleaning trials. This confirms that the desired level of cleanliness is achieved with the current cleaning procedures, which are consequently validated.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ) remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1...... resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma....

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

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    Dewasurendra Rajika L

    2012-08-01

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

  19. Accuracy of a Plasmodium falciparum specific histidine-rich protein 2 rapid diagnostic test in the context of the presence of non-malaria fevers, prior anti-malarial use and seasonal malaria transmission

    NARCIS (Netherlands)

    Kiemde, Francois; Bonko, Massa Dit Achille; Tahita, Marc Christian; Lompo, Palpouguini; Rouamba, Toussaint; Tinto, Halidou; Boele van Hensbroek, Michael; Mens, Petra F.; Schallig, Henk D. F. H.

    2017-01-01

    It remains challenging to distinguish malaria from other fever causing infections, as a positive rapid diagnostic test does not always signify a true active malaria infection. This study was designed to determine the influence of other causes of fever, prior anti-malarial treatment, and a possible

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Malaria is a public health problem in Uganda; affecting mainly women and children. Effective treatment has been hampered by over-diagnosis and over-treatment with anti-malarial drugs among patients presenting with fever. In order to understand the effect of drug pressure on sulfadoxine-pyrimetham......Malaria is a public health problem in Uganda; affecting mainly women and children. Effective treatment has been hampered by over-diagnosis and over-treatment with anti-malarial drugs among patients presenting with fever. In order to understand the effect of drug pressure on sulfadoxine...

  1. Chalcone analogue as potent anti-malarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study

    Directory of Open Access Journals (Sweden)

    Jufrizal Syahri

    2017-08-01

    Conclusions: An in vitro antimalarial assay of the prepared chalcone derivative (3a–g showed an excellent and good antiplasmodial activity against the chloroquine-sensitive Pf3D7 strain. In silico antimalarial studies revealed that 3a–g made binding interaction with both sensitive-protein (1J3I.pdb and resistance-protein (4DP3.pdb, which means that they were both active against chloroquine-sensitive and resistant plasmodium strain.

  2. Fake and Counterfeit Drug: A review

    African Journals Online (AJOL)

    World Health Organization. Counterfeit medicines. World Health Organization. Fact sheet No 275 revised 2006. 5. Burns W. News: WHO launches taskforce to fight counterfeit drugs. Bull World Health Organization,. 2006; 84:689-90. 6. Rozendaal J. Fake anti-malarials circulating in. Cambodia. Bull Mekong Malaria Forum, ...

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

    Science.gov (United States)

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

    2016-02-17

    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.

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

    Directory of Open Access Journals (Sweden)

    Kreuels Benno

    2008-10-01

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

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

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    Wurtz Nathalie

    2012-06-01

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

  6. Impact of intermittent preventive anti-malarial treatment on the growth and nutritional status of preschool children in rural Senegal (west Africa).

    Science.gov (United States)

    Ntab, Balthazar; Cissé, Badara; Boulanger, Denis; Sokhna, Cheikh; Targett, Geoffrey; Lines, Jo; Alexander, Neal; Trape, Jean-François; Simondon, François; Greenwood, Brian M; Simondon, Kirsten B

    2007-09-01

    Negative consequences of malaria might account for seasonality in nutritional status in children in the Sahel. We report the impact of a randomized, double-blind, placebo-controlled trial of seasonal intermittent preventive anti-malarial treatment on growth and nutritional status in 1,063 Senegalese preschool children. A combination of artesunate and sulfadoxine-pyrimethamine was given monthly from September to November. In the intervention arm, mean weight gain was significantly greater (122.9 +/- 340 versus 42.9 +/- 344 [SD] g/mo, P < 0.0001) and losses in triceps and subscapular skinfold measurements were less (-0.39 +/- 1.01 versus -0.66 +/- 1.01 mm/mo, and -0.15 +/- 0.64 versus -0.36 +/- 0.62 mm/mo, respectively, P < 0.0001 for both). There was no difference in height increments. The prevalence of wasting increased significantly in the control arm (4.6% before versus 9.5% after, P < 0.0001), but remained constant in intervention children: 5.6% versus 7.0% (P = 0.62). The prevention of malaria would improve child nutritional status in areas with seasonal transmission.

  7. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

    Directory of Open Access Journals (Sweden)

    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  8. Compliance with a three-day course of artesunate-mefloquine combination and baseline anti-malarial treatment in an area of Thailand with highly multidrug resistant falciparum malaria

    Directory of Open Access Journals (Sweden)

    Na-Bangchang Kesara

    2010-02-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is presently recommended by the World Health Organization as first-line treatment for uncomplicated Plasmodium falciparum malaria in several countries, as a mean of prolonging the effectiveness of first-line malaria treatment regimens. A three-day course of artesunate-mefloquine (4 mg/kg body weight once daily for three consecutive days, plus 15 and 10 mg/kg body weight mefloquine on the first and second days has been adopted by Malaria Control Programme of Thailand as first-line treatment for uncomplicated falciparum malaria all over the country since 2008. The gametocytocydal anti-malarial drug primaquine is administered at the dose of 30 mg (0.6 mg/kg on the last day. The aim of the present study was to assess patient compliance of this combination regimen when applied to field condition. Methods A total of 240 patients (196 males and 44 females who were attending the malaria clinics in Mae-Sot, Tak Province and presenting with symptomatic acute uncomplicated falciparum malaria, with no reappearance of Plasmodium vivax parasitaemia during follow-up were included into the study. The first dose of the treatment was given to the patients under direct supervision. All patients were given the medication for self-treatment at home and were requested to come back for follow-up on day 3 of the initial treatment. Baseline (day 0 and day 3 whole blood mefloquine and plasma primaquine concentrations were determined by high performance liquid chromatography. Results Two patients had recrudescence on days 28 and 35. The Kaplan-Meier estimate of the 42-day efficacy rate of this combination regimen was 99.2% (238/240. Based on whole blood mefloquine and plasma primaquine concentrations on day 3 of the initial treatment, compliance with mefloquine and primaquine in this three-day artesunate-mefloquine combination regimen were 96.3% (207/215, and 98.5% (197/200, respectively. Baseline mefloquine

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

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    Duparc Stephan

    2011-08-01

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

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

    Science.gov (United States)

    2011-01-01

    Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is common in populations living in malaria endemic areas. G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone-artesunate (CDA) phase III clinical trial programme. Methods Study participants, aged > 1 year, with microscopically confirmed uncomplicated Plasmodium falciparum malaria, and haemoglobin ≥ 70 g/L or haematocrit ≥ 25%, were recruited into two clinical trials conducted in six African countries (Burkina Faso, Ghana, Kenya, Nigeria, Tanzania, Mali). G6PD genotype of the three most common African forms, G6PD*B, G6PD*A (A376G), and G6PD*A- (G202A, A542T, G680T and T968C), were determined and used for frequency estimation. G6PD phenotype was assessed qualitatively using the NADPH fluorescence test. Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration, temperature, asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg (both given once daily for three days) or six-dose artemether-lumefantrine. Results Of 2264 malaria patients enrolled, 2045 had G6PD genotype available and comprised the primary analysis population (1018 males, 1027 females). G6PD deficiency prevalence was 9.0% (184/2045; 7.2% [N = 147] male hemizygous plus 1.8% [N = 37] female homozygous), 13.3% (273/2045) of patients were heterozygous females, 77.7% (1588/2045) were G6PD normal. All deficient G6PD*A- genotypes were A376G/G202A. G6PD phenotype was available for 64.5% (1319/2045) of patients: 10.2% (134/1319) were G6PD deficient, 9.6% (127/1319) intermediate, and 80.2% (1058/1319) normal. Phenotype test specificity in detecting hemizygous males was 70.7% (70/99) and 48.0% (12/25) for homozygous females. Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin (p = 0.154), adjusted mean baseline temperature (p = 0.9617), or

  11. Effect of external stress on density and size of glandular trichomes in full-grown Artemisia annua, the source of anti-malarial artemisinin.

    Science.gov (United States)

    Kjær, Anders; Grevsen, Kai; Jensen, Martin

    2012-01-01

    Glandular trichomes (GT) of Artemisia annua produce valuable compounds for pharmaceutical and industrial uses, most notably the anti-malarial artemisinin. Our aim was to find out whether the density, number and size of GT can be manipulated to advantage by environmental stress. A range of external stress treatments, including stress response regulators, was therefore given to fully grown plants under field and greenhouse conditions. In a field experiment (Ex1), seed-grown plants were subjected to chemical or physical stress and plants analysed after 5 weeks. In a greenhouse experiment (Ex2), three groups of clonally derived plants were stressed at weekly intervals for 5 weeks. Stress treatments included sandblasting, leaf cutting and spraying with jasmonic acid, salicylic acid, chitosan oligosaccharide (COS), H(2)O(2) (HP) and NaCl (SC)at different concentrations. Leaves from an upper and a lower position on the plants were analysed by fluorescence microscopy to determine the density and size of GT. Densities of GT on upper leaves of full-grown A. annua plants generally showed no response to external stress and only plants from one clone of Ex2 supported the hypothesis that increased density of GT was inducible in upper leaves by stress (significant for SC, HP and COS). The density of GT on lower leaves was not affected by stress in any experiment. Glandular trichomes were significantly smaller on the lower leaves in response to stress in Ex2, and a similar non-significant trend was observed in Ex1. The results indicate a dynamic system in which stress treatments of large A. annua plants had a minor promoting effect on the initiation of GT in developing leaves, and a maturing effect of GT later in the lifetime of the individual GT. The hypothesis that applying stress can induce larger GT or more numerous GT was rejected.

  12. Assessment of the effectiveness of the CD3+ tool to detect counterfeit and substandard anti-malarials

    National Research Council Canada - National Science Library

    Batson, JaCinta S; Bempong, Daniel K; Lukulay, Patrick H; Ranieri, Nicola; Satzger, R Duane; Verbois, Leigh

    2016-01-01

    .... The technologies were evaluated for sensitivity in determining counterfeit/substandard (The term counterfeit or falsified is used in this article to refer to medicines that carry a false representation of identity or source...

  13. Enhanced production of an anti-malarial compound artesunate by hairy root cultures and phytochemical analysis of Artemisia pallens Wall.

    Science.gov (United States)

    Pala, Zarna; Shukla, Vishnu; Alok, Anshu; Kudale, Subhash; Desai, Neetin

    2016-12-01

    Artemisinin and its derivatives are still one of the most effective drugs for the treatment of malaria. Artemisia pallens commonly known as Dhavanam, is an aromatic herb belonging to the family Asteraceae. Increasing the artemisinin content of A. pallens by genetic engineering would improve the availability of this much needed drug. In the present study, Agrobacterium rhizogenes (strain NCIM 5140) mediated genetic transformation of Artemisia pallens were carried out for hairy root induction. The effect of different media (Half MS, MS, MS along with BAP 0.5 mg/l and MS along with Kinetin 0.5 mg/l) and type of explants (leaf and stem) on hairy root induction and culture were also studied. Maximum transformation efficiency (70.0 %) was observed in case of stem explants when it was co-cultivated with Agrobacterium rhizogenes and kept on half strength MS media. Artesunate is a derivative of artemisinin, was quantified using HPLC from dried aerial extract and hairy roots. The content of artesunate in hairy roots was increased up to twofold as compared to aerial part of Artemisia pallens. The maximum amount of artesunate found in hairy roots was 5.62 ± 0.16 μg/g of dry weight. Apart from artesunate the other phytochemicals like alkaloids, polyphenols, and flavonoids are important because they impart the medicinal properties in this plant. Therefore, we have also quantified total alkaloids, flavonoids and polyphenolic content in the aerial part of the plants. The total alkaloids and flavonoids content were found 1.72 ± 0.00 mg/g dry weight in aqueous extract and 3.8 ± 0.00 mg/g in methanolic extract in terms of colchicine and rutin equivalents, respectively. Similarly, total phenolic content is 3.70 ± 0.01 mg/g in ethanolic extract in terms of tannic acid equivalent.

  14. SENYAWA AKTIF ANTIKANKER PAYUDARA DAN ANTIMALARIA DARI TUMBUHAN DADAP AYAM (ERHYTHRINA VALERIEGATA SECARA IN VITRO (Anti Breast-cancer and anti-malarial Active Compounds of Erithrina Variegata by in Vitro Test

    Directory of Open Access Journals (Sweden)

    Tati Herlina

    2012-03-01

    Full Text Available ABSTRAK Tumbuhan Erythrina variegata (Leguminosae secara tradisional dikenal oleh masyarakat Indonesia sebagai obat antikanker dan antimalaria. Bagian tumbuhan ini yang biasa digunakan sebagai bahan pengobatan adalah daun dan kulit batang, tapi kandungan senyawa kimia aktif biologisnya belum banyak dilaporkan. Tujuan penelitian ini adalah untuk mengungkapkan senyawa aktif antikanker dan antimalaria secara in vitro yang terdapat di dalam daun dan kulit batang E. variegata. Penelitian dilakukan dengan cara ekstraksi metanol dan fraksionasi dari daun dan kulit batang E. variegata yang dipandu dengan uji antikanker secara in vitro terhadap sel kanker payudara T47D menggunakan metode Sulforodamin B (SRB dan uji antimalaria secara in vitro terhadap Plasmodium falciparum 3D7 (sensitif klorokuin dan K1 (resisten klorokuin menggunakan metode laktatdehidrogenase (LDH. Selanjutnya dilakukan pemisahan fraksi etil asetat daun dan kulit batang E. variegata yang dipantau dengan uji antikanker dan antimalaria secara in vitro menggunakan kombinasi kolom kromatografi diperoleh tiga senyawa aktif (1, 2, dan 3. Struktur kimia senyawa aktif (1, 2, dan 3 ditetapkan berdasarkan data-data spektroskopi dan diidentifikasikan sebagai turunan triterpenoid pentasiklik glikosida(1; flavonoid, eristagallin A (2; dan steroid, (22E-5α,8α-epidioksiergosta-6,22-dien-3β-ol (3. Senyawa (1 menunjukkan aktivitas antimalaria secara in vitro terhadap P. falciparum strain 3D7 (sensitif klorokuin dengan IC50 1,8 µg/mL dan terhadap strain K1 (resisten klorokuin dengan IC50 3,3 µg/mL. Senyawa (2 dan (3 menunjukkan aktivitas antikanker secara in vitro terhadap sel kanker payurada T47D dengan IC50 masing-masing 3,0 dan 3,2 µg/mL. Tumbuhan E. variegata mempunyai potensi sebagai bahan dasar obat herbal antikanker payudara dan antimalaria. ABSTRACT Erythrina variegata (Leguminosae plant used traditionaly as plant of  anti-cancer and anti-malarial in Indonesia. The leaves and stem bark of

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

    Energy Technology Data Exchange (ETDEWEB)

    Yedidi, Ravikiran S.; Liu, Zhigang; Wang, Yong; Brunzelle, Joseph S.; Kovari, Iulia A.; Woster, Patrick M.; Kovari, Ladislau C.; Gupta, Deepak (LECOM); (WSI); (NWU); (MUSC); (WSU)

    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.

  16. Biochemical characterization of the bifunctional enzyme dihydrofolate reductase-thymidylate synthase from Leishmania (Viannia) and its evaluation as a drug target.

    Science.gov (United States)

    Osorio, Edison; Aguilera, Carolina; Naranjo, Nelson; Marín, Marcel; Muskus, Carlos

    2013-01-01

    Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. Although this bifunctional enzyme is also a potential drug target for treatment of leishmaniasis, there have been no reports on its efficacy against Leishmania (Viannia) species. The gene encoding the bifunctional DHFR and thymidylate synthase (TS) of Le. (V.) braziliensis was isolated and expressed in E. coli. The enzyme was purified and characterized. The inhibitory effects of antifolates and four aporphine alkaloids on its activity were evaluated. The full-length gene consists of a 1560-bp open reading frame encoding a 58 kDa translated peptide containing DHFR and TS domains linked together in a single polypeptide chain. The recombinant DHFR-TS enzyme revealed Km and Vmax values of 55.35 ± 4.02 µ M (mean ± SE) and 0.02 ± 5.34 x 10 -4 µ M/min respectively for dihydrofolic acid (H₂F). The Le. braziliensis rDHFR-TS have Ki values for antimicrobial antifolates in the µM range. Methotrexate (MTX) was a more-potent inhibitor of enzymatic activity (Ki = 22.0 µM) than trimethoprim (Ki = 33 µM) and pyrimethamine (Ki = 68 µM). These Ki values are significantly lower than those obtained for the aporphine alkaloids. The results of the study show the inhibitory effect of antifolate drugs on enzymatic activity, indicating that Le. braziliensis rDHFR-TS could be a model to studying antifolate compounds as potential antiprotozoal drugs.

  17. Reviews Evaluating the Anti-Plasmodium, Anti-Pyretic and ...

    African Journals Online (AJOL)

    Discovery and Innovation ... With the introduction of cheap anti-malaria drugs, there was marked reduction in the use of local herbal medicine. ... Key Words: medicinal plants, local traditional medicine, malaria, anti-malarial properties, antipyretic and analgesic properties, concoctions, efficacy, resistance, generic ...

  18. Trends in malaria cases, hospital admissions and deaths following scale-up of anti-malarial interventions, 2000-2010, Rwanda.

    Science.gov (United States)

    Karema, Corine; Aregawi, Maru W; Rukundo, Alphonse; Kabayiza, Alain; Mulindahabi, Monique; Fall, Ibrahima S; Gausi, Khoti; Williams, Ryan O; Lynch, Michael; Cibulskis, Richard; Fidele, Ngabo; Nyemazi, Jean-Pierre; Ngamije, Daniel; Umulisa, Irenee; Newman, Robert; Binagwaho, Agnes

    2012-07-23

    unchanged. Rainfall and temperature remained favourable for malaria transmission. The annual all-cause mortality in children under-five in household surveys declined from 152 per 1,000 live births during 2001-2005, to 76 per 1,000 live births in 2006-2010 (55% decline). The five-year cumulative number of all-cause deaths in hospital declined 28% (8,051 to 5,801) during the same period. A greater than 50% decline in confirmed malaria cases, admissions and deaths at district hospitals in Rwanda since 2005 followed a marked increase in ITN coverage and use of ACT. The decline occurred among both children under-five and in those five years and above, while hospital utilization increased and suitable conditions for malaria transmission persisted. Declines in malaria indicators in children under 5 years were more striking than in the older age groups. The resurgence in cases associated with decreased ITN coverage in 2009 highlights the need for sustained high levels of anti-malarial interventions in Rwanda and other malaria endemic countries.

  19. Trends in malaria cases, hospital admissions and deaths following scale-up of anti-malarial interventions, 2000–2010, Rwanda

    Directory of Open Access Journals (Sweden)

    Karema Corine

    2012-07-01

    -malaria diseases in all age groups either increased or remained unchanged. Rainfall and temperature remained favourable for malaria transmission. The annual all-cause mortality in children under-five in household surveys declined from 152 per 1,000 live births during 2001–2005, to 76 per 1,000 live births in 2006–2010 (55% decline. The five-year cumulative number of all-cause deaths in hospital declined 28% (8,051 to 5,801 during the same period. Conclusions A greater than 50% decline in confirmed malaria cases, admissions and deaths at district hospitals in Rwanda since 2005 followed a marked increase in ITN coverage and use of ACT. The decline occurred among both children under-five and in those five years and above, while hospital utilization increased and suitable conditions for malaria transmission persisted. Declines in malaria indicators in children under 5 years were more striking than in the older age groups. The resurgence in cases associated with decreased ITN coverage in 2009 highlights the need for sustained high levels of anti-malarial interventions in Rwanda and other malaria endemic countries.

  20. Adverse drug reactions in Nigerian children: a retrospective review of reports submitted to the Nigerian Pharmacovigilance Centre from 2005 to 2012.

    Science.gov (United States)

    Obebi Cliff-Eribo, Kennedy; Sammons, Helen; Star, Kristina; Ralph Edwards, I; Osakwe, Adeline; Choonara, Imti

    2016-11-01

    Adverse drug reactions (ADRs) in children recorded in national pharmacovigilance databases in high-income countries have been analysed. Nigeria has a population of 31 million children and became a member of the WHO Programme for International Drug Monitoring in 2004 since when it has been submitting reports of suspected ADRs to the WHO Global Individual Case Safety Report database, VigiBase. To gain information on reported ADRs in Nigerian children aged 0-17 years in VigiBase from 2005 to 2012. The data were analysed for annual reports, age and sex of patients, type of reporters, suspected drugs and adverse reactions. The most commonly reported ADRs and suspected drugs were ranked, and drugs associated with the fatalities were evaluated. A total of 297 reports of 473 ADRs in 297 children were received from doctors, pharmacists, other health-care professionals and consumers during the period. ADRs were most frequently reported for anti-retrovirals (74, 24%), antibiotics (71, 23%) and anti-malarials (60, 20%). The most frequently reported ADRs were rash (15.2%), fever (10.3%) and pruritus (6.8%). Anti-infective agents were responsible for more than half of the reports. Twenty-one children (7%) died, eight from acute renal failure. Seven of the cases of acute renal failure were associated with contaminated paracetamol/diphenhydramine hydrochloride and herbal medicines used for teething problems. In the majority of cases, the products were contaminated with diethylene glycol. There were 14 cases of Stevens-Johnson syndrome, three of which were fatal. Anti-infective agents (antibiotics, anti-malarials and anti-retrovirals) were associated with a majority of the ADRs. Stevens-Johnson syndrome was the most frequent severe ADR. Some of the fatalities were associated with sub-standard and herbal medications.

  1. Evaluation of in vivo antimalarial activity of the ethanolic leaf extracts ...

    African Journals Online (AJOL)

    Prof. Ogunji

    Malaria has remained a leading cause of morbidity and mortality in tropical countries of the world due ... development and sustenance of resistant strains of the parasite to commonly and affordable anti- malarial drugs .... Statistical analysis: Data obtained were analysed using student's t-test and one way analysis of variance ...

  2. A Genome Wide Association Study of Plasmodium falciparum Susceptibility to 22 Antimalarial Drugs in Kenya

    OpenAIRE

    Wendler, Jason P.; Okombo, John; Amato, Roberto; Miotto, Olivo; Kiara, Steven M.; Mwai, Leah; Pole, Lewa; O'Brien, John; Manske, Magnus; Alcock, Dan; Drury, Eleanor; Sanders, Mandy; Samuel O Oyola; Malangone, Cinzia; Jyothi, Dushyanth

    2014-01-01

    Background Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. Methods and Principal Findings Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malari...

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

    Directory of Open Access Journals (Sweden)

    Marcel Kaiser

    2013-09-01

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

  4. Evaluation of in vivo antimalarial activity of the ethanolic leaf extracts ...

    African Journals Online (AJOL)

    countries of the world due to the resistance posed by malaria parasites to most commonly affordable anti-malarials. The anti plasmodial activities of the ethanolic leaf extracts of Chromolaena odorata and Cymbopogon citratus on chloroquine sensitive Plasmodium berghei berghei in mice was evaluated. C. odorata and C.

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

    Directory of Open Access Journals (Sweden)

    Madeeha Malik

    2013-01-01

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

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

    Science.gov (United States)

    Wendler, Jason P; Okombo, John; Amato, Roberto; Miotto, Olivo; Kiara, Steven M; Mwai, Leah; Pole, Lewa; O'Brien, John; Manske, Magnus; Alcock, Dan; Drury, Eleanor; Sanders, Mandy; Oyola, Samuel O; Malangone, Cinzia; Jyothi, Dushyanth; Miles, Alistair; Rockett, Kirk A; MacInnis, Bronwyn L; Marsh, Kevin; Bejon, Philip; Nzila, Alexis; Kwiatkowski, Dominic P

    2014-01-01

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

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

    OpenAIRE

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-06-01

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

  9. Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania

    Science.gov (United States)

    Zuccotto, Fabio; Martin, Andrew C. R.; Laskowski, Roman A.; Thornton, Janet M.; Gilbert, Ian H.

    1998-05-01

    Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

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

    Directory of Open Access Journals (Sweden)

    Diana Ortiz

    Full Text Available 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.

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

    Science.gov (United States)

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

    2017-05-25

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

  12. Evaluation of drug-drug interactions among patients with chronic ...

    African Journals Online (AJOL)

    Introduction: The risk of drug-drug interactions (DDIs) is high in patients with chronic kidney disease (CKD) necessitating dose adjustments or the avoidance of drug combinations. This study aimed to evaluate DDIs among patients with CKD in the University of Nigeria Teaching Hospital (UNTH), Enugu, South-East Nigeria.

  13. Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries.

    Science.gov (United States)

    Dow, Geoffrey S; Liu, Jun; Lin, Gina; Hetzell, Brian; Thieling, Sarah; McCarthy, William F; Tang, Douglas; Smith, Bryan

    2015-11-26

    Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that

  14. Drug Usage Evaluation of Dapsone

    Science.gov (United States)

    Kannan, G.; Vasantha, J.; Rani, N. Vanitha; Thennarasu, P.; Kousalya, K.; Anuradha, P.; Reddy, C. Umamaheswara

    2009-01-01

    Dapsone has been the principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy. It is also widely used by dermatologists in varied skin conditions like dermatitis herpetiformis, bullous pemphigoid, Behcet's disease, lupus erythematous and a host of other skin diseases. Hence an attempt has been made to review the utilization and qualitative evaluation of dapsone over a period of 6 months in a tertiary care teaching hospital. The study consisted of 80 patients (54 leprosy and 26 non-leprosy patients), prescribed with dapsone 100 mg oral once daily. The prescribing patterns of dapsone in leprosy and other dermatological conditions (non-leprosy) were analyzed and the safety, efficacy and appropriateness of the doses prescribed were reviewed. The adverse drug reactions observed in the study population were type I Lepra reactions, gastrointestinal side effects (abdominal pain and anorexia), peripheral neuropathy, other nervous side effects (insomnia, headache and vertigo) and other adverse reactions (fever and tinnitus). Patient information leaflets were distributed to patients to educate on the appropriate use of dapsone. PMID:20502558

  15. Center for Drug Evaluation and Research

    Data.gov (United States)

    Federal Laboratory Consortium — The Center for Drug Evaluation and Research(CDER) performs an essential public health task by making sure that safe and effective drugs are available to improve the...

  16. What happened to anti-malarial markets after the Affordable Medicines Facility-malaria pilot? Trends in ACT availability, price and market share from five African countries under continuation of the private sector co-payment mechanism.

    Science.gov (United States)

    Tougher, Sarah; Hanson, Kara; Goodman, Catherine

    2017-04-25

    The private sector supplies anti-malarial treatment for large proportions of patients in sub-Saharan Africa. Following the large-scale piloting of the Affordable Medicines Facility-malaria (AMFm) from 2010 to 2011, a private sector co-payment mechanism (CPM) provided continuation of private sector subsidies for quality-assured artemisinin combination therapies (QAACT). This article analyses for the first time the extent to which improvements in private sector QAACT supply and distribution observed during the AMFm were maintained or intensified during continuation of the CPM through 2015 in Kenya, Madagascar, Nigeria, Tanzania and Uganda using repeat cross-sectional outlet survey data. QAACT market share in all five countries increased during the AMFm period (p market share was maintained or improved post-AMFm in Nigeria, Tanzania and Uganda, but statistically significant declines were observed in Kenya and Madagascar. In 2014/5, QAACT market share was highest in Kenya and Uganda (48.2 and 47.5%, respectively) followed by Tanzania (39.2%), Nigeria (35.0%), and Madagascar (7.0%). Four of the five countries experienced significant decreases in median QAACT price during the AMFm period. Private sector QAACT prices were maintained or further reduced in Tanzania, Nigeria and Uganda, but prices increased significantly in Kenya and Madagascar. SP prices were consistently lower than those of QAACT in the AMFm period, with the exception of Kenya and Tanzania in 2011, where they were equal. In 2014/5 QAACT remained two to three times more expensive than the most popular non-artemisinin therapy in all countries except Tanzania. Results suggest that a private sector co-payment mechanism for QAACT implemented at national scale for 5 years was associated with positive and sustained improvements in QAACT availability, price and market share in Nigeria, Tanzania and Uganda, with more mixed results in Kenya, and few improvements in Madagascar. The subsidy mechanism as implemented

  17. Therapeutic Efficacy of Artemether-Lumefantrine for Treatment of ...

    African Journals Online (AJOL)

    The samples were evaluated by real-time polymerase chain reaction (RT-PCR) for identification and ... commonly available anti-malarial drugs has ... Patients who had history of serious side ..... Looareesuwan S, White NJ. et al: Mefloquine.

  18. High resolution melting: a useful field-deployable method to measure dhfr and dhps drug resistance in both highly and lowly endemic Plasmodium populations.

    Science.gov (United States)

    Ndiaye, Yaye Dié; Diédhiou, Cyrille K; Bei, Amy K; Dieye, Baba; Mbaye, Aminata; Mze, Nasserdine Papa; Daniels, Rachel F; Ndiaye, Ibrahima M; Déme, Awa B; Gaye, Amy; Sy, Mouhamad; Ndiaye, Tolla; Badiane, Aida S; Ndiaye, Mouhamadou; Premji, Zul; Wirth, Dyann F; Mboup, Souleymane; Krogstad, Donald; Volkman, Sarah K; Ahouidi, Ambroise D; Ndiaye, Daouda

    2017-04-19

    Emergence and spread of drug resistance to every anti-malarial used to date, creates an urgent need for development of sensitive, specific and field-deployable molecular tools for detection and surveillance of validated drug resistance markers. Such tools would allow early detection of mutations in resistance loci. The aim of this study was to compare common population signatures and drug resistance marker frequencies between two populations with different levels of malaria endemicity and history of anti-malarial drug use: Tanzania and Sénégal. This was accomplished by implementing a high resolution melting assay to study molecular markers of drug resistance as compared to polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) methodology. Fifty blood samples were collected each from a lowly malaria endemic site (Sénégal), and a highly malaria endemic site (Tanzania) from patients presenting with uncomplicated Plasmodium falciparum malaria at clinic. Data representing the DHFR were derived using both PCR-RFLP and HRM assay; while genotyping data representing the DHPS were evaluated in Senegal and Tanzania using HRM. Msp genotyping analysis was used to characterize the multiplicity of infection in both countries. A high prevalence of samples harbouring mutant DHFR alleles was observed in both population using both genotyping techniques. HRM was better able to detect mixed alleles compared to PCR/RFLP for DHFR codon 51 in Tanzania; and only HRM was able to detect mixed infections from Senegal. A high prevalence of mutant alleles in DHFR (codons 51, 59, 108) and DHPS (codon 437) were found among samples from Sénégal while no mutations were observed at DHPS codons 540 and 581, from both countries. Overall, the frequency of samples harbouring either a single DHFR mutation (S108N) or double mutation in DHFR (C59R/S108N) was greater in Sénégal compared to Tanzania. Here the results demonstrate that HRM is a rapid, sensitive, and field

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

    Directory of Open Access Journals (Sweden)

    Dillip Angel

    2010-06-01

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

  20. Development of cultured Plasmodium falciparum blood-stage malaria cell banks for early phase in vivo clinical trial assessment of anti-malaria drugs and vaccines.

    Science.gov (United States)

    Stanisic, Danielle I; Liu, Xue Q; De, Sai Lata; Batzloff, Michael R; Forbes, Tanya; Davis, Christopher B; Sekuloski, Silvana; Chavchich, Marina; Chung, Wendy; Trenholme, Katharine; McCarthy, James S; Li, Tao; Sim, B Kim Lee; Hoffman, Stephen L; Good, Michael F

    2015-04-07

    The ability to undertake controlled human malaria infection (CHMI) studies for preliminary evaluation of malaria vaccine candidates and anti-malaria drug efficacy has been limited by the need for access to sporozoite infected mosquitoes, aseptic, purified, cryopreserved sporozoites or blood-stage malaria parasites derived ex vivo from malaria infected individuals. Three different strategies are described for the manufacture of clinical grade cultured malaria cell banks suitable for use in CHMI studies. Good Manufacturing Practices (GMP)-grade Plasmodium falciparum NF54, clinically isolated 3D7, and research-grade P. falciparum 7G8 blood-stage malaria parasites were cultured separately in GMP-compliant facilities using screened blood components and then cryopreserved to produce three P. falciparum blood-stage malaria cell banks. These cell banks were evaluated according to specific criteria (parasitaemia, identity, viability, sterility, presence of endotoxin, presence of mycoplasma or other viral agents and in vitro anti-malarial drug sensitivity of the cell bank malaria parasites) to ensure they met the criteria to permit product release according to GMP requirements. The P. falciparum NF54, 3D7 and 7G8 cell banks consisted of >78% ring stage parasites with a ring stage parasitaemia of >1.4%. Parasites were viable in vitro following thawing. The cell banks were free from contamination with bacteria, mycoplasma and a broad panel of viruses. The P. falciparum NF54, 3D7 and 7G8 parasites exhibited differential anti-malarial drug susceptibilities. The P. falciparum NF54 and 3D7 parasites were susceptible to all anti-malaria compounds tested, whereas the P. falciparum 7G8 parasites were resistant/had decreased susceptibility to four compounds. Following testing, all defined release criteria were met and the P. falciparum cell banks were deemed suitable for release. Ethical approval has been obtained for administration to human volunteers. The production of cultured P

  1. Development, use and evaluation of drugs

    DEFF Research Database (Denmark)

    Hansen, E H; Launsø, Laila

    1987-01-01

    . Drugs offer a standard solution to health problems independent of the individuals' social life. Thus drugs become a tool which function in agreement with the disintegrated and achievement-orientated approach to disease as it is organized today. In general the statements in this article are not limited......The article presents various perspectives of drug technology and health care policy in Denmark. Drugs dominate as the most widely used treatment technology in the health care system and the use of drugs is steadily increasing. The pharmaceutical industry's development of drugs is based...... on an economic estimate of developments, expenditures, marketing costs and the anticipated share of the market. Controlled clinical trials have become the main form of documentation required by the health authorities. This method is insufficient to evaluate the (side) effects of the drugs when in actual use...

  2. Cost Evaluation of Commonly Prescribed Antihypertensive Drugs ...

    African Journals Online (AJOL)

    Cost Evaluation of Commonly Prescribed Antihypertensive Drugs and the Pattern of Prescription among Doctors in the Lagos University Teaching Hospital. ... It was concluded that the prescribing of the new generation drugs i.e. Calcium channel blockers, ACE inhibitors with supposedly little or no metabolic side effects is a ...

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

    Directory of Open Access Journals (Sweden)

    Veljko Veljkovic

    2015-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Jason P Wendler

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

  5. Evaluation of pharmacy and therapeutics committee drug evaluation reports.

    Science.gov (United States)

    Majercik, P L; May, J R; Longe, R L; Johnson, M H

    1985-05-01

    Pharmacy and therapeutics (P & T) committee drug evaluation reports prepared by pharmacies and drug information centers (DICs) and product package inserts were compared with standard guidelines to evaluate their quality. Letters were sent to 143 hospital pharmacies asking them to submit a previously prepared drug evaluation report on temazepam, moxalactam disodium, or atenolol. The reports and package inserts for these three drugs were evaluated by the presence of 40 elements derived from the published ASHP guidelines for drug evaluation report preparation. Responses were obtained from 124 (87%) pharmacies; however, only 80 reports (60 DIC-prepared and 20 pharmacy-prepared) were received. The reports contained a mean of 28 of the 40 (70%) possible elements. The most frequently omitted elements were AHFS number, potential unlabeled uses, drug-drug interactions, drug-disease-laboratory test interactions, risk and benefit data, prevention and treatment of side effects, comparisons with established treatment, and disadvantages of the drug under consideration. Although the reports prepared by the DICs and pharmacies contained the same amount of information, the DIC-prepared reports included data more frequently on supply sources, therapeutic indications, approved labeling, comparison with established treatment, bioavailability and pharmacokinetics, and recommendations. Most of the reports contained more elements than the corresponding package inserts. The product package inserts did not contain the comparative elements required for P & T committee decisions. Both the pharmacy- and DIC-prepared reports failed to contain all 40 elements recommended in the standard guidelines, suggesting the need for more thorough reports.

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

    Directory of Open Access Journals (Sweden)

    Joël Lelièvre

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

  7. Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature.

    Science.gov (United States)

    Costa, Gabriel Luíz; Amaral, Lara Cotta; Fontes, Cor Jesus Fernandes; Carvalho, Luzia Helena; de Brito, Cristiana Ferreira Alves; de Sousa, Taís Nóbrega

    2017-04-19

    Parasite resistance to anti-malarials represents a great obstacle for malaria elimination. The majority of studies have investigated the association between single-nucleotide polymorphisms (SNPs) and drug resistance; however, it is becoming clear that the copy number variation (CNV) is also associated with this parasite phenotype. To provide a baseline for molecular surveillance of anti-malarial drug resistance in the Brazilian Amazon, the present study characterized the genetic profile of both markers in the most common genes associated with drug resistance in Plasmodium falciparum and Plasmodium vivax isolates. Additionally, these data were compared to data published elsewhere applying a systematic review of the literature published over a 20-year time period. The genomic DNA of 67 patients infected by P. falciparum and P. vivax from three Brazilian States was obtained between 2002 and 2012. CNV in P. falciparum multidrug resistance gene-1 (pfmdr1), GTP cyclohydrolase 1 (pfgch1) and P. vivax multidrug resistance gene-1 (pvmdr1) were assessed by real-time PCR assays. SNPs in the pfmdr1 and pfcrt genes were assessed by PCR-RFLP. A literature search for studies that analysed CNP in the same genes of P. falciparum and P. vivax was conducted between May 2014 and March 2017 across four databases. All analysed samples of P. falciparum carried only one copy of pfmdr1 or pfgch1. Although the pfcrt K76T polymorphism, a determinant of CQ resistance, was present in all samples genotyped, the pfmdr1 N86Y was absent. For P. vivax isolates, an amplification rate of 20% was found for the pvmdr1 gene. The results of the study are in agreement with the low amplification rates for pfmdr1 gene evidenced in the Americas and Africa, while higher rates have been described in Southeast Asia. For P. vivax, very low rates of amplification for pvmdr1 have been described worldwide, with exceptions in French Guiana, Cambodia, Thailand and Brazil. The present study was the first to evaluate

  8. Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development.

    Science.gov (United States)

    Palanisamy, Satheesh Kumar; Rajendran, N M; Marino, Angela

    2017-02-01

    This present study reviewed the chemical diversity of marine ascidians and their pharmacological applications, challenges and recent developments in marine drug discovery reported during 1994-2014, highlighting the structural activity of compounds produced by these specimens. Till date only 5% of living ascidian species were studied from drugs are the main area of interest in the screening of MNPs from ascidians (64%), followed by anti-malarial (6%) and remaining others. FDA approved ascidian compounds mechanism of action along with other compounds status of clinical trials (phase 1 to phase 3) are discussed here in. This review highlights recent developments in the area of natural products chemistry and biotechnological approaches are emphasized.

  9. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

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

    2016-02-09

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

  10. Economic evaluation in collaborative hospital drug evaluation reports

    Directory of Open Access Journals (Sweden)

    Ana Ortega

    2015-09-01

    Full Text Available Objective: economic evaluation is a fundamental criterion when deciding a drug’s place in therapy. The MADRE method (Method for Assistance in making Decisions and Writing Drug Evaluation Reports is widely used for drug evaluation. This method was developed by the GENESIS group of the Spanish Society of Hospital Pharmacy (SEFH, including economic evaluation. We intend to improve the economic aspects of this method. As for the direction to take, we have to first analyze our previous experiences with the current methodology and propose necessary improvements. Method: economic evaluation sections in collaboratively conducted drug evaluation reports (as the scientific society, SEFH with the MADRE method were reviewed retrospectively. Results: thirty-two reports were reviewed, 87.5% of them included an economic evaluation conducted by authors and 65.6% contained published economic evaluations. In 90.6% of the reports, a Budget impact analysis was conducted. The cost per life year gained or per Quality Adjusted Life Year gained was present in 14 reports. Twenty-three reports received public comments regarding the need to improve the economic aspect. Main difficulties: low quality evidence in the target population, no comparative studies with a relevant comparator, non-final outcomes evaluated, no quality of life data, no fixed drug price available, dosing uncertainty, and different prices for the same drug. Conclusions: proposed improvements: incorporating different forms of aid for non-drug costs, survival estimation and adapting published economic evaluations; establishing criteria for drug price selection, decision-making in conditions of uncertainty and poor quality evidence, dose calculation and cost-effectiveness thresholds depending on different situations.

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

    Energy Technology Data Exchange (ETDEWEB)

    Petzold, Christopher; Keasling, Jay

    2011-07-18

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    and supporting the clinical management and treatment for co-infected individuals. METHODS: A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and malaria co-infection. Focus group discussions were held with people receiving treatment for HIV and/or malaria......, and in-depth interviews with health workers responsible for HIV care and members of the clinical trial team. Data were analysed inductively to identify themes and develop theoretical narratives. RESULTS: Results suggest that people living with HIV perceived malaria to be more harmful to them due...

  13. Evaluation of drug interactions with nanofibrillar cellulose.

    Science.gov (United States)

    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. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Evaluation of a Flipped Drug Literature Evaluation Course.

    Science.gov (United States)

    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.

  15. Economic evaluation of artesunate and three quinine regimens in the treatment of severe malaria in children at the Ebolowa Regional Hospital-Cameroon: a cost analysis.

    Science.gov (United States)

    Maka, Daniel Ethe; Chiabi, Andreas; Obadeyi, Bolaji; Mah, Evelyn; Nguefack, Séraphin; Nana, Pamela; Mbacham, Wilfred; Mbonda, Elie

    2016-12-07

    Severe malaria is a leading cause of morbidity and mortality in under-fives in sub-Saharan Africa. Recently quinine has been replaced by artesunate as the first-line drug in the treatment of severe malaria in Cameroon. Artesunate has been shown to be cost-effective in African children, but whether these findings are transferable to Cameroonian children remains to be explored. To conduct a cost-analysis of four different regimens used in the treatment from the perspective of the healthcare payer. An economic evaluation alongside a randomized comparative study was conducted in children aged 3 months to 15 years, admitted at the Ebolowa Regional Hospital with severe malaria due to Plasmodium falciparum. Patients were randomized to receive one of the four treatment alternatives. Group 1 (ARTES) received parenteral artesunate at 2.4 mg/kg at H0, H12, H24 and then once daily; Group 2 (QLD) received a loading dose of quinine base at 16.6 mg/kg followed 8 h later by an 8-hourly maintenance dose of 8.3 mg/kg quinine base; Group 3 (QNLD3) received 8.3 mg/kg quinine base every 8 h, and Group 4 (QNLD2) received 12.5 mg/kg quinine base every 12 h. The main outcome measure for effectiveness of treatment was the parasite reduction rate. Based on a healthcare perspective, an evaluation of direct medical costs was done, including costs of anti-malarials, nursing care materials, adjuvant treatment, laboratory investigations, hospitalisation and professional fees. Guided by a cost minimalization approach, the relative costs of these treatment alternatives was compared and reported. Overall cost was higher for ARTES group at $65.14 (95% CI $57.68-72.60) than for quinine groups ($52.49-$62.40), but the difference was not statistically significant. Cost of the anti-malarial drug was significantly higher for artesunate-treated patients than for quinine-treated patients, whereas cost of hospitalization was significantly lower for artesunate-treated patients than for quinine

  16. [Drug evaluation: new requirements and perspectives].

    Science.gov (United States)

    Addis, Antonio; Rocchi, Francesca

    2006-11-01

    Lately the European and international regulatory Agencies, responsible for the evaluation of drugs, have not been capable to implement regulatory processes guiding clinical practice efficiently. The sudden withdrawal of innovative drugs, the incapacity of assuring independence, the not controlled trend of pharmaceutical expenditure are signals of the failure of a system which should respond to the mandate of public health and market regulation. Some intrinsic limits of present regulatory systems arise because regulatory Agencies approve medicinal products on the basis of minimum standards of efficacy or owing to fast registration procedures which do not allow to assure the real efficacy and safety of the product approved. Non-inferiority and equivalence trials, short duration studies conducted on small populations (not representing the real setting of utilization in clinical practice) are often considered sufficient for drug registration. Moreover, Agencies often lack data on the safety of approved products and based on post-marketing surveillance and monitoring plans which can assure the real profile of drug safety. Owing to the institution of the Italian Medicines Agency (AIFA), Italy has lately approached European standards of regulation and proposed a new original regulatory approach attempting to go beyond some of the main limitations described above. The main points the model is based on are: promotion of use appropriateness through the analysis of experiences occurring in the area; promotion of independent drug research in order to collect data reliable and useful for drug regulation; publication and distribution of independent information on drug utilization for health professionals. The Italian approach tries to bring regulatory provisions close to clinical practice by promoting a correct and rational use of drugs and developing new areas of intervention for research, vigilance and information.

  17. Nonlinear mixed-effects modelling of in vitro drug susceptibility and molecular correlates of multidrug resistant Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Julie A Simpson

    Full Text Available The analysis of in vitro anti-malarial drug susceptibility testing is vulnerable to the effects of different statistical approaches and selection biases. These confounding factors were assessed with respect to pfmdr1 gene mutation and amplification in 490 clinical isolates. Two statistical approaches for estimating the drug concentration associated with 50% effect (EC50 were compared: the commonly used standard two-stage (STS method, and nonlinear mixed-effects modelling. The in vitro concentration-effect relationships for, chloroquine, mefloquine, lumefantrine and artesunate, were derived from clinical isolates obtained from patients on the western border of Thailand. All isolates were genotyped for polymorphisms in the pfmdr1 gene. The EC50 estimates were similar for the two statistical approaches but 15-28% of isolates in the STS method had a high coefficient of variation (>15% for individual estimates of EC50 and these isolates had EC50 values that were 32 to 66% higher than isolates derived with more precision. In total 41% (202/490 of isolates had amplification of pfmdr1 and single nucleotide polymorphisms were found in 50 (10%. Pfmdr1 amplification was associated with an increase in EC50 for mefloquine (139% relative increase in EC50 for 2 copies, 188% for 3+ copies, lumefantrine (82% and 75% for 2 and 3+ copies respectively and artesunate (63% and 127% for 2 and 3+ copies respectively. In contrast pfmdr1 mutation at codons 86 or 1042 were associated with an increase in chloroquine EC50 (44-48%. Sample size calculations showed that to demonstrate an EC50 shift of 50% or more with 80% power if the prevalence was 10% would require 430 isolates and 245 isolates if the prevalence was 20%. In conclusion, although nonlinear mixed-effects modelling did not demonstrate any major advantage for determining estimates of anti-malarial drug susceptibility, the method includes all isolates, thereby, potentially improving confirmation of candidate

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

    Directory of Open Access Journals (Sweden)

    Andrew Marit

    2007-06-01

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

  19. Formulation development and evaluation of the anti-malaria properties of sustained release artesunate-loaded solid lipid microparticles based on phytolipids.

    Science.gov (United States)

    Chinaeke, E E; Chime, S A; Onyishi, V I; Attama, A A; Okore, V C

    2015-01-01

    CONTEXTS: Artemisinins and its derivatives are considered the basis in the treatment of Plasmodium falciparum malaria due to their high potency and rapid action. However, they have short half life, low solubility, and poor oral bioavailability, hence the need to formulate sustained release lipid particulate dosage form of these drugs. To formulate and evaluate artesunate-loaded solid lipid microparticles (SLMs) based on structured lipid matrices consisting of soybean oil and dika wax. The lipid matrices were characterized by differential scanning calorimetry (DSC), small-angle X-ray diffraction (SAXD), and wide-angle X-ray diffraction (WAXD). The SLMs were prepared by hot melt-homogenization. Time-dependent particle size analysis, time-dependent pH stability studies, encapsulation efficiency (EE%), and in vitro drug release were carried out on the SLMs. In vivo anti-malarial studies were performed using a modified Peter's 4-day suppressive protocol using Plasmodium berghei infected mice. Thermograms of the lipid matrices showed modifications in the microstructure of dika wax as a result of inclusion of soybean oil. SAXD and WAXD diffractograms showed that the lipid matrices were found to be non-lamellar. Particle size of SLM increased with time, while the pH was almost constant. The SLMs had maximum EE% of 80.6% and sustained the release of artesunate more than the reference tablet. In vivo pharmacodynamic studies showed that the SLMs had significant (p daily in the treatment of malaria.

  20. New insight in isoprenoids biosynthesis process and future prospects for drug designing in Plasmodium

    Directory of Open Access Journals (Sweden)

    Gagandeep Singh Saggu

    2016-09-01

    Full Text Available The MEP (Methyl Erythritol Phosphate isoprenoids biosynthesis pathway is an attractive drug target to combat malaria, due to its uniqueness and indispensability for the parasite. It is functional in the apicoplast of Plasmodium and its products get transported to the cytoplasm, where they participate in glycoprotein synthesis, electron transport chain, tRNA modification and several other biological processes. Several compounds have been tested against the enzymes involved in this pathway and amongst them Fosmidomycin, targeted against IspC (DXP reductoisomerase enzyme and MMV008138 targeted against IspD enzyme have shown good anti-malarial activity in parasite cultures. Fosmidomycin is now-a-days prescribed clinically, however, less absorption, shorter half-life, and toxicity at higher doses, limits its use as an anti-malarial. The potential of other enzymes of the pathway as candidate drug targets has also been determined. This review details the various drug molecules tested against these targets with special emphasis to Plasmodium. We corroborate that MEP pathway functional within the apicoplast of Plasmodium is a major drug target, especially during erythrocytic stages. However, the major bottlenecks, bioavailability and toxicity of the new molecules needs to be addressed, before considering any new molecule as a potent antimalarial.

  1. 76 FR 60505 - Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop...

    Science.gov (United States)

    2011-09-29

    ... 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, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is opening a comment period for the...

  2. 76 FR 45268 - Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop

    Science.gov (United States)

    2011-07-28

    ... HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. SUMMARY: The Food and Drug Administration (FDA) is announcing a public workshop regarding the...

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

    Directory of Open Access Journals (Sweden)

    Nsimba Stephen ED

    2006-01-01

    Full Text Available Abstract Malaria is a leading cause of death in Sub-Saharan Africa. Tanzania changed its malaria treatment policy from chloroquine (CQ to Sulphadoxine-Pyrimethamine (SP as first line drug in August 2001. We wanted to assess the perception and behaviour about SP after phasing out chloroquine which was very popular, cheap, available, and was preferred by many people for self-medication in homes as it was considered to have minimal side effects. Focus Group Discussions (FGDs were carried out after one year of the anti-malarial drug treatment policy change in the country. The FGD themes were on malaria for under-five children and other age groups, anti-malarial drug use through self-medications, specific experiences people had about SP drug for both mothers/guardians, men in the communities and health workers. A total of twelve FGDs were performed with mothers/guardians, men and health workers in the selected public health care facilities in the district. In the FGDs people feared adverse reactions from SP; its slow ability of reducing fever and self-treatment in this case was less reported from the mothers/guardians groups. However, SP was reported by health workers to be administered using the direct observation approach under supervision in their health care facilities. This was done in order to increase compliance as there were worries that some mothers were throwing away the drug if they were instructed by health workers to go and administer SP to their sick children at home. Based on this information, it is obvious that fear and negative perceptions about SP drug was common in the study setting. As evidence of this, there was less reported home-stocking and self-medication in the discussions for this particular recommended new first-line anti-malarial. The public has demonstrated a lack of confidence in SP. Furthermore, some health workers expressed obvious fear and negative perceptions towards the drug despite the fact that some FGDs with

  4. The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment.

    Science.gov (United States)

    Maganda, Betty A; Ngaimisi, Eliford; Kamuhabwa, Appolinary A R; Aklillu, Eleni; Minzi, Omary M S

    2015-04-25

    HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation. This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling. Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice

  5. drug use evaluation on cotrimoxazole preventive therapy for people

    African Journals Online (AJOL)

    user

    BACKGROUND: Drug use evaluation is a performance improvement method that focuses on evaluation and improvement of drug use ... KEY WORDS: drug use evaluation, cotrimoxazole, HIV/AIDS, Jimma, Ethiopia. INTRODUCTION .... female was pregnant but the pregnancy history of 11. (35.5%) females was not ...

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

    Directory of Open Access Journals (Sweden)

    Tyner Stuart D

    2012-06-01

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

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

    Science.gov (United States)

    Tyner, Stuart D; Lon, Chanthap; Se, Youry; Bethell, Delia; Socheat, Doung; Noedl, Harald; Sea, Darapiseth; Satimai, Wichai; Schaecher, Kurt; Rutvisuttinunt, Wiriya; Fukuda, Mark M; Chaorattanakawee, Suwanna; Yingyuen, Kritsanai; Sundrakes, Siratchana; Chaichana, Panjaporn; Saingam, Piyaporn; Buathong, Nillawan; Sriwichai, Sabaithip; Chann, Soklyda; Timmermans, Ans; Saunders, David L; Walsh, Douglas S

    2012-06-13

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

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

    Directory of Open Access Journals (Sweden)

    Tenkorang Ofori

    2009-01-01

    Full Text Available Abstract 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

  9. Evaluation of theophylline therapeutic drug monitoring service

    Directory of Open Access Journals (Sweden)

    Neža Rugelj

    2015-05-01

    Full Text Available BackgroundTherapeutic monitoring of theophylline serum levels is required due to its narrow therapeutic range and marked interindividual pharmacokinetic variability. We evaluated therapeutic drug monitoring service for theophylline in Slovenian clinical setting, which currently includes no pharmacokinetic evaluation of measured theophylline serum concentrations. MethodsWe  retrospectively evaluated 127 randomly selected theophylline serum level determinations performed in 2010 in a tertiary clinical setting in Slovenia. Demographic data, information on theophylline dosing and blood sampling was collected from patients’ data files. Authors evaluated the appropriateness of the following procedures: indications for theophylline serum concentration measurement, timing of blood sampling and dosage adjustments made after theophylline levels had been reported. On the basis of collected data, population pharmacokinetic model for theophylline was built and further used for the evaluation of dosage adjustments. ResultsOut of 127 cases, 107 (84.3% had clinically justified indication for theophylline serum level measurement. Near half of measurements (44.9% were performed before the steady state of theophylline concentrations was established. 65% of measured concentrations were subtherapeutic and the average measured concentration was below therapeutic range (53.1 μmol/L. Despite subtherapeutic concentrations the dose of theophylline was mainly not increased. Pharmacokinetic model enabled the calculation of average optimal daily dose which was significantly higher than the average actual daily dose used (876 mg vs. 572 mg, p < 0.001. ConclusionsTheophylline TDM service should be optimized and pharmacokinetic interpretation of theophylline serum levels should be integrated into clinical practice.

  10. Approved Drug Products with Therapuetic Equivalence Evaluations (Orange Book)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The publication Approved Drug Products with Therapeutic Equivalence Evaluations (the List, commonly known as the Orange Book) identifies drug products approved on...

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

    Science.gov (United States)

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

    2015-05-05

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

  12. Optimizing the HRP-2 in vitro malaria drug susceptibility assay using a reference clone to improve comparisons of Plasmodium falciparum field isolates

    Directory of Open Access Journals (Sweden)

    Rutvisuttinunt Wiriya

    2012-09-01

    Full Text Available Abstract Background Apparent emerging artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia requires development of practical tools to monitor for resistant parasites. Although in vitro anti-malarial susceptibility tests are widely used, uncertainties remain regarding interpretation of P. falciparum field isolate values. Methods Performance parameters of the W2 P. falciparum clone (considered artemisinin “sensitive” were evaluated as a reference for the HRP-2 immediate ex vivo assay. Variability in W2 IC50s was assessed, including intra- and inter-assay variability among and between technicians in multiple experiments, over five freeze-thaw cycles, over five months of continuous culture, and before and after transport of drug-coated plates to remote field sites. Nominal drug plate concentrations of artesunate (AS and dihydroartemisinin (DHA were verified by LC-MS analysis. Plasmodium falciparum field isolate IC50s for DHA from subjects in an artemisinin-resistant area in Cambodia were compared with W2 susceptibility. Results Plate drug concentrations and day-to-day technical assay performance among technicians were important sources of variability for W2 IC50s within and between assays. Freeze-thaw cycles, long-term continuous culture, and transport to and from remote sites had less influence. Despite variability in W2 susceptibility, the median IC50s for DHA for Cambodian field isolates were higher (p Conclusion The W2 reference clone improved the interpretability of field isolate susceptibility from the immediate ex vivo HRP-2 assay from areas of artemisinin resistance. Methods to increase the reproducibility of plate coating may improve overall assay interpretability and utility.

  13. Optimizing the HRP-2 in vitro malaria drug susceptibility assay using a reference clone to improve comparisons of Plasmodium falciparum field isolates.

    Science.gov (United States)

    Rutvisuttinunt, Wiriya; Chaorattanakawee, Suwanna; Tyner, Stuart D; Teja-Isavadharm, Paktiya; Se, Youry; Yingyuen, Kritsanai; Chaichana, Panjaporn; Bethell, Delia; Walsh, Douglas S; Lon, Chanthap; Fukuda, Mark; Socheat, Duong; Noedl, Harald; Schaecher, Kurt; Saunders, David L

    2012-09-13

    Apparent emerging artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia requires development of practical tools to monitor for resistant parasites. Although in vitro anti-malarial susceptibility tests are widely used, uncertainties remain regarding interpretation of P. falciparum field isolate values. Performance parameters of the W2 P. falciparum clone (considered artemisinin "sensitive") were evaluated as a reference for the HRP-2 immediate ex vivo assay. Variability in W2 IC50s was assessed, including intra- and inter-assay variability among and between technicians in multiple experiments, over five freeze-thaw cycles, over five months of continuous culture, and before and after transport of drug-coated plates to remote field sites. Nominal drug plate concentrations of artesunate (AS) and dihydroartemisinin (DHA) were verified by LC-MS analysis. Plasmodium falciparum field isolate IC50s for DHA from subjects in an artemisinin-resistant area in Cambodia were compared with W2 susceptibility. Plate drug concentrations and day-to-day technical assay performance among technicians were important sources of variability for W2 IC50s within and between assays. Freeze-thaw cycles, long-term continuous culture, and transport to and from remote sites had less influence. Despite variability in W2 susceptibility, the median IC50s for DHA for Cambodian field isolates were higher (p <0.0001) than the W2 clone (3.9 nM), both for subjects with expected (less than 72 hours; 6.3 nM) and prolonged (greater or equal to 72 hours; 9.6 nM) parasite clearance times during treatment with artesunate monotherapy. The W2 reference clone improved the interpretability of field isolate susceptibility from the immediate ex vivo HRP-2 assay from areas of artemisinin resistance. Methods to increase the reproducibility of plate coating may improve overall assay interpretability and utility.

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

    DEFF Research Database (Denmark)

    Mbonye, Anthony K.; Lal, Sham; Cundill, Bonnie

    2013-01-01

    shops on presenting symptoms, the consultation process, treatment received, and malaria diagnoses. Malaria diagnosis made by drug shop vendors were confirmed by the study team through microscopy examination of a blood slide to ascertain whether appropriate treatment was received. RESULTS: Among febrile......BACKGROUND: Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial...... to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of, and factors associated with, appropriate treatment of malaria to enable effective design and implementation...

  15. Evaluation Results From Prospective Drug Utilization Review: Medicaid Demonstrations

    OpenAIRE

    Kidder, David; Bae, Jay

    1999-01-01

    In 1992 HCFA awarded two cooperative agreements for demonstrations of prospective drug utilization review (PDUR). Iowa tested an on-line prospective drug utilization review (OPDUR) system. Washington tested payments to pharmacists for providing non-dispensing “cognitive services” (CS). In this article the authors report on an evaluation of these demonstrations and on three assessments of retrospective drug utilization review (RDUR) interventions. The evaluation failed to detect effects of eit...

  16. Modulated evaluation metrics for drug-based ontologies.

    Science.gov (United States)

    Amith, Muhammad; Tao, Cui

    2017-04-24

    Research for ontology evaluation is scarce. If biomedical ontological datasets and knowledgebases are to be widely used, there needs to be quality control and evaluation for the content and structure of the ontology. This paper introduces how to effectively utilize a semiotic-inspired approach to ontology evaluation, specifically towards drug-related ontologies hosted on the National Center for Biomedical Ontology BioPortal. Using the semiotic-based evaluation framework for drug-based ontologies, we adjusted the quality metrics based on the semiotic features of drug ontologies. Then, we compared the quality scores before and after tailoring. The scores revealed a more precise measurement and a closer distribution compared to the before-tailoring. The results of this study reveal that a tailored semiotic evaluation produced a more meaningful and accurate assessment of drug-based ontologies, lending to the possible usefulness of semiotics in ontology evaluation.

  17. Prevalence of cutaneous drug eruptions in adult Nigerians with HIV/AIDS.

    Science.gov (United States)

    Salami, T A T; Asalu, A F; Samuel, S O

    2010-06-01

    Adverse cutaneous drug eruptions are dreaded complication of drug use and this is more so when it occurs in the setting of human immune virus (HIV) infection and acquired immune deficiency syndrome (AIDS). This study aims to look at the prevalence of cutaneous drug eruptions in adult Nigerians with HIV/AIDS and find out the etiological agents, outcome, and prognosis of such occurrence in Irrua Specialist Teaching Hospital, Irrua Edo State Nigeria. A retrospective study of cutaneous drug eruptions in patients with HIV/AIDS managed in this centre over the past five years (between January 2001 and December 2005 prior to initiation of antiretroviral therapy) was carried out. A total of 900 patients with HIV/AIDS were managed during this period (antiretroviral treatment was not available during this period). Twenty five of these patients (2.8%) not had cutaneous drug eruptions (2.8%). Erythema multiforme major or Steven Johnson Syndrome (SJS)-40% and Toxic epidermal necrolysis (TEN)-20% were the most frequent types of adverse cutaneous drug events found while combination antituberculosis agent of Isoniazid/Thiacethazone (64%) and anti malarial Sulphadoxine/Pyrimethamine (20%) were the notable culprit drugs found to be responsible for these. There was a 20% fatality rate. Treatment of tuberculosis which is the most common AIDS presenting illness with anti tuberculosis regimen that includes thiacethazone and the ready availability of anti malarials over the counter without prescription are responsible for the findings of this study. Avoiding drugs such as those found to be culprit agents in this study in patients with HIV/AIDS; right prescription practice by health practitioners as well as more intense health education of the public on the hazards of self prescription will all go a long way in minimising the occurrence of these events.

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

    Science.gov (United States)

    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

  19. Fabrication and efficacy evaluation of chloroquine nanoparticles in CFA-induced arthritic rats using TNF-α ELISA.

    Science.gov (United States)

    Bhalekar, Mangesh R; Upadhaya, Prashant G; Madgulkar, Ashwini R

    2016-03-10

    Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, stimulates various immune cells especially macrophages, causing release of various proinflammatory cytokines such as TNF-α leading to persistent synovitis. Chloroquine, an anti-malarial drug inhibits the production of TNF-α, thus, halting the disease progression. The aim of the present study was fabrication, characterization and demonstration of kinetic and dynamic efficacy of chloroquine loaded solid lipid nanoparticles (CQ-SLNs) in arthritic rats and in lowering TNF-α levels. CQ-SLNs were prepared using melt homogenization method and subjected to lyophilization. The particle size, zeta potential, PDI and entrapment efficiency were found to be 113.6±0.15nm, -27.8±1.21mV, 0.125±0.03 and 93.45±0.43% respectively. Ex vivo endocytic uptake studies revealed engrossment of endocytic pathways in the uptake of SLN from intestine. Plasma drug profile upon pharmacokinetic evaluation demonstrated increased AUC, half-life and decreased elimination rate of the drug. Pharmacodynamic studies revealed reduction in the paw volume, bone erosion and cartilage destruction, the same was also reflected in histopathological studies. The TNF-α ELISA concluded that the TNF-α level was significantly reduced in the synovial fluid upon treatment with CQ-SLN, thus, leading to the conclusion that CQ-SLN could be used as a potential in reducing inflammatory TNF-α at the arthritic site and halting the disease progression. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Evaluation of drug-drug interaction screening software combined with pharmacist intervention.

    Science.gov (United States)

    Moura, Cristiano S; Prado, Nília M; Belo, Najara O; Acurcio, Francisco A

    2012-08-01

    Drug-drug interactions (DDI) in hospitalized patients are highly prevalent and an important source of adverse drug reactions. DI computerized screening system can prevent the occurrence of some of these events. To evaluate the impact of drug-drug interaction (DDI) screening software combined with active intervention in preventing drug interactions. The study was conducted at General Hospital of Vitória da Conquista (HGVC), Brazil. A quasi-experimental study was used to evaluate the impact of IM-Pharma, a locally developed drug-drug interaction screening system, coupled with pharmacist intervention on adverse drug events in the hospital setting. The proportion of patients co-prescribed two interacting drugs were measured in two phases, prior the implementation of IM-Pharma and during the intervention period. DDI rates per 100 patient days were calculated before and after implementation. Risk ratios were estimated by Poisson regression models. A total of 6,834 instances of drug-drug interactions were identified; there was an average of 3.3 DDIs per patient in phase one and 2.5 in phase two, a reduction of 24 % (P = 0.03). There was a 71 % reduction in high-severity drug-drug interaction (P < 0.01). The risk for all DDIs decreased 50 % after the implementation of IM-Pharma (P < 0.01), and for those with high-severity, the reduction was 81 % (P < 0.01). The performance of IM-Pharma combined with pharmacist intervention was positive with an expressive reduction in the risk of DDIs.

  1. Anticancer Effect of AntiMalarial Artemisinin Compounds

    African Journals Online (AJOL)

    In view of the emerging data, specific interactions with .... monoclonal antibodies may abolish artemisinin activity. ..... would imply treating multiple molecular aberrations with fewer ..... of SP2/0 myeloma cells through affecting NFkappaB p65.

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

    African Journals Online (AJOL)

    -diethyl-N4-(3,6,9- trimethyldecahydro- 3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl) pentane-1,4-diamine}. The structure of DHA-CQ was determined from spectroscopic data (IR, 1H & 13C NMR, MS). The compound was screened at ...

  3. Anticancer Effect of AntiMalarial Artemisinin Compounds

    African Journals Online (AJOL)

    leading to cell death.[33,48] Artemisinin sensitivity depends upon the level of expression of antiapoptotic (Bcl2) and proapoptotic genes (Bax) in a cancer cell line.[49] Apoptosis is rapidly induced by artemisinin in many cancer cell lines where mitochondrial membrane damage plays a central role in this process of cell death.

  4. Need for multicriteria evaluation of generic drug policies.

    Science.gov (United States)

    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. Copyright © 2015. Published by Elsevier Inc.

  5. Evaluation of Drug Utilization Pattern for Patients of Bronchial ...

    African Journals Online (AJOL)

    2017-10-26

    Oct 26, 2017 ... Demographic details, brand/ generic name, indication, route, dosage, frequency ... KEYWORDS: Airway, pharmaco-epidemiology, pharmacy, public health, survey. Evaluation of Drug Utilization Pattern for Patients .... also found a low overall awareness level regarding national guidelines among physicians.

  6. Evaluation of methylene blue, pyrimethamine and its combination on an in vitro Neospora caninum model.

    Science.gov (United States)

    Pereira, Luiz Miguel; Vigato-Ferreira, Isabel Cristina; DE Luca, Gabriela; Bronzon DA Costa, Cássia Mariana; Yatsuda, Ana Patrícia

    2017-05-01

    Neospora caninum is an apicomplexan parasite strongly related to reproductive problems in cattle. The neosporosis control is not well established and several fronts are under development, predominantly based on immune protection, immunomodulation and chemotherapy. The use of anti-malarial drugs as therapeutic sources has, in theory, considerable potential for any apicomplexan. Drugs such as methylene blue (MB) and pyrimethamine (Pyr) represent therapeutic options for malaria; thus, their use for neosporosis should be assessed. In this work, we tested the effects of MB and Pyr on N. caninum proliferation and clearance, using LacZ-tagged tachyzoites. The drugs inhibited at nanomolar dosages and its combination demonstrated an antagonistic interaction in proliferation assays, according to the Chou and Talalay method for drug combination index. However, the drug combination significantly improved the parasite in vitro clearance. The repositioning of well-established drugs opens a short-term strategy to obtain low-cost therapeutics approaches against neosporosis.

  7. Intracranial self-stimulation to evaluate abuse potential of drugs.

    Science.gov (United States)

    Negus, S Stevens; Miller, Laurence L

    2014-07-01

    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. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  8. Formulation and Evaluation of Rifampicin Liposomes for Buccal Drug Delivery.

    Science.gov (United States)

    Lankalapalli, Srinivas; Tenneti, V S Vinai Kumar

    2016-01-01

    Drug delivery through liposomes offers several advantages, but still challenging to the researchers for the use of liposomes as carriers in drug delivery due to their poor physical stability, unpredictable drug encapsulation and systemic availability of the loaded drug. The present investigation was planned with an objective to prepare Rifampicin loaded liposomes by using response surface methodology of statistical 32 factorial design and further to formulate them into pastilles for deliver through buccal route thereby to enhance systemic absorption. Rifampicin liposomes were prepared by using different ratios of soya lecithin and cholesterol by solvent Injection method. These liposomes were characterized by using optical microscopy, Scanning Electron Microscopy (SEM) and evaluated for particle size, entrapment efficiency (EE), in vitro and ex vivo drug release. Main effects and interaction terms of the formulation variables were evaluated quantitatively using a mathematical statistical model approach showing that both independent variables have significant (P value membrane (P value: 0.0047) and percentage drug release through porcine buccal membrane (P value: 0.0019). The statistical factorial design of liposomal formulations fulfilled all the requirements of the target set and exhibited suitable values for the selected test parameters. Pastilles were prepared for liposomes using glycerol gelatin base and were found to be soft, smooth with uniform drug content and drug release.

  9. The impact of cancer drug wastage on economic evaluations.

    Science.gov (United States)

    Truong, Judy; Cheung, Matthew C; Mai, Helen; Letargo, Jessa; Chambers, Alexandra; Sabharwal, Mona; Trudeau, Maureen E; Chan, Kelvin K W

    2017-09-15

    The objective of this study was to determine the impact of modeling cancer drug wastage in economic evaluations because wastage can result from single-dose vials on account of body surface area- or weight-based dosing. Intravenous chemotherapy drugs were identified from the pan-Canadian Oncology Drug Review (pCODR) program as of January 2015. Economic evaluations performed by drug manufacturers and pCODR were reviewed. Cost-effectiveness analyses and budget impact analyses were conducted for no-wastage and maximum-wastage scenarios (ie, the entire unused portion of the vial was discarded at each infusion). Sensitivity analyses were performed for a range of body surface areas and weights. Twelve drugs used for 17 indications were analyzed. Wastage was reported (ie, assumptions were explicit) in 71% of the models and was incorporated into 53% by manufacturers; this resulted in a mean incremental cost-effectiveness ratio increase of 6.1% (range, 1.3%-14.6%). pCODR reported and incorporated wastage for 59% of the models, and this resulted in a mean incremental cost-effectiveness ratio increase of 15.0% (range, 2.6%-48.2%). In the maximum-wastage scenario, there was a mean increase in the incremental cost-effectiveness ratio of 24.0% (range, 0.0%-97.2%), a mean increase in the 3-year total incremental budget costs of 26.0% (range, 0.0%-83.1%), and an increase in the 3-year total incremental drug budget cost of approximately CaD $102 million nationally. Changing the mean body surface area or body weight caused 45% of the drugs to have a change in the vial size and/or quantity, and this resulted in increased drug costs. Cancer drug wastage can increase drug costs but is not uniformly modeled in economic evaluations. Cancer 2017;123:3583-90. © 2017 American Cancer Society. © 2017 American Cancer Society.

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

    Science.gov (United States)

    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…

  11. Evaluation of Drug Prescriptions in Oral Surgery | Ehigiator ...

    African Journals Online (AJOL)

    Evaluation of Drug Prescriptions in Oral Surgery. ... To evaluate the pattern of medication prescription in an oral surgery outpatient clinic. A questionnaire was distributed to Resident doctord ... This however buttresses that the management of the orofacial pain and dental infection is inherent in dental practice. Keywords: Drig ...

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

    Directory of Open Access Journals (Sweden)

    Schellenberg Joanna

    2011-12-01

    Full Text Available Abstract 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 P = 0.31. Conclusion The lack of evidence of an effect of IPTi on survival could be a false negative result due to a lack of power or imbalance of unmeasured confounders. Alternatively, there could be no mortality impact of IPTi due to low coverage, late administration, drug resistance, decreased malaria transmission or improvements in vector control and case management. This study raises important questions for programme evaluation design.

  13. Formulation and evaluation of floating drug delivery system of famotidine.

    Science.gov (United States)

    Satishbabu, B K; Sandeep, V R; Ravi, R B; Shrutinag, R

    2010-11-01

    A multiple unit oral floating drug delivery system of famotidine was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. Drug and polymer compatibility was studied by subjecting physical mixtures of drug and polymers to differential scanning calorimetry. Cod liver oil entrapped calcium alginate beads containing famotidine, capable of floating in the gastric condition were formulated and evaluated. The gel beads were prepared by emulsion gelation method by employing sodium alginate alone and mixture of sodium alginate and hydrophilic copolymers such as carbopol 934P and hydroxypropylmethylcellulose K15M grade in three different ratios. The effect of selected factors, such as percentage of oil and amount of copolymers on floating properties was investigated. The beads were evaluated for percent drug loading, drug entrapment efficiency, buoyancy and in vitro drug release. The in vitro drug release study of the beads was carried out in simulated gastric media employing a modified Rosette-Rice test apparatus. Wherein, the apparatus was further modified by incorporating a water jacket to the apparatus to circulate hot water to maintain 37±2° for throughout the release study. All the oil entrapped calcium alginate beads floated if a sufficient amount of oil was used. Beads formulated employing sodium alginate alone could not sustain the drug release up to 8 h, whereas beads formulated with mixture of sodium alginate and copolymers demonstrated sustained release of famotidine up to 8 h. The results suggested that cod liver oil entrapped calcium alginate beads were promising as a carrier for intragastric floating drug delivery of famotidine.

  14. Drug Use Evaluation of Three Widely Prescribed Antibiotics in a

    Directory of Open Access Journals (Sweden)

    Mehdi Mohammadi

    2015-10-01

    Full Text Available Background: Drug utilization studies are helpful in understanding the current practice. We have conducted a retrospective study to evaluate the relevant use of a group of most commonly prescribed antibiotics in a teaching hospital in Iran.  The results of this study may be of help for clinicians to improve the patient care.Methods: Patients who received parenteral ceftazidim, vancomycin and amikacin from December2010 to May 2011 were enrolled in this study. Patient’s data including demographic, length of Hospital stay, drug allergy, first and final diagnosis were recorded in a predesigned data collection form. American Hospital Formulary Services (AHFS book were used as a reference for evaluation of study drug indication and dosing according to diagnosis and microbiological culture. Defined Daily Dose (DDD of each drug extracted from Anatomic and Therapeutic Chemical classification system (ATC/DDD and drug usage data evaluated by calculating the ratio of prescribed drug to its DDD.Results: The ratio of prescribed daily dose to DDD was 0.78, 0.95 and 0.86 for amikacin, ceftazidime and vancomycin respectively. Between amikacin group, 43 patients (86% received drug empirically, the number of empiric treatments for ceftazidim and vancomycin were 45(90% and 44 patients (88%. The renal function tests (Blood Urea Nitrogen, Serum Creatinin were evaluated in 56% of amikacin group, 64% in ceftazidime group and 78% in vancomycin group.Conclusion: The results of this study indicate the need to establish continuing medical education (CME courses for physicians to familiarize them with standards required to use and monitor these agents.

  15. Retrospective evaluation of adverse drug reactions induced by antihypertensive treatment

    Science.gov (United States)

    Rende, Pierandrea; Paletta, Laura; Gallelli, Giuseppe; Raffaele, Gianluca; Natale, Vincenzo; Brissa, Nazareno; Costa, Cinzia; Gratteri, Santo; Giofrè, Chiara; Gallelli, Luca

    2013-01-01

    The use of cardiovascular drugs is related to the development of adverse drug reactions (ADRs) in about 24% of the patients in the Cardiovascular Care Unit. Here, we evaluated the ADRs in patients treated with antihypertensive drugs. The study was conducted in two phases: In the first phase, we performed a retrospective study on clinical records of Clinical Divisions (i.e., Internal Medicine Operative Unit and Geriatric Operative Unit) from January 1, 2012 to December 31, 2012. Moreover from January 1, 2013 to March 30, 2013 we performed a prospective study on the outpatients attending the Emergency Department (ED) of the Pugliese-Ciaccio Hospital of Catanzaro, by conducting patient interviews after their informed consent was obtained. The association between a drug and ADR was evaluated using the Naranjo scale. We recorded 72 ADRs in the Clinical Divisions and six in the ED, and these were more frequent in women. Using the Naranjo score, we showed a probable association in 92% of these reactions and a possible association in 8%. The most vulnerable age group involved in ADRs was that of the elderly patients. In conclusion, our results indicate that antihypertensive drugs may be able to induce the development of ADRs, particularly in elderly women receiving multiple drug treatment. Therefore, it is important to motivate the healthcare providers to understand their role and responsibility in the detection, management, documentation, and reporting of ADRs, as also all the essential activities for optimizing patient safety. PMID:24347982

  16. Drug-Level Monitoring on Admission for Presurgical Epilepsy Evaluation.

    Science.gov (United States)

    Constantinescu, Irina; Korff, Christian M; Vulliemoz, Serge; Picard, Fabienne; Seeck, Margitta

    2017-01-01

    Evaluation for surgical treatment is offered to patients who do not respond to antiepileptic drugs. Pseudo-pharmacoresistance (PPR) has been described in the context of impaired compliance, incorrect diagnosis of epilepsy or pharmacological interference resulting in too low blood levels. We were interested to determine the frequency and causes of PPR in patients admitted for presurgical evaluation. We reviewed 553 drug levels in 199 patients and analyzed the relative frequency of drugs below reference range (10 and 20% below the range). Patients who had at least one serum level below the 10% cut-off amounted to 33% and 9% of patients had at least one serum level below the 20% cut-off. Only in 2 patients (1%), this was due to poor compliance. Low levels were equally frequent in mono- or polytherapy. Drugs that were most frequently found out of range were phenytoin, valproate, and topiramate. In monotherapy, lamotrigine was often prescribed in too low dosages. Low drug levels are frequently observed in surgical candidates due to pharmacological interference or insufficient dosing. Poor compliance or incorrect diagnosis does not appear to be a significant concern in this patient group. Our data strengthen the need for regular drug monitoring even in advanced chronic epilepsy to avoid unnecessary health costs by too low and ineffective dosages. © 2017 S. Karger AG, Basel.

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

    Science.gov (United States)

    Wirjanata, Grennady; Handayuni, Irene; Zaloumis, Sophie G; Chalfein, Ferryanto; Prayoga, Pak; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Noviyanti, Rintis; Simpson, Julie A; Price, Ric N; Marfurt, Jutta

    2016-03-02

    In vitro drug susceptibility testing of malaria parasites remains an important component of surveillance for anti-malarial drug resistance. The half-maximal inhibition of growth (IC50) is the most commonly reported parameter expressing drug susceptibility, derived by a variety of statistical approaches, each with its own advantages and disadvantages. In this study, licensed computer programs WinNonlin and GraphPad Prism 6.0, and the open access programs HN-NonLin, Antimalarial ICEstimator (ICE), and In Vitro Analysis and Reporting Tool (IVART) were tested for their ease of use and ability to estimate reliable IC50 values from raw drug response data from 31 Plasmodium falciparum and 29 P. vivax clinical isolates tested with five anti-malarial agents: chloroquine, amodiaquine, piperaquine, mefloquine, and artesunate. The IC50 and slope estimates were similar across all statistical packages for all drugs tested in both species. There was good correlation of results derived from alternative statistical programs and non-linear mixed-effects modelling (NONMEM) which models all isolate data simultaneously. The user-friendliness varied between packages. While HN-NonLin and IVART allow users to enter the data in 96-well format, IVART and GraphPad Prism 6.0 are capable to analyse multiple isolates and drugs in parallel. WinNonlin, GraphPad Prism 6.0, IVART, and ICE provide alerts for non-fitting data and incorrect data entry, facilitating data interpretation. Data analysis using WinNonlin or ICE took the longest computationally, whilst the offline ability of GraphPad Prism 6.0 to analyse multiple isolates and drugs simultaneously made it the fastest among the programs tested. IC50 estimates obtained from the programs tested were comparable. In view of processing time and ease of analysis, GraphPad Prism 6.0 or IVART are best suited for routine and large-scale drug susceptibility testing.

  18. US-Based Drug Cost Parameter Estimation for Economic Evaluations.

    Science.gov (United States)

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

    2015-07-01

    In the United States, 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. 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. The shapes of the empirical distributions among the 3 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 with a published estimate of $305 (range = $51-$523). Our Rules create a simple and transparent approach to creating cost estimates of drug products and assessing 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 1-way or probabilistic sensitivity analyses. © The Author(s) 2014.

  19. Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action.

    Science.gov (United States)

    de Souza, Nicolli B; Carmo, Arturene M L; da Silva, Adilson D; França, Tanos C C; Krettli, Antoniana U

    2014-12-02

    Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC(50)) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC(50) value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activity in vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of

  20. Evaluation of Adverse Drug Reactions to Artemisinin-based ...

    African Journals Online (AJOL)

    ... to evaluate the incidence of adverse reactions to antimalarial drugs among residents of a Nigeria university community with a focus on artemisinin-based combination therapy (ACT). Specifically, the profile of use, and the reporting culture of people with respect to experienced reactions were noted. Method: Questionnaires ...

  1. Evaluation of Information Contained in Drug Advertisement and ...

    African Journals Online (AJOL)

    Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v14i3.25. Original Research Article. Evaluation of Information Contained in Drug Advertisement and Promotion Materials in Nigeria. Maxwell Ogochukwu Adibe1*, Nneka Uchenna Igboeli1, Chukwuemeka Michael. Ubaka1, Patrick Obinna Udeogaranya1, ...

  2. Stability and drug dissolution evaluation of Qingkailing soft/hard ...

    African Journals Online (AJOL)

    Stability and drug dissolution evaluation of Qingkailing soft/hard capsules based on multi-component quantification and fingerprint pattern statistical analysis. Ruyu Sun, Huihui Teng, Xiaonan Chen, Shuang Guo, Shan Jia, Mengcheng Zheng, Yang Lu, Jie Bai, Pengyue Li, Shouying Du ...

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

    Science.gov (United States)

    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.

  4. The Utility of a Population Approach in Drug-Drug Interaction Assessments: A Simulation Evaluation.

    Science.gov (United States)

    Wang, Diane D; Yu, Yanke; Kassir, Nastya; Zhu, Min; Hanley, William D; Earp, Justin C; Chow, Andrew T; Gupta, Manish; Hu, Chuanpu

    2017-10-01

    This study aims at evaluating the utility of the population pharmacokinetics approach in therapeutic protein drug-drug-interaction (DDI) assessment. Simulations were conducted for 2 representative victim drugs, methotrexate and trastuzumab, using a parallel-group design with and without the interaction drug. The effect of a perpetrator on the exposure of the victim drug is described as the ratio of clearance/apparent clearance of the victim drug given with or without the perpetrator. The power of DDI assessment was calculated as the percentage of runs with 90% confidence interval of the estimated DDI effect within 80% to 125% for the scenarios of no DDI, benchmarked with the noncompartmental approach with intensive sampling. The impact of the number of subjects, the number of sampling points per subject, sampling time error, and model misspecification on the power of DDI determination were evaluated. Results showed that with equal numbers of subjects in each arm, the population pharmacokinetics approach with sparse sampling may need about the same or a higher number of subjects compared to a noncompartmental approach in order to achieve similar power. Increasing the number of subjects, even if only in the study drug alone arm, can increase the power. Sampling or dosing time error had notable impacts on the power for methotrexate but not for trastuzumab. Model misspecification had no notable impacts on the power for trastuzumab. Overall, the population pharmacokinetics approach with sparse sampling built in phase 2/3 studies allows appropriate DDI assessment with adequate study design and analysis and can be considered as an alternative to dedicated DDI studies. © 2017, The American College of Clinical Pharmacology.

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

    Directory of Open Access Journals (Sweden)

    Soh Byoung

    2013-02-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Li Yan; Liu Dan; Chang Qing; Liu Dandan; Xia Ying; Liu Shuwen; Peng Nanfang; Yang Xu [Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Huazhong Normal University, Wuhan 430079 (China); Ai Hanhua [College of Physical Science and Technology, Huazhong Normal University, Wuhan 430079 (China); Xi Zhuge, E-mail: yangxu@mail.ccnu.edu.cn [Tianjin Institutes of Health and Environmental Medicine, Tianjin 300050 (China)

    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.

  7. Evaluation of drug therapy problems among renal patients receiving ...

    African Journals Online (AJOL)

    Conclusion: Drug therapy problems among renal patients were high. Inappropriate drug selection and drug interactions were the commonest drug therapy problems. The acceptance of pharmacists' interventions by prescribers was appreciable. Keywords: Drug therapy problems, Renal patients, Therapy, Intervention, ...

  8. Evaluation of mesotherapy as a transdermal drug delivery tool.

    Science.gov (United States)

    Kim, S; Kye, J; Lee, M; Park, B

    2016-05-01

    There has been no research about the exact mechanism of transdermal drug delivery during mesotherapy. We aimed to evaluate whether the commercial mesogun can be an appropriate technique for a transdermal drug delivery. We injected blue ink into the polyurethane foam or pig skin with three types of mesotherapy using a commercial mesogun, or local made intradermal injector, or a manual injection of syringe. To assess the internal pressure of the cylinder and drug delivery time, we designed the evaluation setup using a needle tip pressure transducer. All types of injectors induced adequate penetration of blue ink into the polyurethane foam without backflow. In the pig skin, blue ink leaked out rapidly with the backward movement of the needle in the commercial mesogun in contrast to the local made injector or the manual injection of syringe. When the time for backward movement of the syringe approaches 1000 ms, the cylinder pressure of the syringe is saturated at around 25 mmHg which can be translated into the dermal pressure of the pig skin. There should be sufficient time between the insertion and withdrawal of the needle of injector for the adequate transdermal drug delivery and it must be considered for mesotherapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Evaluation of drug provocation test-related anxiety in patients with drug hypersensitivity.

    Science.gov (United States)

    Soyyiğit, Şadan; Aydın, Ömür; Yılmaz, İnsu; Özdemir, Seçil Kepil; Cankorur, Vesile Şentürk; Atbaşoğlu, Cem; Çelik, Gülfem Elif

    2016-09-01

    Drug provocation tests (DPTs) are important in the treatment of patients with drug hypersensitivity (DH), but they carry certain hypersensitivity reaction risks, which lead to procedure-related concerns in patients. To investigate DPT-related anxiety and its effect on long-term use of tested drugs. The study included patients who underwent DPT from July 1, 2009, to July 1, 2012. After recording the patients' history and characteristics, a variety of psychiatric (Hospital Anxiety and Depression Scale, Panic and Agoraphobia Scale, and the Maudsley Obsessive-Compulsive Inventory) and quality-of-life (36-item Short Form Health Survey) tests were performed. DPT-related anxiety was also evaluated using a visual analog scale. The patients were requestioned about whether they had used the tested drug within 1 year. A total of 126 patients were included in the study. According to the Hospital Anxiety and Depression Scale, 23.4% and 30.6% of the patients had depression and anxiety symptoms, respectively. The mean (SD) visual analog scale anxiety scores after a negative DPT result were lower than those before DPTs (2 [2.5] after vs 5.2 [3.4] before; P anxiety related to drug reactions, despite negative DPT results and symptoms indicated for use of the drug. Our findings suggest that DPTs in themselves cause significant anxiety in patients with DH. Importantly, anxiety levels decreased after a negative test result. However, our results also suggested that a negative DPT result is not convincing enough for some patients to use the tested drug when needed in the future. Therefore, supporting strategies appear to be the most effective way to eliminate DH-related anxiety of patients. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  10. Evaluation of the Drug Treatment and Persistence of Onychomycosis

    Directory of Open Access Journals (Sweden)

    Andrew W. Campbell

    2004-01-01

    Full Text Available Onychomycosis is a common nail disease responsible for approximately 50% of diseases of the nail. It occurs more in the elderly, though several cases have been reported among children. Several factors influence, such as climate, geography, and migration. The two dermatophytes most commonly implicated in onychomycosis are Trichophyton rubrum and T. mentagrophytes, accounting for more than 90% of onychomycoses. Nonetheless, several other toxigenic molds have been implicated. For convenience, onychomycosis is divided into four major clinical presentations: distal subungal, which is the most common form of the disease; proximal subungal, which is the most common form found in patients with human immunodeficiency virus infection; superficial; and total dystrophic onychomycosis. Epidemiology of onychomycosis in adults and children is evaluated and the most common clinical symptoms addressed. Although the risk factors are discussed, the multifactorial nature of onychomycosis makes this inexhaustible. The diagnosis and treatments are difficult and the choice of appropriate antifungal drugs complex and require the knowledge of the chemical structures of the metabolites of the molds that cause onychomycosis and their interaction with the antifungal drugs. This is true because most of the antifungal drugs are derived from mold/fungal metabolism. Treatment with griseofulvin and amphotericin is displaced by the use of newer drugs from azole compounds, pyrimidines, and allylamines derivatives. Amorolfine, itraconazole, and ciclopirox nail lacquer solution 8 have gained support globally, but the side effects, drug resistance, and persistence of the disease are still a serious concern to the patients, just as economics and quality of life. Hence, the search for safer and more efficacious drug treatments are continuing.

  11. Merging Traditional Chinese Medicine with Modern Drug Discovery Technologies to Find Novel Drugs and Functional Foods

    Science.gov (United States)

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

    2011-01-01

    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

  12. A replication and methodological critique of the study "Evaluating drug trafficking on the Tor Network"

    National Research Council Canada - National Science Library

    Munksgaard, Rasmus; Demant, Jakob; Branwen, Gwern

    2016-01-01

    .... Dolliver's 2015 article "Evaluating drug trafficking on the Tor Network: Silk Road 2, the Sequel" addresses this theme by evaluating drug trafficking on one of the most well-known cryptomarkets, Silk Road 2.0...

  13. Direct comparison of the histidine-rich protein-2 enzyme-linked immunosorbent assay (HRP-2 ELISA) and malaria SYBR green I fluorescence (MSF) drug sensitivity tests in Plasmodium falciparum reference clones and fresh ex vivo field isolates from Cambodia.

    Science.gov (United States)

    Chaorattanakawee, Suwanna; Tyner, Stuart D; Lon, Chanthap; Yingyuen, Kritsanai; Ruttvisutinunt, Wiriya; Sundrakes, Siratchana; Sai-gnam, Piyaporn; Johnson, Jacob D; Walsh, Douglas S; Saunders, David L; Lanteri, Charlotte A

    2013-07-12

    Performance of the histidine-rich protein-2 enzyme-linked immunosorbent assay (HRP-2 ELISA) and malaria SYBR Green I fluorescence (MSF) drug sensitivity tests were directly compared using Plasmodium falciparum reference strains and fresh ex vivo isolates from Cambodia against a panel of standard anti-malarials. The objective was to determine which of these two common assays is more appropriate for studying drug susceptibility of "immediate ex vivo" (IEV) isolates, analysed without culture adaption, in a region of relatively low malaria transmission. Using the HRP-2 and MSF methods, the 50% inhibitory concentration (IC50) values against a panel of malaria drugs were determined for P. falciparum reference clones (W2, D6, 3D7 and K1) and 41 IEV clinical isolates from an area of multidrug resistance in Cambodia. Comparison of the IC50 values from the two methods was made using Wilcoxon matched pair tests and Pearson's correlation. The lower limit of parasitaemia detection for both methods was determined for reference clones and IEV isolates. Since human white blood cell (WBC) DNA in clinical samples is known to reduce MSF assay sensitivity, SYBR Green I fluorescence linearity of P. falciparum samples spiked with WBCs was evaluated to assess the relative degree to which MSF sensitivity is reduced in clinical samples. IC50 values correlated well between the HRP-2 and MSF methods when testing either P. falciparum reference clones or IEV isolates against 4-aminoquinolines (chloroquine, piperaquine and quinine) and the quinoline methanol mefloquine (Pearson r = 0.85-0.99 for reference clones and 0.56-0.84 for IEV isolates), whereas a weaker IC50 value correlation between methods was noted when testing artemisinins against reference clones and lack of correlation when testing IEV isolates. The HRP-2 ELISA produced a higher overall success rate (90% for producing IC50 best-fit sigmoidal curves), relative to only a 40% success rate for the MSF assay, when evaluating ex

  14. Observational Pharmacoepidemiology in the Drug Safety and Effectiveness Evaluation

    Directory of Open Access Journals (Sweden)

    José Cabrita

    2017-04-01

    Full Text Available Observational epidemiological studies have been used in the medicines context for more than 40 years, contributing to characterize drug use patterns and safety, efficacy and effectiveness profiles. Its use has been increased in recognition of the clinical trials limitations to assess the therapeutic and iatrogenic potential of the medicines after its commercialization. The evolution of the regulatory framework for pharmacovigilance, requiring post-marketing studies, post-authorization safety studies (PASS and the post-authorization efficacy studies (PAES to approve certain drugs, reinforced the importance of observational pharmacoepidemiology for the characterization of the medicines safety and effectiveness profiles. Pharmacoepidemiological research can be carried out from field studies designed to obtain the necessary information or in databases with health records of population samples that already contain the information. This 2nd option is more efficient and more and more frequent. Although, observational research from field studies continues to have its space, the increasing availability of databases allowed a new development to observational pharmacoepidemiology. Indeed, access to automated records databases with up-to-date information on medical prescriptions and global health care to representative population samples with long follow-up periods is a valuable tool for the study of drug use patterns and therapeutic and iatrogenic potential in routine clinical practice. In this context, observational pharmacoepidemiology reinforces its role as a scientific area particularly suitable for evaluating the safety and the effectiveness of the medicines in the “real world”, making a relevant contribution to overcome the gap in translating the evidence from the clinical trials for clinical practice.

  15. 75 FR 34452 - Center for Drug Evaluation and Research Data Standards Plan; Availability for Comment

    Science.gov (United States)

    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... Administration (FDA) is announcing the availability for public comment of the draft document entitled ``CDER Data...

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

    NARCIS (Netherlands)

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

    2004-01-01

    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

  17. 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.

    Science.gov (United States)

    Kahn, Maria; LaRue, Nicole; Bansil, Pooja; Kalnoky, Michael; McGray, Sarah; Domingo, Gonzalo J

    2013-08-20

    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. 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. 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. 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 both the development and evaluation of

  18. Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery.

    Science.gov (United States)

    Prestwich, Glenn D

    2008-01-01

    The acceptance of the new paradigm of 3-D cell culture is currently constrained by the lack of a biocompatible material in the marketplace that offers ease of use, experimental flexibility, and a seamless transition from in vitro to in vivo applications. I describe the development of a covalently cross-linked mimic of the extracellular matrix (sECM), now commercially available, for 3-D culture of cells in vitro and for translational use in vivo. These bio-inspired, biomimetic materials can be used "as is" in drug discovery, toxicology, cell banking, and, ultimately, medicine. For cell therapy and the development of clinical combination products, the sECM biomaterials must be highly reproducible, manufacturable, approvable, and affordable. To obtain integrated, functional, multicellular systems that recapitulate tissues and organs, the needs of the true end users, physicians and patients, must dictate the key design criteria. In chemical terms, the sECM consists of chemically-modified hyaluronan (HA), other glycosaminoglycans (GAGs), and ECM polypeptides containing thiol residues that are cross-linked using biocompatible polyvalent electrophiles. For example, co-cross-linking the semisynthetic thiol-modified HA-like GAG with thiol-modified gelatin produces Extracel as a hydrogel. This hydrogel may be formed in situ in the presence of cells or tissues to provide an injectable cell-delivery vehicle. Alternately, an Extracel hyrogel can be lyophilized to create a macroporous scaffold, which can then be employed for 3-D cell culture. In this Account, we describe four applications of sECMs that are relevant to the evaluation of drug efficacy and drug toxicity. First, the uses of sECMs to promote both in vitro and in vivo growth of healthy cellularized 3-D tissues are summarized. Primary or cell-line-derived cells, including fibroblasts, chondrocytes, hepatocytes, adult and embryonic stem cells, and endothelial and epithelial cells have been used. Second, primary

  19. Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults.

    Science.gov (United States)

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2015-11-01

    Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated. Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed. Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50-0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46-0.55]). C max and AUC0-∞ for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77-0.85] and 0.73 [0.69-0.77], respectively). Adverse events were consistent with known safety profiles. Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status.

  20. Evaluation of two closed-system drug transfer device in the antineoplastic drug elaboration process

    Directory of Open Access Journals (Sweden)

    Sandra Gómez-Álvarez

    2016-01-01

    Full Text Available Objective: to assess the impact of two closed-system drug transfer device on the local and environmental contamination and preparation times in the process of preparation of parenteral chemotherapy compared to the standard system. Method: prospective observational study. Two different closed- systems providers, Care Fusion® and Icu Medical®, were compared to standard preparation. 15 nurses of Pharmacy Department prepared 5 preparations each one, one with the standard procedure and four using closed-systems. To evaluate the contamination, a fluorescein solution 0.5% was prepared. Two kind of contamination were evaluated, local (three points connection: closed-system connect vial, syringe and final infusion bags and environmental (gloves and countertop. Percentage of contaminated preparations was obtained in each one. Time taken by each nurse in each preparation was recorded. Results: 75 preparations were prepared. Local contamination was reduced 21% and 75% in closed-system Icu Medical® and Care Fusion® respectively. Care Fusion® closed system, local contamination was significantly lower than the standard system to the vial, syringe and final package, while Icu Medical® closed-systems only was significantly lower in the connection to the vial. Time of preparation was increased significantly with the use of closed-system between 23.4 and 30.5 seconds. Conclusions: both closed-systems drug transfer device have shown an improvement in contamination than the use of the standard system. However, preparation time has been significantly increased with the use of both systems

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

    Science.gov (United States)

    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.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    , 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...

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

    Science.gov (United States)

    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.

  4. 78 FR 8446 - Center for Drug Evaluation and Research; Prescription Drug Labeling Improvement and Enhancement...

    Science.gov (United States)

    2013-02-06

    ... prescription drug products and reducing the likelihood of medication errors. FDA implemented standardized... voluntarily converts to PLR format. \\4\\ Data obtained from http://labels.fda.gov . Generic drugs approved... show that only 10 percent of generic drug labeling has been converted to the PLR format.\\5\\ Since...

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

    Science.gov (United States)

    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%. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  6. Evaluation of case management of uncomplicated malaria in Haiti: a national health facility survey, 2012.

    Science.gov (United States)

    Landman, Keren Z; Jean, Samuel E; Existe, Alexandre; Akom, Eniko E; Chang, Michelle A; Lemoine, Jean Frantz; Mace, Kimberly E

    2015-10-09

    Malaria is a public health concern in Haiti, although there are limited data on its burden and case management. National malaria guidelines updated in 2012 recommend treatment with chloroquine and primaquine. In December 2012, a nationally-representative cross-sectional survey of health facilities (HFs) was conducted to determine malaria prevalence among febrile outpatients and malaria case management quality at baseline before scale-up of diagnostics and case management training. Among all 833 HFs nationwide, 30 were selected randomly, in proportion to total HFs per region, for 2-day evaluations. Survey teams inventoried HF material and human resources. Outpatients of all ages were screened for temperature >37.5 °C or history of fever; those without severe symptoms were consented and enrolled. Providers evaluated and treated enrolled patients according to HF standards; the survey teams documented provider-ordered diagnostic tests and treatment decisions. Facility-based test results [microscopy and malaria rapid diagnostic tests (RDTs)] were collected from HF laboratories. Blood smears for gold-standard microscopy, and dried blood spots for polymerase chain reaction (PCR) were obtained. Malaria diagnostic capacity, defined as completing a test for an enrolled patient or having adequate resources for RDTs or microscopy, was present in 11 (37 %) HFs. Among 459 outpatients screened, 257 (56 %) were febrile, of which 193 (75 %) were eligible, and 153 (80 %) were enrolled. Among 39 patients with facility-level malaria test results available on the survey day, 11 (28 %) were positive, of whom 6 (55 %) were treated with an anti-malarial. Twenty-seven (95 %) of the 28 patients testing negative were not treated with an anti-malarial. Of 114 patients without test results available, 35 (31 %) were presumptively treated for malaria. Altogether, 42 patients were treated with an anti-malarial, one (2 %) according to Haiti's 2012 guidelines. Of 140 gold-standard smears, none

  7. [Evaluation of efficacy and safety of drugs absorbed through skin using their physicochemical parameters].

    Science.gov (United States)

    Oshizaka, Takeshi; Todo, Hiroaki; Sugibayashi, Kenji

    2012-01-01

    Skin has been paid attention as a site of application of prescription drugs, over-the-counter drugs (non-prescription drugs) and cosmetics. Skin permeation and skin concentration of the compounds should be considered after topical administration, as well as their blood concentration to evaluate efficacy and safety. Since the evaluation of the amount of drugs permeated through skin is important for topically applied drugs, studies on the skin permeation has been greatly advanced. In addition, many reports proved that skin permeabilities of drugs could be predicted from physicochemical parameters of drugs. On the other hand, few reports have been found on the prediction of skin concentration of drugs. Furthermore, many experimented problems are left to determine the skin concentration of drugs: severe consume of human or animal skins, difficult removal of applied drugs from the skin surface, low drug extraction ratio from skin and low sensitivity to determine skin concentration of drugs, and requirement of long time measurement. Thus, fast and accurate measurement of skin concentration of applied drugs are urgently required. This report describes the relationship between skin permeation and skin concentration, and the prediction of skin concentration of drugs using skin permeation parameters of drugs.

  8. Performance Evaluation of Wastewater Treated Plant for Ninava Drug Factory

    Directory of Open Access Journals (Sweden)

    Amar Hamad

    2013-05-01

    Full Text Available In this study the characteristics of raw and treated wastewater from Ninava drug factory were evaluated. The results revealed that the strength of raw wastewater can be classified as medium concentrated wastewater with respect to its BOD5 since the average value is 231.7 mg/l. In addition a strong correlations were found between many characteristics of raw waste. The characteristics of produced effluent from waste water treatment plant of the factory were within the Iraqi specification for the disposed wastewater constraints in 1997, where the average is 7.8 for pH, 40mg/l for SS, 2.8 mg/l for PO4-3, 45 mg/l for BOD5 and 104.3 mg/l for COD. The heavy metals concentrations for both raw and treated wastewater is to be less than those of the related literatures for Tigris river, municipal wastewater and water supply in Mosul city, the average heavy metal concentrations of raw and treated wastewater were 0.5 mg/l for Iron, 0.2 mg/l for zinc and 0.005 mg/l for copper, and there is no significant difference between raw and treated heavy metal concentrations.

  9. Efficacy evaluation of syringe pump developed for continuous drug infusion.

    Science.gov (United States)

    Jung, Bongsu; Seo, Kwang-Suk; Kwon, Suk Jin; Lee, Kiyoung; Hong, Suyong; Seo, Hyounsoon; Kim, Gi-Young; Park, Geun-Mook; Jeong, Juhee; Seo, Soowon

    2016-12-01

    In dental intravenous sedation, continuous intravenous infusion of a low-dose drug requires an infusion pump such as a syringe pump. To develop a new syringe pump for clinical use, the functions of the pump must meet certain international standards. Various safety and efficacy tests must be performed on the syringe pump, as stipulated by these standards, and an approval must be received from the approving agency based on such test results. The authors of the present study developed a novel syringe pump and performed efficacy evaluation by testing its infusion speed at 1 and 25 ml/h, and infusion performance testing at 2 and 24 h. Moreover, performance evaluation was conducted by comparing the novel pump to an existing pump with the infusion speed varied from 1 to 5 ml/h. In the efficacy testing on the newly developed syringe pump, infusion with the infusion speed initially set to 1 ml/h resulted in infusion speeds of 1.00 and 0.99 ml/h in the 2- and 24-h assessment, respectively. Changing the infusion speed setting to 25 ml/h resulted in an infusion speed of 25.09 and 23.92 ml/h in the 2- and 24-h assessment, respectively. These results show no significant differences when compared with other commercially available pumps. The efficacy testing of the newly developed syringe pump showed the accuracy to be within tolerance. Based on these findings, we believe that the newly developed syringe pump is suitable for clinical use.

  10. 76 FR 72422 - Draft Guidance for Industry on Evaluating the Effectiveness of Anticoccidial Drugs in Food...

    Science.gov (United States)

    2011-11-23

    ...: The Food and Drug Administration (FDA) is announcing the availability of draft guidance for industry... Doc No: 2011-30149] DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0784] Draft Guidance for Industry on Evaluating the Effectiveness of Anticoccidial Drugs in...

  11. Evaluation of Information Contained in Drug Advertisement and ...

    African Journals Online (AJOL)

    (55.0 %), drug interaction (51.3 %), pharmacokinetics (36.3 %) and revision date of the information. (21.0 %). Conclusion: This study reveals that advertising materials used in promoting drugs in Nigeria have incomplete information and the physical characteristics of the materials are not adequate. It seems that.

  12. Evaluation of Information Contained in Drug Advertisement and ...

    African Journals Online (AJOL)

    Other contents of the materials were mechanism of action (70.3 %), overdoses information (55.0 %), drug interaction (51.3 %), pharmacokinetics (36.3 %) and revision date of the information (21.0 %). Conclusion: This study reveals that advertising materials used in promoting drugs in Nigeria have incomplete information ...

  13. Evaluating the Implementation of Drug Decriminalization in Tijuana Mexico: Police and Public Health

    OpenAIRE

    Arredondo Sanchez Lira, Jaime

    2017-01-01

    This research seeks to evaluate the impact of drug policy reform in Mexico within the larger Latin American context. Through theoretical and statistical analyses, I use the case study of the municipal Police Department in Tijuana to understand the implementation of Mexico’s 2009 “narcomenudeo” drug policy reform that decriminalized drug possession for personal consumption. Using internal unpublished police data, I demonstrate that the policy shift did not appear to impact the policing of drug...

  14. Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

    Directory of Open Access Journals (Sweden)

    January Weiner 3rd

    2016-08-01

    Full Text Available In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

  15. Evaluating drug prices, availability, affordability, and price components: implications for access to drugs in Malaysia.

    Directory of Open Access Journals (Sweden)

    Zaheer Ud Din Babar

    2007-03-01

    Full Text Available 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

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

    Science.gov (United States)

    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

  17. Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies.

    Science.gov (United States)

    Williamson, Beth; Riley, Robert J

    2017-12-01

    Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management ('manage the baggage') later in drug development. A key challenge in DDI prediction is the discrepancies between reported models. Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application. Expert opinion: Over the past decade, static models have evolved from simple [I]/ki models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or 'manage the baggage'.

  18. Therapeutic Efficacy of Artemether-Lumefantrine for Treatment of ...

    African Journals Online (AJOL)

    (DOAJ), African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts. INTRODUCTION. Widespread resistance of malaria parasites to commonly available anti-malarial drugs has necessitated countries to review and deploy new anti-malarial drug policies to ensure effective case management [1].

  19. Establishing malaria parasite transfection technology in South Africa

    CSIR Research Space (South Africa)

    Van Brummelen, AC

    2010-01-01

    Full Text Available The most important contributing factor to the current malaria crisis is the rapid spread of parasite resistance to available anti-malarial drugs. Anti-malarial drug resistance is critical and the need for compounds with novel modes of action...

  20. Advanced Drug Delivery Systems - a Synthetic and Biological Applied Evaluation

    DEFF Research Database (Denmark)

    Bjerg, Lise Nørkjær

    Specific delivery of drugs to diseased sites in the body is a major topic in the development of drug delivery system today. Especially, the field of cancer treatment needs improved drug delivery systems as the strong dose-limiting side effects of chemotherapy today often present a barrier...... unloading of the encapsulated drug have been tried optimized in a variety of ways. Many propose the use of small molecules, such as vitamins and peptides, for active targeting of the liposomes to overexpressed receptors on the cancerous tissue. Once located close to the diseased site a trigger mechanism...... function as the targeting moiety on the surface of the liposomes. Several examples of synthetic procedures known from the literature are presented. The chapter is completed with a study covering the conjugation efficiencies of a variety of chemical functionalities. Large differences are revealed between...

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

    OpenAIRE

    Negus, S. Stevens; 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...

  2. Evaluation of two closed-system drug transfer device in the antineoplastic drug elaboration process

    National Research Council Canada - National Science Library

    Sandra Gómez-Álvarez; Begoña Porta-Oltra; Marta Hernandez-Griso; Francisca Pérez-Labaña; Mónica Climente-Martí

    2016-01-01

    Objective: to assess the impact of two closed-system drug transfer device on the local and environmental contamination and preparation times in the process of preparation of parenteral chemotherapy compared to the standard system. Method...

  3. Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target.

    Science.gov (United States)

    Leitsch, David; Müller, Joachim; Müller, Norbert

    2016-12-01

    The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs. TrxR was overexpressed approximately 10-fold in G. lamblia WB C6 cells by placing the trxR gene behind the arginine deiminase (ADI) promoter on a plasmid. Likewise, a mutant TrxR with a defective disulphide reductase catalytic site was strongly expressed in another G. lamblia WB C6 cell line. Susceptibilities to five antigiardial drugs, i.e. metronidazole, furazolidone, nitazoxanide, albendazole and auranofin were determined in both transfectant cell lines and compared to wildtype. Further, the impact of all five drugs on TrxR activity in vivo was measured. Overexpression of TrxR rendered G. lamblia WB C6 more susceptible to metronidazole and furazolidone but not to nitazoxanide, albendazole, and auranofin. Of all five drugs tested, only auranofin had an appreciably negative effect on TrxR activity in vivo, albeit to a much smaller extent than expected. Overexpression of TrxR and mutant TrxR had hardly any impact on growth of G. lamblia WB C6, although the enzyme also exerts a strong NADPH oxidase activity which is a source of oxidative stress. Our results constitute first direct evidence for the notion that TrxR is an activator of metronidazole and furazolidone but rather question that it is a relevant drug target of presently used antigiardial drugs. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Evaluation of dibutyrylchitin as new excipient for sustained drug release.

    Science.gov (United States)

    Casettari, Luca; Cespi, Marco; Castagnino, Enzo

    2012-08-01

    Dibutyrylchitin (DBC), a lipophilic chitin diester, has been synthesized from chitin and butyric anhydride with methanesulfonic acid as catalyst. Exhaustive esterification of free alcoholic groups of chitin was assessed by FT-IR and (1)H-NMR spectroscopy. High degree of alkyl substitution allowed DBC to acquire an almost completely lipophilic character. Tablets of paracetamol and metformin employing DBC as major excipient, in comparison with starch, microcrystalline cellulose, lactose and polyvinylpyrrolidone, were prepared and rates of drug release were checked by dissolution test assays. DBC released drug at a lower rate than that of the other tested materials. A comparison study of rate release of metformin from DBC tablets and from metformin-hydroxypropyl methylcellulose prolonged release oral formulation available on the market has been also curried out. Under the same conditions and in the presence of the same amount of loaded drug, DBC released 64% of metformin whereas hypromellose-based tablets released 87%.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kevin J. Lee

    2014-10-01

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

  7. An outpatient drug program for adolescent students: preliminary evaluation.

    Science.gov (United States)

    Gottheil, E; Rieger, J A; Farwell, B; Lieberman, D

    1977-01-01

    Adolescent students with drug problems were rostered by their schools at the program facility one-half day per week. Treatment was aimed at increasing communicativeness through art, video, music, group therapy, and individual counseling when appropriate. After 4 months, school personnel, students, and treatment staff indicated that drug taking had decreased and general adjustment improved. Statistically, the treatment group (N = 42) improved significantly more than a control group (N = 37) in school attendance. They also tended to do better in academic, behavior, and work habit grades although these differences did not reach statical significance. Further similar early intervention studies are warranted.

  8. Evaluation of commercial multi-drug oral fluid devices to identify 39 new amphetamine-designer drugs.

    Science.gov (United States)

    Nieddu, Maria; Burrai, Lucia; Trignano, Claudia; Boatto, Gianpiero

    2014-03-01

    Recently, the diffusion on the black market of new psychoactive substances not controlled and often sold as 'legal highs', is exponentially increasing in Europe. Generally, the first analysis for these drugs involves an immunoassay screening in urine or plasma. Actually, there is growing interest in the use of oral fluid (OF) as alternative specimen over conventional biological fluids for drug testing, because of the significant advantages, as a non-invasive collection under direct observation without undue embarrassment or invasion of privacy, and a good correlation with plasma analytical data. Few assays have been developed for detection of new psychoactive compounds in biological samples, so it is important to investigate how they may or may not react in pre-existing commercial immunoassays. In this paper, two different multi-drugs oral fluid screen devices (OFDs) (Screen® Multi-Drug OFD and GIMA One Step Multi-Line Screen Test OFD) were evaluated to determine the cross-reactivity of thirty-nine new amphetamine designer drugs, including twelve substances officially recognized as illicit by italian legislation. Cross-reactivity towards most drugs analyzed was <1 in assays targeting amphetamine (AMP) or methamphetamine (MET). Only two (p-methoxyamphetamine and p-methoxymethamphetamine) of all tested amphetamines gave a positive result. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Evaluation of drug therapy problems among renal patients receiving ...

    African Journals Online (AJOL)

    Purpose: To determine the prevalence of drug therapy problems (DTPs), identify the types of DTPs and assess outcomes of DTP interventions among renal patients receiving care in three Nigerian tertiary hospitals. Methods: This prospective descriptive study was conducted in nephrology units of three tertiary hospitals in ...

  10. Evaluation of Drug Utilization Pattern for Patients of Bronchial ...

    African Journals Online (AJOL)

    Prescriptions were examined for order, number, and therapeutic class of drugs in addition to poly-pharmacy and appropriateness. Patients having ... Conclusion: Prescription pattern was mainly in accordance with standard guidelines with some knowledge and technical gaps in prescription writing methodology. Keywords: ...

  11. Evaluation of Drug Quality (III): Determination of Ciprofloxacin ...

    African Journals Online (AJOL)

    The concentration of ciprofloxacin hydrochloride tablets in the Nigerian market was analyzed using both back-titration and UV-visible spectrophotometric methods. The results obtained showed that different brands contained different concentrations of the drug; some brands contained lower concentrations while others were ...

  12. Sex Stereotyping in Drug Advertisements: Evaluation of the Informal Curriculum.

    Science.gov (United States)

    Wolfe, Mary L.; And Others

    A study to determine sex stereotyping in drug advertisements in five professional journals is reported. The first four studies examined advertisements from general medical journals; the fifth study obtained its data from a psychiatric journal. The journals are "Medical Economics,""American Family Physician,""Modern Medicine,""Journal of the…

  13. Evaluation of the adverse drug reaction surveillance system ...

    African Journals Online (AJOL)

    Results: The surveillance system did not meet up to its objectives as it failed to detect the adverse drug reactions and there was no monitoring of increases in known events. Fewer than half (43%) of the participants were aware of at least 2 objectives of the surveillance system but 83% of health workers willing to participate.

  14. Evaluating adverse drug reactions among HAART patients in a ...

    African Journals Online (AJOL)

    The high prevalence of HIV in KwaZulu-Natal Province, South Africa, has greatly increased the demand for antiretroviral therapy (ART), resulting in an exponential increase in the number of patients initiated on highly active antiretroviral treatment (HAART). However, little information about adverse drug reactions in these ...

  15. Evaluation of Drug Load and Polymer by Using a 96-Well Plate Vacuum Dry System for Amorphous Solid Dispersion Drug Delivery

    National Research Council Canada - National Science Library

    Chiang, Po-Chang; Ran, Yingqing; Chou, Kang-Jye; Cui, Yong; Sambrone, Amy; Chan, Connie; Hart, Ryan

    2012-01-01

    .... A minimal amount of drug was required to evaluate optimal drug load in three different polymers with respect to solubility improvement and solid-state stability of the amorphous drug–polymer system...

  16. The evaluation of drug provocation tests in pediatric allergy clinic: a single center experience.

    Science.gov (United States)

    Vezir, Emine; Erkocoglu, Mustafa; Civelek, Ersoy; Kaya, Aysenur; Azkur, Dilek; Akan, Aysegül; Ozcan, Celal; Toyran, Muge; Ginis, Tayfur; Misirlioglu, Emine Dibek; Kocabas, Can Naci

    2014-01-01

    Drug provocation tests (DPTs) are gold standard to diagnose drug allergy. Our goal was to evaluate the results and safety of diagnostic methods including DPTs during childhood. Between January 2010 and February 2013 DPTs were performed and evaluated, prospectively, in children who attended our pediatric allergy clinic with a suspected drug hypersensitivity reaction. One hundred ninety-eight suspected drug reactions in 175 patients (88 boys and 87 girls) were evaluated. The median age of the subjects at the time of the suspected drug-induced hypersensitivity reaction and at the time of the study was 56 (interquartile range [IQR] = 24-120 months) months and 76 (IQR = 35-149 months) months, respectively. Suspected drugs were beta-lactam antibiotics in 108 cases (54.5%), non-beta-lactam antibiotics in 22 cases (11.1%), and nonsteroid anti-inflammatory drugs in 52 cases (26.3%). The history was compatible with immediate-type reactions in 69 cases (34.8%). Skin-prick tests were not positive in any of the cases. Intradermal tests were positive in three cases (4%). DPTs were positive in 13 (6.8%) of 191 provocation cases, which were performed with culprit drugs. Our results suggest that a positive clinical history is not enough to make a diagnosis of drug allergy, which highlights the significance of undertaking further diagnostic evaluation especially for DPTs.

  17. Evaluation and registration of adverse events in clinical drug trials in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, P.; Bjarnason, N.H.; Dahlof, C.

    2008-01-01

    Tolerability of a drug should be regarded as important as its efficacy. In all four phases of drug development evaluation of adverse events is important. Recommendations for assessment of adverse events in acute and prophylactic clinical drug trials in migraine are given. Tolerability may be indi...... be indirectly assessed using measures of general well-being and eight such tools are presented. Finally, recommendations for reporting of adverse events are given Udgivelsesdato: 2008/7......Tolerability of a drug should be regarded as important as its efficacy. In all four phases of drug development evaluation of adverse events is important. Recommendations for assessment of adverse events in acute and prophylactic clinical drug trials in migraine are given. Tolerability may...

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

    Directory of Open Access Journals (Sweden)

    Mombo-Ngoma Ghyslain

    2010-10-01

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

  19. 77 FR 69634 - Guidance for Industry on Evaluating the Effectiveness of Anticoccidial Drugs in Food-Producing...

    Science.gov (United States)

    2012-11-20

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on Evaluating the Effectiveness of Anticoccidial Drugs in Food-Producing Animals; Availability AGENCY: Food and Drug Administration, HHS. ACTION... industry 217 entitled ``Evaluating the Effectiveness of Anticoccidial Drugs in Food-Producing Animals...

  20. Pharmacognostic and physicochemical evaluation of homoeopathic drug: Erigeron canadensis L.

    OpenAIRE

    Padma Rao Pogaku; Subramanian Palani; Sudhakar Penthala; P Sreeman Narayana; Nagaraju Mukkamula

    2017-01-01

    Background: Erigeron canadensis L. is an erect annual herb belonging to the family Asteraceae. Aerial parts are used in Homoeopathy for bruises, cough, dysuria, gonorrhea, haemorrhages, haemorrhoids, spermatorrhea, and wounds. Objective: The pharmacognostic and physicochemical studies have been carried out to facilitate the use of correct species and lay down standards of raw drug materials. Materials and Methods: Pharmacognostic studies of the leaf and stem of authentic samples of E. canaden...

  1. Pharmacognostic and physicochemical evaluation of homoeopathic drug: Erigeron canadensis L.

    Directory of Open Access Journals (Sweden)

    Padma Rao Pogaku

    2017-01-01

    Full Text Available Background: Erigeron canadensis L. is an erect annual herb belonging to the family Asteraceae. Aerial parts are used in Homoeopathy for bruises, cough, dysuria, gonorrhea, haemorrhages, haemorrhoids, spermatorrhea, and wounds. Objective: The pharmacognostic and physicochemical studies have been carried out to facilitate the use of correct species and lay down standards of raw drug materials. Materials and Methods: Pharmacognostic studies of the leaf and stem of authentic samples of E. canadensis L. have been carried out. Physicochemical parameters of the raw drug include extractive values, ash value, and formulation; besides weight per mL, total solids, and alcohol content, high-performance thin layer chromatography (HPTLC and ultraviolet (UV studies are given. Results: Epidermal cells often possess crystals of calcium oxalate. Stomata are anomocytic, anisocytic, and tetracytic types. Trichomes are uniseriate and conical in structure. The mid vein in transection is flat on adaxial and is ribbed toward abaxial, with a secretory cavity beneath the central vascular bundle. Stem in transection is round. The vascular tissue is made of several vascular bundles in a ring. Crystals of calcium oxalate occur in the epidermis, cortex, and pith of stem. In mature stem, secondary xylem is well developed with a reduced phloem. The determined physicochemical data, namely, extractive values, ash values, and preparation of for raw drug and weight per mL, total solids, and alcohol content besides UV and HPTLC profile for finished product are provided. Conclusions: The presented morphoanatomical features along with powder microscopic and organoleptic characters and physicochemical data are diagnostic to establish the standards for ensuring quality and purity of the drug.

  2. Plant Glandular Trichomes

    Indian Academy of Sciences (India)

    resistance to several anti-malarial drugs. Chinese scientists have made good progress in identifying an anti-malarial chemical, artemisinin, from the glandular trichomes of the wormwood,. Artemisia annua. In a recent study, artemisinin was found to cure. 143 cases of chloroqUIne-resistant falciparum malaria and 141.

  3. Evaluating the molecule-based prediction of clinical drug responses in cancer.

    Science.gov (United States)

    Ding, Zijian; Zu, Songpeng; Gu, Jin

    2016-10-01

    Molecule-based prediction of drug response is one major task of precision oncology. Recently, large-scale cancer genomic studies, such as The Cancer Genome Atlas (TCGA), provide the opportunity to evaluate the predictive utility of molecular data for clinical drug responses in multiple cancer types. Here, we first curated the drug treatment information from TCGA. Four chemotherapeutic drugs had more than 180 clinical response records. Then, we developed a computational framework to evaluate the molecule based predictions of clinical responses of the four drugs and to identify the corresponding molecular signatures. Results show that mRNA or miRNA expressions can predict drug responses significantly better than random classifiers in specific cancer types. A few signature genes are involved in drug response related pathways, such as DDB1 in DNA repair pathway and DLL4 in Notch signaling pathway. Finally, we applied the framework to predict responses across multiple cancer types and found that the prediction performances get improved for cisplatin based on miRNA expressions. Integrative analysis of clinical drug response data and molecular data offers opportunities for discovering predictive markers in cancer. This study provides a starting point to objectively evaluate the molecule-based predictions of clinical drug responses. jgu@tsinghua.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

    Science.gov (United States)

    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. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

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

    Science.gov (United States)

    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…

  6. An Evaluation of an Innovative Drug Education Program: First Year Results.

    Science.gov (United States)

    Schaps, Eric; And Others

    An innovative drug education course was taught to seventh and eighth graders and evaluated in a true experiment. Students learned Lasswell's framework for understanding human needs and motives, a systematic decision-making procedure, and information about the pharmacological, psychological, and social consequences of licit and illicit drug use.…

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

    Science.gov (United States)

    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…

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

    Science.gov (United States)

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

  9. [Evaluation of the carbohydrate metabolism in the drug addict].

    Science.gov (United States)

    Arnalich, F; Monereo, A; Arribas, J R; Grande, C; Camacho, J; Barbado, F J; Vázquez, J J

    1989-04-01

    A prospective study to determine the carbohydrate metabolism in 23 intravenous drug users (IVDU) was carried out. 13 of them had no infection complications (group A), while the other 10 had acute associated infectious (group B). Both groups showed basal glycemia, insulin and glycosylated hemoglobin levels, similar to the control determinations. There were no correlations between these parameters and the hepatic function test alterations or the immunological changes in the IVDU. Our results showed that there were no alterations in the carbohydrates metabolism of the IVDU with a normal nutritional state, in spite of the well-known hypoglycemic effects of opiates in the experimental animal mode.

  10. Drug and Vaccine Evaluation in the Human Aotus Plasmodium Falciparum Model

    National Research Council Canada - National Science Library

    Obaldia

    2002-01-01

    The purpose of this report is to present data on the evaluation of drugs and vaccines in the human malaria/Aotus lemurinus lemurinus monkey model experimentally infected with Plasmodium falciparum or vivax...

  11. Evaluation of Student Learning in a Nonprescription Drug Course without Examinations.

    Science.gov (United States)

    Popovich, Nicholas G.; VanVeldhuizen-Scott, Meri Kay

    1994-01-01

    A pharmacy course in nonprescription drugs in which student evaluation was based on homework assignments, written reflective paragraphs, and class attendance but not examinations was seen by students as enhancing their personal sense of responsibility for learning. (Author/MSE)

  12. Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults.

    Science.gov (United States)

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2015-02-01

    Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the

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

    Science.gov (United States)

    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. Copyright © 2012 John Wiley & Sons, Ltd.

  14. Drug safety evaluation of dronedarone in atrial fibrillation.

    Science.gov (United States)

    De Ferrari, Gaetano M; Dusi, Veronica

    2012-11-01

    Dronedarone was developed with the intent of replicating the antiarrhythmic effects of amiodarone, while minimizing its side effects. Side effects reported in eight randomized clinical trials are discussed, comparing dronedarone and placebo (DAFNE, EURIDIS, ADONIS, ERATO, ANDROMEDA, ATHENA, PALLAS, total number of patients treated with dronedarone 5347), or dronedarone and amiodarone (DIONYSOS, total number of patients treated with dronedarone 249). The results of the first trials, including ATHENA, set high expectations by suggesting that dronedarone may decrease the risk of hospitalization (and even cardiovascular mortality) among patients with paroxysmal and persistent atrial fibrillation (AF), and that it could be regarded as an easy-to-use drug that could be prescribed by general practitioners; unfortunately, dronedarone has not met these expectations. Dronedarone may increase mortality and heart failure hospitalization in patients with advanced NYHA class and in patients with permanent AF, preventing its use in these settings. In addition to gastrointestinal side effects that may lead to discontinuation in 5 - 10% of patients, dronedarone may induce very rare but severe liver and lung toxicity. Despite these limitations and its relatively limited antiarrhythmic potency, dronedarone may still be a useful drug for well-selected patients.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-27

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

  16. In vitro evaluation of Moringa oleifera gum for colon-specific drug delivery.

    Science.gov (United States)

    Singhal, Anil Kumar; Jarald, Edwin E; Showkat, Ahmad; Daud, Anwar

    2012-01-01

    Moringa gum obtained from stem of the plant Moringa oleifera Lam. belonging to family Moringaceae. Number of naturally occurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotin sulphate), algal (alginates) or microbial (dextran) origin. The present study was evaluated Moringa oleifera gum as a carrier for colon specific drug delivery using in vitro drug release studies. Six formulations of curcumin were prepared using varying concentration of Moringa oleifera gum containing 50 mg curcumin by wet granulation method. Tablets were subjected for evaluation by studying the parameter like hardness, friability, drug content uniformity and in vitro drug release study. Hardness was found to be in the range of 5.5 to 7.3 kg/cm(2), the percentage friability was in the range of 0.60 to 0.89%, and tablet showed 98.99% to 99.89% of the labeled amount of curcumin indicating uniformity in drug content. In vitro drug release study was performed using simulated stomach, intestinal and colonic fluid. The susceptibility of Moringa gum to colonic bacteria was also assessed using drug release study with rat caecal contents. 30% Moringa gum containing formulation (F-3) was shown better drug released that is 90.46%, at the end of 24 h of dissolution study in the presence of rat caecal contents in comparison to 40% Moringa gum containing formulation (F-4) that was 78.03%. The results illustrate the usefulness of Moringa olefera gum as a potential carrier for colon-specific drug delivery.

  17. In vitro release of diclofenac diethylamine from gels: evaluation of generic semisolid drug products in Brazil

    Directory of Open Access Journals (Sweden)

    Karin Goebel

    2013-06-01

    Full Text Available In order for the pharmacological action of a topical dermal drug product to occur, the drug must first be released from the vehicle to be available to penetrate the skin layers and reach the site of action. Drug release is mainly dependent on the characteristics of the formulation. Currently, to register a generic or a similar drug product in Brazil performance testing of topical drug products for local action is not required. In this context, this aim of this study was to evaluate the in vitro release of commercial diclofenac diethylamine gel products available on the Brazilian pharmaceutical market, using the vertical diffusion cell method. Factors which may influence the test, such as the type of membrane used, and the effect of the formulation characteristics on the diffusion rate were evaluated. Brazilian legislation currently allows generic drug products to contain excipients other than the reference drug, which may affect the drug release from the vehicle. Only one of the four generic drug products tested could be considered equivalent to the reference Cataflam Emulgel®. The cellulose acetate and polyethersulfone membranes tested were found to be interchangeable in the in vitro release studies carried out on this product.

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

    Science.gov (United States)

    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…

  19. Examination of risk evaluation and mitigation strategies and drug safety in the US.

    Science.gov (United States)

    Rodriguez-Monguio, Rosa; Spielberger, Kerry; Seoane-Vazquez, Enrique

    2014-01-01

    The Food and Drug Administration Amendment Act of 2007 (FDAAA 2007) enabled the US Food and Drug Administration (FDA) to require risk evaluation and mitigation strategies (REMS) for a drug or biologic to ensure that its benefits outweigh the risks. This study sought to evaluate REMS approved and released by the FDA since the program inception in 2008, to assess the characteristics of REMS approved and to calculate the time lag between FDA drug application approval and REMS approval. Data were derived from Approved Drug Products with Therapeutic Equivalence Evaluations, Approved REMS and Drugs@FDA. Data included generic availability, application type and approval date, therapeutic class and FDA review class, orphan designation, priority review and market status. The FDA approved REMS for 259 marketing applications (217 new drug applications -NDAs, 10 abbreviated NDAs, and 32 biologic license applications) in the study period. The FDA granted orphan designation to 11.4% of active ingredients with REMS and priority review to 38.4% of the NDAs with REMS. The largest number of REMS approvals was for nervous system products (31.8% of total approved REMS) and antineoplastic and immunomodulating agents (15.3%). The FDA approved REMS for one in three biologics and one in thirteen chemical entities available in the market. A pharmaceutical product can be in the market for an average of 14 years before the FDA identifies and evaluates the risk problems that warrant the approval of a REMS. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Evaluation of Biosourced Alkyd Nanoemulsions as Drug Carriers

    Directory of Open Access Journals (Sweden)

    Siew Yong Teo

    2015-01-01

    Full Text Available Novel oil-in-water (O/W nanoemulsions were formulated using short, medium, and long oil length alkyds synthesized from palm kernel oil by a two-stage alcoholysis-polyesterification reaction. Alkyd/surfactant/water ternary phase diagrams identified a composition of 1% alkyd, 9% Tween 80, and 90% water where spontaneous production of nanoemulsions occurred. The pH, droplet size, and zeta potential of all formulations were in the range of 6.4–6.6, 11–14 nm, and −6 mV to −8 mV, respectively. Rheological studies showed that the nanoemulsions displayed non-Newtonian shear thinning behavior at low shear rates up to 20 s−1 with conversion to Newtonian behavior above this shear rate. All nanoemulsions were found to be stable against phase separation on storage at 4°C and 25°C for three months. Short oil length alkyd nanoemulsions exhibited significantly higher stability compared with medium and long oil length alkyd nanoemulsions, as demonstrated by an absence of phase separation and only minor changes of droplet size on storage at an elevated temperature of 45°C for 3 months. The drug carrying capacity and storage stability of the nanoemulsions were assessed using phenytoin. The entrapment efficiency of alkyd nanoemulsions was in excess of 90% and loss of phenytoin content was restricted to less than 4% during storage of the nanoemulsions for three months at 4°C, 25°C, and 45°C. Taken together, these findings indicate that nanoemulsions prepared from palm kernel oil-based alkyds offer potential as nanocarriers for drug delivery applications.

  1. Evaluating adverse drug event reporting in administrative data from emergency departments: a validation study

    Science.gov (United States)

    2013-01-01

    Background Adverse drug events are a frequent cause of emergency department presentations. Administrative data could be used to identify patients presenting with adverse drug events for post-market surveillance, and to conduct research in patient safety and in drug safety and effectiveness. However, such data sources have not been evaluated for their completeness with regard to adverse drug event reporting. Our objective was to determine the proportion of adverse drug events to outpatient medications diagnosed at the point-of-care in emergency departments that were documented in administrative data. Methods We linked the records of patients enrolled in a prospective observational cohort study on adverse drug events conducted in two Canadian tertiary care emergency departments to their administrative data. We compared the number of adverse drug events diagnosed and recorded at the point-of-care in the prospective study with the number of adverse drug events recorded in the administrative data. Results Among 1574 emergency department visits, 221 were identified as adverse drug event-related in the prospective database. We found 15 adverse drug events documented in administrative records with ICD-10 codes clearly indicating an adverse drug event, indicating a sensitivity of 6.8% (95% CI 4.0–11.2%) of this code set. When the ICD-10 code categories were broadened to include codes indicating a very likely, likely or possible adverse event to a medication, 62 of 221 events were identifiable in administrative data, corresponding to a sensitivity of 28.1% (95% CI 22.3-34.6%). Conclusions Adverse drug events to outpatient medications were underreported in emergency department administrative data compared to the number of adverse drug events diagnosed and recorded at the point-of-care. PMID:24219303

  2. Evaluation of Anxiety and Depression Among Female Spouses of Iranian Male Drug Dependents

    Science.gov (United States)

    Noori, Roya; Jafari, Firoozeh; Moazen, Babak; Khoddami Vishteh, Hamid Reza; Farhoudian, Ali; Narenjiha, Hooman; Rafiey, Hassan

    2015-01-01

    Background: Existing evidences suggest the more vulnerability of spouses of drug dependents, in exposure to mental disorders. Objectives: This study aimed to evaluate the associated parameters of anxiety and depression among female spouses of male drug dependents. Patients and Methods: With a cross-sectional design in 2010, a total of 237 Iranian women were selected and divided into three groups: 1. non-drug-dependent wives who had non-drug-dependent husbands (Group I), 2. non-drug-dependent wives who had drug-dependent husbands (Group II), and 3. drug-dependent wives who had drug-dependent husbands (Group III). Socio-demographic characteristics were collected by a checklist, and the levels of anxiety and depression were measured through the Hospital Anxiety and Depression Scale (HADS). Linear regression was applied for determination of anxiety and depression predictors. Results: Mean age of the participants was about 35 years, and mean duration of marriage was 14 years. Drug dependence of the husband (P = 0.010) and lower monthly income of the family (P = 0.007) predicted the higher level of anxiety among the participants, while older age (P = 0.031), shorter marital duration (P = 0.016), and lower educational level (P = 0.045) in addition to spousal drug dependence (P = 0.023), and lower family income (P = 0.014) were significantly associated with higher levels of depression. Conclusions: Findings of the present study demonstrate that spousal drug dependence and lower monthly income were common predictors of anxiety and depression among spouses of drug dependents in Iran, while older age, shorter marital duration and lower educational level were predictors of depression. However, more research is needed to find casual relationships between spousal drug dependence and mental health in Iran. PMID:25861583

  3. Psyllium arabinoxylan: carboxymethylation, characterization and evaluation for nanoparticulate drug delivery.

    Science.gov (United States)

    Bhatia, Meenakshi; Ahuja, Munish

    2015-01-01

    The objective of present investigation was to optimize the interaction between carboxymethylated psyllium arabinoxylan and chitosan to prepare polyelectrolyte naoparticles for drug delivery applications. Arabinoxylan extracted from psyllium was carboxymethylated by reacting with monochloroacetic acid under alkaline conditions. Carboxymethylation of psyllium arabinoxylan was observed to increase its crystallinity, improve thermal stability and decrease the viscosity. Further, the effect of concentrations of carboxymethylated arabinoxylan and chitosan on the particle size and particle size distribution of ibuprofen loaded polyelectrolyte nanoparticles was screened using two-factor, three-level central composite experimental design. The results of optimization study revealed that the formation of nanometric polyelectrolyte is favored at the median level of carboxymethylated arabinoxylan and chitosan concentration. The optimal concentrations of carboxymethylated arabinoxylan and chitosan were found to be 0.0779% (w/v) and 0.0693% (w/v) respectively, which provided polyelectrolyte particles of size 337.2 nm and polydispersity index 0.335. Further, polyelectrolyte complex nanoparticles were found to release ibuprofen over a prolonged period of 10h following Higuchi's square root release kinetics with the mechanism of release being combination of diffusion and erosion of matrix. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Drug prescribing pattern for under-fives in a paediatric clinic in South-Western Nigeria.

    Science.gov (United States)

    Fadare, Joseph; Olatunya, Oladele; Oluwayemi, Oludare; Ogundare, Olatunde

    2015-01-01

    The audit of drug prescribing pattern in under-five children is essential in identifying the various types of non-rational prescribing such as polypharmacy and irrational use of antimicrobials. The primary objective of this study was to determine the drug prescribing pattern for children aged below five years attending the paediatric outpatient clinic of a tertiary hospital in Ado-Ekiti, South-West Nigeria. A cross-sectional study was carried out using the medical records of patients who attended the paediatric clinic of the hospital between April 1 and October 30, 2013. The medical records of patients aged below five years were selected monthly for the period of the study using a regular interval ratio. Drug use indicators were assessed using the WHO guidelines on investigation of drug use in health care facilities. There were 293(55.7%) prescriptions collected from male patients and 233(44.3% from female patients with a total of 1369 prescribed drugs (2.6 ± 1.1 drugs per prescription). A total of three hundred and seventy-four (71.1%) patients had at least one antibiotic prescribed with antibiotics accounting for 28.2% of all drugs prescribed, while 13.5% of all encounters had an injection prescribed. Prescribing by generic name was done in 68.9 ± 26.5% of all prescribed medications, and 60.4% of all prescribed medications were from the latest version of the Nigerian Essential Drug List. Three hundred and twelve children (59.3%) had at least one anti-malarial drug prescribed while analgesics drugs accounted for 6.1% of all prescriptions. This study showed that over-prescription of antibiotics, significant use of injections and prescribing by generic name are real issues among Nigerian paediatric prescribers.

  5. Drug evaluation studies in neonates: how to overcome the current limitations.

    Science.gov (United States)

    Allegaert, Karel; Smits, Anne; van den Anker, John

    2018-02-08

    Introduction Regulatory initiatives have stimulated drug research in infants, but the potential impact of drugs to improve health outcome in neonates remains underexplored. Areas covered In this review, we focus on current limitations in drug evaluation studies and how to overcome these. The low volume of studies has additional weaknesses such as single center studies, non-commercial sponsorship, overrepresentation of high postulated risk reductions, and underrepresentation of therapeutic exploratory studies. Master protocols and selection criteria for neonatal centers to participate in studies are useful to improve logistics related to performance. Limitations also relate to inaccurate assessment of drug effects (efficacy/safety). This is because of poor symptom recognition, case definitions, and suboptimal data on adverse drug reactions (ADRs) epidemiology. To overcome these limitations, it is necessary to develop core outcome sets, reference values, and specific ADR tools. The limitations identified and approaches suggested to improve drug evaluation are illustrated using neonatal abstinence syndrome as an example. Expert Commentary We anticipate to see an evolving neonatal clinical pharmacology discipline driven by neonatal pathophysiology and knowledge. Multidisciplinary collaborative efforts between health care providers, academia, pharmaceutical industry, advocacy groups and regulatory agencies are crucial to improve the impact of drug evaluation studies in neonates.

  6. Formulation and evaluation of bilayered gastroretentable mucoadhesive patch for stomach-specific drug delivery.

    Science.gov (United States)

    Pandey, Suneel; Jirwankar, Prachi; Mehta, Sandip; Pandit, Sachin; Tripathi, Pushpendra; Patil, Arun

    2013-08-01

    The aim of the present work was to develop and evaluate stomach-specific controlled release, gastroretentable mucoadhesive patch of lercanidipine HCl. This drug is essentially soluble in gastric pH range of 1- 4 and have a partition coefficient (log p-value) of 6.1; according to this concept, it has been decided to formulate the gastroretentive bioadhesive patch. The patch system consisted of a drug release rate controlling film, using the combination of Eudragit RSPO and RLPO; mucoadhesive film by using the combination of various hydrophilic polymers. Bilayered patch were made by using the selected batch of two films using the layering method and evaluated for the various parameters like in vitro swelling study, ex vivo mucoadhesive strength. Film was folded into a hard gelatin capsule, evaluated for in vitro drug release in pH 1.2 containing 0.2% (w/v) sodium lauryl sulphate (SLS), and in vivo bioavailability in rabbits. Patches could control the drug release up to 12 h, having mucoadhesion strength in the range of 4.05±0.4 N to 4.52±0.12 N. In vivo bioavailability results indicate that the gastroretentive patch system provides a novel way to retain the drug matrix for the longer period of time in a stomach, enhance drug absorption and thereby offer a promising strategy for gastroretentive mucoadhesive drug delivery for the lercanidipine HCl.

  7. A Synthetic Biology Project - Developing a single-molecule device for screening drug-target interactions.

    Science.gov (United States)

    Firman, Keith; Evans, Luke; Youell, James

    2012-07-16

    This review describes a European-funded project in the area of Synthetic Biology. The project seeks to demonstrate the application of engineering techniques and methodologies to the design and construction of a biosensor for detecting drug-target interactions at the single-molecule level. Production of the proteins required for the system followed the principle of previously described "bioparts" concepts (a system where a database of biological parts - promoters, genes, terminators, linking tags and cleavage sequences - is used to construct novel gene assemblies) and cassette-type assembly of gene expression systems (the concept of linking different "bioparts" to produce functional "cassettes"), but problems were quickly identified with these approaches. DNA substrates for the device were also constructed using a cassette-system. Finally, micro-engineering was used to build a magnetoresistive Magnetic Tweezer device for detection of single molecule DNA modifying enzymes (motors), while the possibility of constructing a Hall Effect version of this device was explored. The device is currently being used to study helicases from Plasmodium as potential targets for anti-malarial drugs, but we also suggest other potential uses for the device. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  8. Identification of natural peptides as a new class of antimalarial drugs by in silico approaches.

    Science.gov (United States)

    Samy, Ramar Perumal; Foo, Sok Lin; Franco, Octavio L; Stiles, Bradley G; Kumar, Alan P; Sethi, Gautam; Lim, Lina Hk

    2017-01-01

    Malaria is one of the most widespread and serious parasitic diseases worldwide. Currently available antimalarial drugs have side effects, and many strains of Plasmodia have developed resistance to such drugs. The present review examines the use of annexins and of natural peptides from snake venom as a new class of anti-malarial agents, with the key property of reducing inflammation. Severe cases of malaria manifest elevated serum levels of liver enzymes, inflammation, fibrin deposition, apoptosis, and reduction in peripheral CD8+ T cells. The annexin-A1/5 proteins trigger inflammation via increased expression of diverse cytokines (tumor necrosis factor alpha, interleukin-1 beta, interleukin-10), however, by shielding microbial phospholipids they prevent injury via damage-associated molecular patterns (DAMPs). Here, we also review an in silico-based bioengineering approach that may allow for a better design, synthesis and characterization of novel peptides from snake venom as a more effective approach to treatment due to their improved antimalarial activity.

  9. 77 FR 35689 - Guidance for Industry on Irritable Bowel Syndrome-Clinical Evaluation of Drugs for Treatment...

    Science.gov (United States)

    2012-06-14

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on Irritable Bowel Syndrome--Clinical Evaluation of Drugs for Treatment; Availability; Correction AGENCY: Food and Drug Administration, HHS. ACTION: Notice; correction. SUMMARY: The Food and Drug Administration (FDA) is correcting a notice that appeared...

  10. [Safety evaluation of anticancer drugs circuit in a regional hospital in Tunisia].

    Science.gov (United States)

    Sahli, Jihène; El Ghardallou, Meriam; Bougmiza, Iheb; Henchiri, Besma; Limam, Manel; Mejdoub, Rim; Mtiraoui, Ali; Ajmi, Thouraya

    2016-01-01

    Nowadays, the circuit of drugs is a plague. This situation may cause serious harm to patients. In this context, we conducted a study with the aim to describe and evaluate the circuit of anticancer drugs in a Tunisian regional hospital. This is an evaluative study of the risk of anticancer drugs, conducted over a period of 15 days during the year 2014 in the Department of Cancer Research of the Regional Hospital of Gafsa (Tunisia). The evaluation method is based on that conducted by the project "SECURIMED" and developed by the Coordination Committee of the Clinical Evaluation and Quality in Aquitaine (CCECQA) in France. In our study, the observation of anticancer drugs circuit has revealed some deficiencies. We noted that the roles of the various actors are subject sometimes to tasks shifting, which may sometimes be dangerous. The study also revealed a lack and an inadequacy with the standards in terms of the necessary equipment for the preparation of the anticancer drugs. Securing drugs circuit should be a priority included in all national processes and shared by all stakeholders to achieve a premium goal: the quality of care and patient safety.

  11. [The history of developing anticancer Drugs and their evaluation guidelines in Japan].

    Science.gov (United States)

    Maeda, Hideki; Kurokawa, Tatsuo

    2014-01-01

    The cancer therapies currently available do not yet offer fully satisfactory treatments, even in 21st century, and efforts and progress are being made daily in the area of drug development. Anticancer drugs, which play the leading role in cancer therapy, are being developed dynamically around the world, and Japan is not an exception. Looking back on the history of developing anticancer drugs, cytotoxic drugs were the mainstream of drug development until the end of the 20th century. In the 21st century, they have been replaced by molecularly targeted drugs, and thus the development of cytotoxic drugs has been declining rapidly. There were various approaches to the development of anticancer drugs and clinical trial endpoints until the 1980s. In 1991, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was issued. From 2000 onwards, there was vigorous discussion on the clinical trial endpoints of anticancer drugs in the United States. In conjunction with this discussion, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was revised in 2005. The revised guidelines required survival data at the time of filing a new drug application (NDA) as a general rule. Around 2005, a bridging strategy was promoted as the "International Conference on Harmonization E5" was promulgated among Japan, the U.S. and EU, resulting in an outflow of clinical trials to overseas, with more non-Japanese survival data generated outside of Japan used for NDAs than Japanese data. Subsequently, the "Guideline for Basic Principles on Global Clinical Trials" was issued in 2007, which promoted the change in the mainstream approach from a bridging strategy to a pivotal, global study involving Japan. Thus, an era of full-fledged globalization in clinical trials began. We believe Japan will need systems to enhance the motivation for anticancer drug development, such as an expedited program or pediatric program, from now on. We hope that the

  12. Cell-penetrable lysine dendrimers for anti-cancer drug delivery: synthesis and preliminary biological evaluation.

    Science.gov (United States)

    Zhao, Jing; Zhou, Rui; Fu, Xiaoyu; Ren, Wen; Ma, Lifang; Li, Ran; Zhao, Yi; Guo, Li

    2014-07-01

    Improving the cell penetration and enhancing the cell selectivity of drugs have been approved for overcoming the major drawbacks of chemotherapeutic agents: the toxicity to normal cells and the drug resistance in tumors. In this paper, lysine dendrimers (G1-G3) were chosen as novel cell-penetrating carriers for anti-cancer drugs based on the internalization mechanism of cell-penetrating peptides and the characteristics of dendritic peptides. After labeling with fluorescein isothiocyanate (FITC), the cell-penetrable capacity of lysine dendrimers was certified by flow cytometric analysis. In a preliminary biological evaluation, the conjugates of lysine dendrimers and 5-fluorouracil showed the expected advantages: stable drug release, low toxicity to normal cells, and moderate inhibition of tumor cells. These results imply that cell-penetrable lysine dendrimers could be potential carriers in drug delivery of anti-cancer medicine. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Evaluation of trypanocidal drugs used for human African trypanosomosis against Trypanosoma lewisi

    Science.gov (United States)

    Dethoua, Mariette; Nzoumbou-Boko, Romaric; Truc, Philippe; Daulouède, Sylvie; Courtois, Pierrette; Bucheton, Bruno; Cuny, Gérard; Semballa, Silla; Vincendeau, Philippe

    2013-01-01

    Trypanosomes from animals are potential pathogens for humans. Several human cases infected by Trypanosoma lewisi, a parasite of rats, have been reported. The number of these infections is possibly underestimated. Some infections were self-cured, others required treatment with drugs used in human African trypanosomosis. An in vitro evaluation of these drugs and fexinidazole, a new oral drug candidate, has been performed against T. lewisi in comparison with T. brucei gambiense. All have comparable activities against the two parasites. Suramin was not effective. In vivo, drugs were tested in rats immunosuppressed by cyclophosphamide. The best efficacy was obtained for fexinidazole, and pentamidine (15 mg/kg): rats were cured in 7 and 10 days respectively. Rats receiving nifurtimox-eflornithine combination therapy (NECT) or pentamidine (4 mg/kg) were cured after 28 days, while melarsoprol was weakly active. The identification of efficient drugs with reduced toxicity will help in the management of new cases of atypical trypanosomosis. PMID:24139487

  14. Drug exposure in register-based research—An expert-opinion based evaluation of methods

    Science.gov (United States)

    Taipale, Heidi; Koponen, Marjaana; Tolppanen, Anna-Maija; Hartikainen, Sirpa; Ahonen, Riitta; Tiihonen, Jari

    2017-01-01

    Background In register-based pharmacoepidemiological studies, construction of drug exposure periods from drug purchases is a major methodological challenge. Various methods have been applied but their validity is rarely evaluated. Our objective was to conduct an expert-opinion based evaluation of the correctness of drug use periods produced by different methods. Methods Drug use periods were calculated with three fixed methods: time windows, assumption of one Defined Daily Dose (DDD) per day and one tablet per day, and with PRE2DUP that is based on modelling of individual drug purchasing behavior. Expert-opinion based evaluation was conducted with 200 randomly selected purchase histories of warfarin, bisoprolol, simvastatin, risperidone and mirtazapine in the MEDALZ-2005 cohort (28,093 persons with Alzheimer’s disease). Two experts reviewed purchase histories and judged which methods had joined correct purchases and gave correct duration for each of 1000 drug exposure periods. Results The evaluated correctness of drug use periods was 70–94% for PRE2DUP, and depending on grace periods and time window lengths 0–73% for tablet methods, 0–41% for DDD methods and 0–11% for time window methods. The highest rate of evaluated correct solutions for each method class were observed for 1 tablet per day with 180 days grace period (TAB_1_180, 43–73%), and 1 DDD per day with 180 days grace period (1–41%). Time window methods produced at maximum only 11% correct solutions. The best performing fixed method TAB_1_180 reached highest correctness for simvastatin 73% (95% CI 65–81%) whereas 89% (95% CI 84–94%) of PRE2DUP periods were judged as correct. Conclusions This study shows inaccuracy of fixed methods and the urgent need for new data-driven methods. In the expert-opinion based evaluation, the lowest error rates were observed with data-driven method PRE2DUP. PMID:28886089

  15. Drugs or disease: evaluating salivary function in RA patients

    Directory of Open Access Journals (Sweden)

    Sandra Regina TORRES

    Full Text Available Abstract Oral complications of RA may include temporomandibular joint disorders, mucosa alterations and symptoms of dry mouth. The aim of this study was to evaluate the salivary gland function of subjects with rheumatoid arthritis (RA comparing it to healthy controls. Subjects with other systemic conditions known to affect salivary functions were excluded. A questionnaire was applied for the evaluation of xerostomia. Resting and chewing-stimulated salivary flow rates (SFR were obtained under standard conditions. There were 145 subjects included of the study (104 RA and 38 controls. About 66.7% of the RA subjects and 2.4% in control group presented xerostomia. The median resting SFR were 0.24 ml/min for RA subjects and 0.40 mL/min for controls (p = 0.04. The median stimulated SFR were 1.31 mL/min for RA subjects and 1.52 ml/min for controls (p = 0.33. No significant differences were found between resting and stimulated SFR of RA subjects not using xerogenic medications and controls. There was significantly higher number of subjects presenting hyposalivation in the RA group than among controls, even when subjects using xerogenic medications were eliminated from the analysis. In conclusion, hyposalivation and xerostomia were more frequent among RA subjects not using xerogenic medication than among controls, although there were no significant differences in the median SFR between groups.

  16. Blood pressure reduction, persistence and costs in the evaluation of antihypertensive drug treatment – a review

    Directory of Open Access Journals (Sweden)

    Hasford Joerg

    2009-03-01

    Full Text Available Abstract Background Blood pressure lowering drugs are usually evaluated in short term trials determining the absolute blood pressure reduction during trough and the duration of the antihypertensive effect after single or multiple dosing. A lack of persistence with treatment has however been shown to be linked to a worse cardiovascular prognosis. This review explores the blood pressure reduction and persistence with treatment of antihypertensive drugs and the cost consequences of poor persistence with pharmaceutical interventions in arterial hypertension. Methods We have searched the literature for data on blood pressure lowering effects of different antihypertensive drug classes and agents, on persistence with treatment, and on related costs. Persistence was measured as patients' medication possession rate. Results are presented in the form of a systematic review. Results Angiotensin II receptor blocker (ARBs have a competitive blood pressure lowering efficacy compared with ACE-inhibitors (ACEi and calcium channel blockers (CCBs, beta-blockers (BBs and diuretics. 8 studies describing the persistence with treatment were identified. Patients were more persistent on ARBs than on ACEi and CCBs, BBs and diuretics. Thus the product of blood pressure lowering and persistence was higher on ARBs than on any other drug class. Although the price per tablet of more recently developed drugs (ACEi, ARBs is higher than that of older ones (diuretics and BBs, the newer drugs result in a more favourable cost to effect ratio when direct drug costs and indirect costs are also considered. Conclusion To evaluate drugs for the treatment of hypertension several key variables including the blood pressure lowering effect, side effects, compliance/persistence with treatment, as well as drug costs and direct and indirect costs of medical care have to be considered. ARBs, while nominally more expensive when drug costs are considered only, provide substantial cost savings

  17. Injections, cocktails and diviners: therapeutic flexibility in the context of malaria elimination and drug resistance in Northeast Cambodia.

    Directory of Open Access Journals (Sweden)

    Charlotte Gryseels

    Full Text Available BACKGROUND: Adherence to effective malaria medication is extremely important in the context of Cambodia's elimination targets and drug resistance containment. Although the public sector health facilities are accessible to the local ethnic minorities of Ratanakiri province (Northeast Cambodia, their illness itineraries often lead them to private pharmacies selling "cocktails" and artemether injections, or to local diviners prescribing animal sacrifices to appease the spirits. METHODS: The research design consisted of a mixed methods study, combining qualitative (in-depth interviews and participant observation and quantitative methods (household and cross-sectional survey. RESULTS: Three broad options for malaria treatment were identified: i the public sector; ii the private sector; iii traditional treatment based on divination and ceremonial sacrifice. Treatment choice was influenced by the availability of treatment and provider, perceived side effects and efficacy of treatments, perceived etiology of symptoms, and patient-health provider encounters. Moreover, treatment paths proved to be highly flexible, changing mostly in relation to the perceived efficacy of a chosen treatment. CONCLUSIONS: Despite good availability of anti-malarial treatment in the public health sector, attendance remained low due to both structural and human behavioral factors. The common use and under-dosage of anti-malaria monotherapy in the private sector (single-dose injections, single-day drug cocktails represents a threat not only for individual case management, but also for the regional plan of drug resistance containment and malaria elimination.

  18. Evaluation of Drug Administrations via Enteral Tube of Intensive Care Nurses

    OpenAIRE

    sevim celik

    2014-01-01

    Aim: The aim of this study was to analyze drug administrations via enteral tube of nurses working intensive care unit Material and Method: Cross-sectional descriptive study was realized with 91 intensive care nurses between 19 March and 9 April, 2012. Data were collected by a survey form. Data were evaluated by number, mean, standart deviation, percentages, chi-square and Fisher's exact tests. Results: Before drug administration via enteral tube, it was determined that 70.3% of nurses ...

  19. Use of internet search logs to evaluate potential drug adverse events.

    Science.gov (United States)

    Sarntivijai, S; Abernethy, D R

    2014-08-01

    Internet search logs provide an abundant source of data that can be explored for purposes such as identifying drug exposure-adverse event relationships. The methodology to rigorously conduct such evaluations is not well characterized, and the utility of such analyses is not well defined. In this issue, White and colleagues propose an approach using Internet search logs for this purpose and compare it to parallel analyses conducted using the US Food and Drug Administration's spontaneous reporting database.

  20. Evaluation of Potential Pharmacokinetic Drug-Drug Interaction between Armodafinil and Aripiprazole in Healthy Adults.

    Science.gov (United States)

    Darwish, M; Bond, M; Yang, R; Hellriegel, E T; Robertson, P

    2015-07-01

    Armodafinil, a moderate inducer of cytochrome P450 (CYP) 3A4, has been studied as adjunctive therapy to maintenance medications for major depressive episodes associated with bipolar I disorder. We evaluated the effect of daily dosing with armodafinil on the pharmacokinetics and safety of the CYP3A4 substrate aripiprazole, an atypical antipsychotic used to treat bipolar I disorder. Healthy adults received 15 mg aripiprazole alone and after armodafinil (250 mg/day) pretreatment. Pharmacokinetic parameters were derived from plasma concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole, obtained over 16 days after each aripiprazole administration. Steady-state pharmacokinetics of armodafinil and its 2 circulating metabolites was assessed. Of 36 subjects enrolled, 24 were evaluable for pharmacokinetic analysis. Armodafinil reduced systemic exposure to aripiprazole (Cmax, - 8%; AUC0-∞, -34%) and dehydro-aripiprazole, which is both formed and eliminated in part via CYP3A4 (Cmax, - 10%; AUC0-∞, - 32%). Adverse events were generally consistent with known safety profiles of each agent. Systemic exposure to aripiprazole and dehydro-aripiprazole was moderately reduced following armodafinil pretreatment. The combination was generally well tolerated under the conditions studied. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Evaluation of patch test in identification of causative agent in drug rashes due to antiepileptics

    Directory of Open Access Journals (Sweden)

    Vatve Maneesha

    2000-01-01

    Full Text Available Patch test was evaluated for the identification of causative agent in cutaneous eruptions due to antiepileptics. Patch tests were carried out in twenty patients and ten controls with carbamazepine, phenytoin sodium, phenobarbitone and sodium valproate. Sodium valproate was found tobe irritant in 1 and 5% concentration and further dilution is recommended for patch testing. Patch test was positive in 14 (70% patients and in 7 with suspected drug alone, and remaining 7 were positive with more than one antiepileptic drug. We recommended patch test for identification of causative drug in rashes due to antiepileptics.

  2. Assessment of methodological quality of economic evaluations in belgian drug reimbursement applications.

    Science.gov (United States)

    Simoens, Steven

    2013-01-01

    This paper aims to assess the methodological quality of economic evaluations included in Belgian reimbursement applications for Class 1 drugs. For 19 reimbursement applications submitted during 2011 and Spring 2012, a descriptive analysis assessed the methodological quality of the economic evaluation, evaluated the assessment of that economic evaluation by the Drug Reimbursement Committee and the response to that assessment by the company. Compliance with methodological guidelines issued by the Belgian Healthcare Knowledge Centre was assessed using a detailed checklist of 23 methodological items. The rate of compliance was calculated based on the number of economic evaluations for which the item was applicable. Economic evaluations tended to comply with guidelines regarding perspective, target population, subgroup analyses, comparator, use of comparative clinical data and final outcome measures, calculation of costs, incremental analysis, discounting and time horizon. However, more attention needs to be paid to the description of limitations of indirect comparisons, the choice of an appropriate analytic technique, the expression of unit costs in values for the current year, the estimation and valuation of outcomes, the presentation of results of sensitivity analyses, and testing the face validity of model inputs and outputs. Also, a large variation was observed in the scope and depth of the quality assessment by the Drug Reimbursement Committee. Although general guidelines exist, pharmaceutical companies and the Drug Reimbursement Committee would benefit from the existence of a more detailed checklist of methodological items that need to be reported in an economic evaluation.

  3. Sustained Release and Cytotoxicity Evaluation of Carbon Nanotube-Mediated Drug Delivery System for Betulinic Acid

    Directory of Open Access Journals (Sweden)

    Julia M. Tan

    2014-01-01

    Full Text Available Carbon nanotubes (CNTs have been widely utilized as a novel drug carrier with promising future applications in biomedical therapies due to their distinct characteristics. In the present work, carboxylic acid-functionalized single-walled carbon nanotubes (f-SWCNTs were used as the starting material to react with anticancer drug, BA to produce f-SWCNTs-BA conjugate via π-π stacking interaction. The conjugate was extensively characterized for drug loading capacity, physicochemical properties, surface morphology, drug releasing characteristics, and cytotoxicity evaluation. The results indicated that the drug loading capacity was determined to be around 20 wt% and this value has been verified by thermogravimetric analysis. The binding of BA onto the surface of f-SWCNTs was confirmed by FTIR and Raman spectroscopies. Powder XRD analysis showed that the structure of the conjugate was unaffected by the loading of BA. The developed conjugate was found to release the drug in a controlled manner with a prolonged release property. According to the preliminary in vitro cytotoxicity studies, the conjugate was not toxic in a standard fibroblast cell line, and anticancer activity was significantly higher in A549 than HepG2 cell line. This study suggests that f-SWCNTs could be developed as an efficient drug carrier to conjugate drugs for pharmaceutical applications in cancer chemotherapies.

  4. Evaluation of the resistance of a geopolymer-based drug delivery system to tampering.

    Science.gov (United States)

    Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne

    2014-04-25

    Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-resistant formulations aim to increase the degree of effort required to override the controlled release of the drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a commercial controlled-release tablet using several methods commonly used by drug abusers. Because of its high compressive strength and resistance to heat, much more effort and time was required to extract the drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based formulation maintained its controlled-release characteristics after milling, while the drug was released immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the tampering methods used in this study does not cover all methods that abuser could access, the results obtained by the described methods showed that the geopolymer matrix increased the degree of effort required to override the controlled release of the drug, suggesting that the formulation has improved resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential to make the opioid product less accessible and attractive to non-medical users. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Floating ability and drug release evaluation of gastroretentive microparticles system containing metronidazole obtained by spray drying

    Directory of Open Access Journals (Sweden)

    Laís Nohemann

    2017-04-01

    Full Text Available Abstract Gastroretentive floating microparticles were developed and evaluated for the controlled metronidazole delivery for treatment of gastric disease. Floating microparticles, varying in proportions of chitosan and hydroxypropyl methylcellulose or ethylcellulose, were obtained by spray drying. Floating microparticles were characterized by physicochemical and in vitro studies, according to their floating ability and drug delivery. Microparticles presented mean diameter from 1.05 to 2.20 µm. The infrared spectroscopy confirmed the drug encapsulation and showed no chemical linkage between microparticles components. X-ray diffraction showed changes in the drug`s solid state, from crystalline to amorphous, indicating partial drug encapsulation, due to the presence of some crystalline peaks of metronidazole in microparticles. All microparticles floated immediately in contact of simulated gastric fluid and both floating and drug release profiles were dependent of microparticles composition. Microparticles samples constituted by chitosan and hydroxypropyl methylcellulose revealed the best relationship between floating duration and drug release, remaining floating during the occurrence of the drug release, ideal condition for the floating gastroretentive systems.

  6. Evaluation of contact sensitivity to topical drugs in patients with contact dermatitis

    Directory of Open Access Journals (Sweden)

    Bilge Bülbül Şen

    2013-03-01

    Full Text Available Background and Design: Topical drugs are an important group of contact allergens. The present study aimed to evaluate contact sensitivity to topical drugs in patients with contact dermatitis. Materials and Methods: Between 2003 and 2008, 129 patients were followed up at the Department of Dermatology at Ankara University School of Medicine with clinically suspected contact sensitivity to topical drugs. In this study, the patch test reactions to the European Standard Battery and topical drugs used by the patients and medicament patch test results were evaluated. Results: Positive patch test reaction to one or more allergens was found in 80 (62.0% of 129 patients included in the study. Sixty-one of the 80 patients (61/129, 47.3% had positive patch test reaction to medicaments. Medicament sensitivity was detected in 37.9% (49/129 of subjects. Nitrofurazone was found to be the most common allergen (18.6%. Discussion: The present study showed that topical drugs are a frequent cause of allergic contact dermatitis. Therefore, the probability of contact sensitivity to topical drugs should also be considered in patients with the clinical diagnosis of allergic contact dermatitis and, suspected cases should be evaluated further with patch testing in order to find the responsible allergens.

  7. The US Food and Drug Administration's Risk Evaluation and Mitigation Strategy (REMS) Program - Current Status and Future Direction

    National Research Council Canada - National Science Library

    Jasmanda Wu; Juhaeri Juhaeri

    2016-01-01

      The US Food and Drug Administration (FDA) Amendments Act of 2007 granted the FDA new authorities to enhance drug safety by requiring application holders to submit a proposed Risk Evaluation and Mitigation Strategy (REMS...

  8. Assessment of a Pharmaceutical Advertisement Analysis Module in a Drug Literature Evaluation Course.

    Science.gov (United States)

    Amin, Mohamed Ezzat Khamis; Fattouh, Youssef

    2017-08-01

    Objective. To evaluate the impact of an educational module on students' self-efficacy when analyzing the content of promotional drug brochures (PDBs) and to assess the students' value of PDBs' as an educational tool. Methods. Third-year bachelor of pharmacy students participated in a one-hour lecture and a two-hour laboratory. Students completed a survey before and after participating in the module. Results. The module elicited a statistically significant change in students' self-efficacy beliefs regarding evaluating promotional drug brochures, while the average perceived value of promotional drug brochures did not change significantly after the module. Conclusion. A brief educational module can increase students' self-efficacy in evaluating the content of PDBs.

  9. Assessment of a Pharmaceutical Advertisement Analysis Module in a Drug Literature Evaluation Course

    Science.gov (United States)

    Fattouh, Youssef

    2017-01-01

    Objective. To evaluate the impact of an educational module on students’ self-efficacy when analyzing the content of promotional drug brochures (PDBs) and to assess the students’ value of PDBs’ as an educational tool. Methods. Third-year bachelor of pharmacy students participated in a one-hour lecture and a two-hour laboratory. Students completed a survey before and after participating in the module. Results. The module elicited a statistically significant change in students’ self-efficacy beliefs regarding evaluating promotional drug brochures, while the average perceived value of promotional drug brochures did not change significantly after the module. Conclusion. A brief educational module can increase students’ self-efficacy in evaluating the content of PDBs. PMID:28970613

  10. Taste-Masking Effect of Chlorogenic Acid (CGA) on Bitter Drugs Evaluated by Taste Sensor and Surface Plasmon Resonance on the Basis of CGA-Drug Interactions.

    Science.gov (United States)

    Shiraishi, Sayuko; Haraguchi, Tamami; Nakamura, Saki; Li, Dahong; Kojima, Honami; Yoshida, Miyako; Uchida, Takahiro

    2017-01-01

    The purpose of this study was to evaluate the taste-masking effects of chlorogenic acid (CGA) on bitter drugs using taste sensor measurements and surface plasmon resonance (SPR) analysis of CGA-drug interactions. Six different bitter drugs were used: amlodipine besylate (AMD), diphenhydramine hydrochloride (DPH), donepezil hydrochloride (DNP), rebamipide (RBM), diclofenac sodium (DCF) and etodolac (ETD). Taste sensor outputs were significantly inhibited by the addition of CGA to all drugs. The inhibition ratio of the taste sensor output decreased in the following order DPH>DNP>AMD≈DCF≈RBM≈ETD. The association rate constant (ka) for the interaction between drugs and CGA as evaluated by SPR measurement also decreased in the following order DPH>DNP>AMD>DCF≈ETD≈RBM. It was suggested that basic drugs (AMD, DNP, DPH) associate more easily with CGA than acidic drugs (DCF, RBM, ETD). The inhibition ratios (%) of the taste sensor output of bitter drugs caused by CGA and the association rate constants (ka) between the drugs and CGA were significantly correlated (rs=0.886, ptaste-masking effects of CGA are due to its direct association with the drugs. CGA may therefore be a useful taste-masking agent for basic drugs.

  11. Benchmarking human protein complexes to investigate drug-related systems and evaluate predicted protein complexes.

    Directory of Open Access Journals (Sweden)

    Min Wu

    Full Text Available Protein complexes are key entities to perform cellular functions. Human diseases are also revealed to associate with some specific human protein complexes. In fact, human protein complexes are widely used for protein function annotation, inference of human protein interactome, disease gene prediction, and so on. Therefore, it is highly desired to build an up-to-date catalogue of human complexes to support the research in these applications. Protein complexes from different databases are as expected to be highly redundant. In this paper, we designed a set of concise operations to compile these redundant human complexes and built a comprehensive catalogue called CHPC2012 (Catalogue of Human Protein Complexes. CHPC2012 achieves a higher coverage for proteins and protein complexes than those individual databases. It is also verified to be a set of complexes with high quality as its co-complex protein associations have a high overlap with protein-protein interactions (PPI in various existing PPI databases. We demonstrated two distinct applications of CHPC2012, that is, investigating the relationship between protein complexes and drug-related systems and evaluating the quality of predicted protein complexes. In particular, CHPC2012 provides more insights into drug development. For instance, proteins involved in multiple complexes (the overlapping proteins are potential drug targets; the drug-complex network is utilized to investigate multi-target drugs and drug-drug interactions; and the disease-specific complex-drug networks will provide new clues for drug repositioning. With this up-to-date reference set of human protein complexes, we believe that the CHPC2012 catalogue is able to enhance the studies for protein interactions, protein functions, human diseases, drugs, and related fields of research. CHPC2012 complexes can be downloaded from http://www1.i2r.a-star.edu.sg/xlli/CHPC2012/CHPC2012.htm.

  12. Preparation and Evaluation of Nano-vesicles of Brimonidine Tartrate as an Ocular Drug Delivery System.

    Science.gov (United States)

    Prabhu, P; Nitish, Kumar R; Koland, M; Harish, Nm; Vijayanarayan, K; Dhondge, G; Charyulu, Rn

    2010-10-01

    The objective of the present investigation was to design a vesicular formulation of brimonidine tartrate and evaluate its ability to reduce the dosing frequency and improve the therapeutic efficacy of the drug. Nano-vesicles of brimonidine tartrate were prepared by film hydration method. The prepared vesicles were evaluated for photomicroscopic characteristics, entrapment efficiency, in vitro, and ex-in vitro drug release and in vivo intraocular pressure (IOP) lowering activity. The methods employed for preparation of vesicles produced nano vesicles of acceptable shape and size. The in vitro, and ex-in vitro drug release studies showed that there was slow and prolonged release of the drug, which followed zero-order kinetics. The IOP-lowering activity of nano vesicles was determined and compared with that of pure drug solution and showed that the IOP-lowering action of nano-vesicles sustained for a longer period of time. Stability studies revealed that the vesicle formulations were stable at the temperature range of 2-8°C, with no change in shape and drug content. The results of the study indicate that it is possible to develop a safe and physiologically effective topical formulation that is also convenient for patients.

  13. Evaluation of skin absorption of drugs from topical and transdermal formulations

    Directory of Open Access Journals (Sweden)

    André Luís Morais Ruela

    Full Text Available ABSTRACT The skin barrier function has been attributed to the stratum corneum and represents a major challenge in clinical practice pertaining to cutaneous administration of drugs. Despite this, a large number of bioactive compounds have been successfully administered via cutaneous administration because of advances in the design of topical and transdermal formulations. In vitro and in vivo evaluations of these novel drug delivery systems are necessary to characterize their quality and efficacy. This review covers the most well-known methods for assessing the cutaneous absorption of drugs as an auxiliary tool for pharmaceutical formulation scientists in the design of drug delivery systems. In vitro methods as skin permeation assays using Franz-type diffusion cells, cutaneous retention and tape-stripping methods to study the cutaneous penetration of drugs, and in vivo evaluations as pre-clinical pharmacokinetic studies in animal models are discussed. Alternative approaches to cutaneous microdialysis are also covered. Recent advances in research on skin absorption of drugs and the effect of skin absorption enhancers, as investigated using confocal laser scanning microscopy, Raman confocal microscopy, and attenuated total reflectance Fourier-transform infrared spectroscopy, are reviewed.

  14. Biocompatibility and cytotoxic evaluation of drug-loaded biodegradable guided tissue regeneration membranes.

    Science.gov (United States)

    Thomas, Nebu G; Sanil, George P; Gopimohan, Rajmohan; Prabhakaran, Jayachandran V; Thomas, George; Panda, Amulya K

    2012-10-01

    In periodontology, Guided Tissue Regeneration (GTR) is based on the concept of providing a space for entry of cells with regenerative potential into the wound environment to initiate the regeneration of structures lost due to periodontal disease. First generation GTR membranes were primarily non-absorbable membranes like expanded polytetrafluorethylene which required a second surgery for its removal. This led researchers to explore absorbable materials like collagen and synthetic biodegradable polymers to fabricate GTR membranes. In the present study, biodegradable Polylactic acid (PLA) is used to fabricate membranes with the potential to be used for GTR therapy. Biocompatibility of the PLA membranes were evaluated in a subcutaneous guinea pig model. Antimicrobial effect of the drug-loaded PLA membranes were assessed against a drug-resistant Staphylococcus aureus bacterial isolate. The cytocompatibility of the drug-loaded membranes were evaluated using HeLa cell lines. The PLA membranes were shown to be biocompatible. The drug-loaded PLA membranes showed significant activity against the bacterial isolate. Among the drug-loaded membranes, tetracycline-loaded membrane showed minimal cellular toxicity. The results of this study indicate that biodegradable drug-releasing polylactide membranes have the potential to be used for periodontal regeneration. It has the necessary characteristics of a GTR membrane like biocompatibility, space maintaining ability, and tissue integration. Among the various antimicrobial agents loaded in the PLA membranes, tetracycline-loaded membranes exhibited minimal cellular toxicity against HeLa cells; at the same time showing significant activity against a pathogenic bacterium.

  15. Evaluation of MGIT 960 System for the Second-Line Drugs Susceptibility Testing of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Hyejin Kim

    2013-01-01

    Full Text Available Many laboratories validate DST of the second-line drugs by BACTEC MGIT 960 system. The objective of this study is to evaluate the critical concentration and perform DST for the 2nd line drugs. We evaluated 193 clinical strains of M. tuberculosis isolated from patients in South Korea. Testing the critical concentration of six second-line drugs was performed by MGIT 960 and compared with L-J proportion method. The critical concentration was determined to establish the most one that gave the difference between drug resistance and susceptibility in MGIT960 system. Good agreement of the following concentrations was found: Concordance was 95% for 0.5 μg/mL of moxifloxacin; 93.6%, 1.0 μg/mL of levofloxacin; 97.5%, 2.5 μg/mL of kanamycin; 90.6%, 2.5 μg/mL of capreomycin; 86.2%, 5.0 μg/mL of ethionamide; and 90.8%, 2.0 μg/mL of ρ-aminosalicylic acid. The critical concentrations of the four drugs, moxifloxacin, levofloxacin, kanamycin, and capreomycin, were concordant and reliable for testing 2nd line drug resistance. Further study of ethionamide and ρ-aminosalicylic acid is required.

  16. A retrospective evaluation of the quality of malaria case management at twelve health facilities in four districts in Zambia

    Directory of Open Access Journals (Sweden)

    Pascalina Chanda-Kapata

    2014-06-01

    Conclusions: Malaria case management was characterised by poor adherence to treatment guidelines. The non-adherence was mainly in terms of: inconsistent use of confirmatory tests (rapid diagnostic test or microscopy for malaria; prescribing anti-malarials which are not recommended (e.g. sulphadoxine-pyrimethamine and prescribing anti-malarials to cases testing negative. Innovative approaches are required to improve health worker adherence to diagnosis and treatment guidelines.

  17. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  18. Gastroretentive drug delivery systems: current developments in novel system design and evaluation.

    Science.gov (United States)

    Murphy, Caragh S; Pillay, Viness; Choonara, Yahya E; du Toit, Lisa C

    2009-10-01

    The task of achieving efficient delivery of drugs that have poor bioavailability or narrow absorption windows have plagued the pharmaceutically industry for decades. Thus, much research has been dedicated to the development of novel polymeric-based gastroretentive drug delivery technologies that may optimize the bioavailability and subsequent therapeutic efficacy of such drugs. An effective approach of achieving this is through the prolongation of the gastric residence time employing several gastroretentive drug delivery mechanisms such as the use of buoyant systems, high density systems, magnetic systems, mucoadhesive systems, swelling/expanding systems, superporous hydrogels and the inclusion of gastric motility retarding agents with biocompatible polymeric materials. It is known that variations in the gastric physiology such as, gastric pH, and motility exhibit both intra-as well as inter-subject variability demonstrating a significant impact on the gastric retention time and drug delivery behavior. Nevertheless, gastroretentive drug delivery systems have shown promising results. Therefore, in this mini-review, current research and development in this field (i.e. over the last 3-5 years), the polymeric material used for the design of gastroretentive drug delivery systems and techniques employed for the pharmaceutical evaluation of gastroretentive technologies are comprehensively revealed and discussed in an assimilatory manner.

  19. Influence of pharmacogenetics on drug disposition and response.

    Science.gov (United States)

    Eichelbaum, M; Evert, B

    1996-01-01

    1. Pharmacogenetics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. 2. Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common inherited enzymopathy affecting approximately 400 million people. The main clinical complication associated with G6PD deficiency is haemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans. 3. The activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g. N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. The gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its

  20. Preliminary evaluation of anti-tuberculosis potential of siderophores against drug-resistant Mycobacterium tuberculosis by mycobacteria growth indicator tube-drug sensitivity test

    OpenAIRE

    Gokarn, Karuna; Pal, Ramprasad B.

    2017-01-01

    Background Alternative treatment strategies have become essential in overcoming the problem of drug-resistant Mycobacterium tuberculosis (Mtb). In this preliminary in vitro study, the anti-tuberculosis (anti-TB) activity of exogenous iron chelators (xenosiderophores) such as Exochelin-MS (Exo-MS) and Deferoxamine-B (DFO-B) was evaluated against ten multi-drug-resistant (MDR) and seven pyrazinamide-resistant (PZA R ) Mtb isolates. Methods Mycobacteria Growth Indicator Tube-Drug Susceptibility ...

  1. Building a structured monitoring and evaluating system of postmarketing drug use in Shanghai.

    Science.gov (United States)

    Du, Wenmin; Levine, Mitchell; Wang, Longxing; Zhang, Yaohua; Yi, Chengdong; Wang, Hongmin; Wang, Xiaoyu; Xie, Hongjuan; Xu, Jianglong; Jin, Huilin; Wang, Tongchun; Huang, Gan; Wu, Ye

    2007-01-01

    In order to understand a drug's full profile in the post-marketing environment, information is needed regarding utilization patterns, beneficial effects, ADRs and economic value. China, the most populated country in the world, has the largest number of people who are taking medications. To begin to appreciate the impact of these medications, a multifunctional evaluation and surveillance system was developed, the Shanghai Drug Monitoring and Evaluative System (SDMES). Set up by the Shanghai Center for Adverse Drug Reaction Monitoring in 2001, the SDMES contains three databases: a population health data base of middle aged and elderly persons; hospital patient medical records; and a spontaneous ADR reporting database. Each person has a unique identification and Medicare number, which permits record-linkage within and between these three databases. After more than three years in development, the population health database has comprehensive data for more than 320,000 residents. The hospital database has two years of inpatient medical records from five major hospitals, and will be increasing to 10 hospitals in 2007. The spontaneous reporting ADR database has collected 20,205 cases since 2001 from approximately 295 sources, including hospitals, pharmaceutical companies, drug wholesalers and pharmacies. The SDMES has the potential to become an important national and international pharmacoepidemiology resource for drug evaluation.

  2. Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union.

    Science.gov (United States)

    Kuribayashi, Ryosuke; Yamaguchi, Toru; Sako, Hanaka; Takishita, Tomoko; Takagi, Kazunori

    2017-03-01

    In Japan, the development of generic oral dry powder inhaler (DPI) drug products for marketing approval has recently increased. The Pharmaceuticals and Medical Devices Agency (PMDA) considers the required data for each drug product in the consultation meeting. However, guidelines for DPI drug products have been published by the US Food and Drug Administration and the European Medicines Agency. Recently, the basic principles of bioequivalence evaluations of generic DPI drug products were published in March 2016 by the Ministry of Health, Labour and Welfare. The document mainly outlines the current understanding regarding the bioequivalence evaluations of generic DPI drug products based on knowledge from PMDA consultation meetings. In this review, we compared the bioequivalence evaluations of DPI drug products among Japan, USA, and the European Union and discuss future development of generic DPI drug products in Japan.

  3. The evaluation and use of economic evidence to inform cancer drug reimbursement decisions in Canada.

    Science.gov (United States)

    Yong, Jean H E; Beca, Jaclyn; Hoch, Jeffrey S

    2013-03-01

    Cost-effectiveness evidence is increasingly considered in the reimbursement decisions of pharmaceuticals. In some jurisdictions such as the UK and Canada, pharmaceutical manufacturers are required to submit economic evaluations when seeking reimbursement. Our objectives were to describe the role of economic evidence in the cancer drug review process in Canada, and to investigate the nature of problems encountered in the review and interpretation of economic evidence used in the process. We conducted a retrospective review of cancer drug review meeting minutes and reviewers' comments on pharmacoeconomic studies submitted to the oncology drug review process in Canada. We used pharmacoeconomic reviewers' reports and relevant cancer drug review expert advisory committee meeting minutes during the first year of the review process (April 2007 to March 2008). Fifteen economic submissions were reviewed. One-third of the studies had flaws significant enough that the advisory committee could not determine the cost effectiveness of the drugs from the results. The common issues outlined by the reviewers and committee were related to the uncertainty of comparative clinical benefits, quality of life and costs. The reviewers felt that few analyses provided sufficient sensitivity analyses around key variables to assess the robustness of results. Most problems identified by reviewers are simple to fix and do not involve advanced methods. Canada has a separate review process for making cancer drug funding recommendations, and this process uses both clinical and economic evidence. The committee could not determine the value for money of the drugs from several of the submitted pharmacoeconomic analyses. Transparent analyses and detailed critique of evidence are crucial to the use of economic evidence in reimbursement decisions. Rigorous evaluation is resource intensive and may benefit from a shared drug review process among several jurisdictions.

  4. Evaluating the abuse potential of psychedelic drugs for medical use in humans.

    Science.gov (United States)

    Heal, David J; Gosden, Jane; Smith, Sharon L

    2018-02-07

    Psychedelics comprise drugs come from various pharmacological classes including 5-HT 2A agonists, indirect 5-HT agonists, e.g. MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e. no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e. schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e. drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates [59]. We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence. Copyright © 2018. Published by Elsevier Ltd.

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

    Directory of Open Access Journals (Sweden)

    Simard Frederic

    2008-03-01

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

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

    African Journals Online (AJOL)

    STORAGESEVER

    2010-06-07

    Jun 7, 2010 ... burden of malaria exists with up to 50% of all out patient visits in areas with high malaria transmission and 30 -. 50% of all hospital admissions are attributed to malaria. (WHO, 2005). The disease kills ... A warm infusion of the bark and leaves traditionally is used to relieve fever and toothache. The powdered ...

  7. Carolus Linnaeus, the ash, worm-wood and other anti-malarial plants.

    Science.gov (United States)

    Aydin-Schmidt, Berit; Thorsell, Walborg; Wahlgren, Mats

    2010-12-01

    In 1735 Carolus Linnaeus wrote that quinine was the preferred treatment for malaria but that the bark of the ash (Fraxinus excelsior) and worm-wood (Artemisia absinthium) also had effects on the disease. We here report that lipo- and hydrophilic extracts of the bark of the ash inhibit the in vitro growth of the asexual stages of P. falciparum. The data suggests that the knowledge of the treatment of malaria was already available in Europe some 300 years ago.

  8. In vivo anti-malarial potentials of some plants extracts on ICR-mice ...

    African Journals Online (AJOL)

    Five medicinal plants, Acacia nilotica (Fabaceae), Citrus aurantifolia (Rutaceae), Mangifera indica (Anacardiaceae) Carica papaya (Caricaceae), and Psidium guajava (Myrtaceae) used for the treatment of malaria/ fever by the Hausa people of Kano-Nigeria were selected based on their traditional claims. These were ...

  9. Eniotorin, An Anti-Malarial Coumarin From The Root Bark Of ...

    African Journals Online (AJOL)

    The structures were determined by analysis of the spectroscopic data. The aqueous extract and the isolated compounds exhibited dose-related effect against the P. falciparum malaria parasite in an in-vitro antimalarial assay. Key words: Eniotorin, Quassia undulata, Simaroubaceae, anti-malaria, simaroubaceae. Nig. J. Nat.

  10. Multicenter evaluation of a new closed system drug-transfer device in reducing surface contamination by antineoplastic hazardous drugs.

    Science.gov (United States)

    Bartel, Sylvia B; Tyler, Timothy G; Power, Luci A

    2018-01-16

    Results of a study to evaluate the effectiveness of a recently introduced closed system drug-transfer device (CSTD) in reducing surface contamination during compounding and simulated administration of antineoplastic hazardous drugs (AHDs) are reported. Wipe samples were collected from 6 predetermined surfaces in compounding and infusion areas of 13 U.S. cancer centers to establish preexisting levels of surface contamination by 2 marker AHDs (cyclophosphamide and fluorouracil). Stainless steel templates were placed over the 6 previously sampled surfaces, and the marker drugs were compounded and infused per a specific protocol using all components of the CSTD. Wipe samples were collected from the templates after completion of tasks and analyzed for both marker AHDs. Aggregated results of wipe sampling to detect preexisting contamination at the 13 study sites showed that overall, 66.7% of samples (104 of 156) had detectable levels of at least 1 marker AHD; subsequent testing after CSTD use per protocol found a sample contamination rate of 5.8% (9 of 156 samples). In the administration areas alone, the rate of preexisting contamination was 78% (61 of 78 samples); with use of the CSTD protocol, the contamination rate was 2.6%. Twenty-six participants rated the CSTD for ease of use, with 100% indicating that they were satisfied or extremely satisfied. A study involving a rigorous protocol and 13 cancer centers across the United States demonstrated that the CSTD reduced surface contamination by cyclophosphamide and fluorouracil during compounding and simulated administration. Participants reported that the CSTD was easy to use. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  11. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting

    KAUST Repository

    Abdel-Haleem, Alyaa M.

    2018-01-04

    Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale models (GEMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1), choline, and pantothenate (vitamin B5) metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  12. Quantitative evaluation of learning and memory trace in studies of mnemotropic effects of immunotropic drugs.

    Science.gov (United States)

    Kiseleva, N M; Novoseletskaya, A V; Voevodina, Ye B; Kozlov, I G; Inozemtsev, A N

    2012-12-01

    Apart from restoration of disordered immunological parameters, tactivin and derinat exhibit a pronounced effect on the higher integrative functions of the brain. Experiments on Wistar rats have shown that these drugs accelerated conditioning of food and defense responses. New methods for quantitative evaluation of memory trace consolidation are proposed.

  13. [Guidance of FDA risk evaluation and mitigation strategy and enlightenment to drug risk management of post-marketing Chinese medicine].

    Science.gov (United States)

    Li, Yuanyuan; Xie, Yanming

    2011-10-01

    The FDA risk evaluation and mitigation strategy (REMS) aims to drugs or biological products known or potential serious risk management. Analysis with the example of the content of the Onsolis REMS named FOCOS. Our country can be reference for the analysis of relevant experience and establish a scientific evaluation mechanism, strengthen the drug risk consciousness, promote the rational drug use, organic combined with the before-marketing and post-marketing evaluation of traditional Chinese medicine, and promote the evaluation of risk management of the drug development and improvement.

  14. Evaluation of Herb-Drug Interactions of Hovenia dulcis Fruit Extracts.

    Science.gov (United States)

    Park, Jong Suk; Rehman, Shaheed Ur; Kim, In Sook; Choi, Min Sun; Na, Chun-Soo; Yoo, Hye Hyun

    2017-01-01

    Hovenia dulcis (Rhamnaceae) fruits are popularly used as herbal medicines or dietary supplements in Asian countries due to functions such as liver protection and detoxification from alcohol poisoning. Accordingly, it is very likely for dietary supplemental products, including H. dulcis fruit extracts, to be taken with prescription drugs. In this study, possible food-drug interactions involving H. dulcis fruit extracts were evaluated based on the inhibition of cytochrome P450 (CYP) enzyme activity. The water extract of H. dulcis fruit extracts was incubated in human liver microsomes with CYP-specific substrates. The formation of the CYP-specific metabolites was measured using liquid chromatography-tandem mass spectrometry. H. dulcis fruit extracts showed negligible effects on seven CYP isozyme activities at all concentrations tested. This result suggests that H. dulcis fruit extracts may have minimal pharmacokinetic interactions with coadministered drugs through the modulation of CYP enzymes. Food-drug interactions involving H. dulcis fruit extracts were evaluated.The inhibition of CYPs by H. dulcis extracts was tested.H. dulcis extracts showed negligible effects on CYP activities.H. dulcis extracts may have minimal pharmacokinetic interactions with co-administered drugs. Abbreviations Used: CYP: cytochrome P450 enzymes, HPLC: High performance liquid chromatography, LC-MS/MS : liquid chromatography-tandem mass spectrometry, MRM: multiple-reaction monitoring.

  15. In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery.

    Science.gov (United States)

    Rahimi, Maham; Wadajkar, Aniket; Subramanian, Khaushik; Yousef, Monet; Cui, Weina; Hsieh, Jer-Tsong; Nguyen, Kytai Truong

    2010-10-01

    Previously uncharacterized poly(N-isopropylacrylamide-acrylamide-allylamine)-coated magnetic nanoparticles (MNPs) were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Properties of these nanoparticles such as size, biocompatibility, drug loading efficiency, and drug release kinetics were evaluated in vitro for targeted and controlled drug delivery. Spherical core-shell nanoparticles with a diameter of 100 nm showed significantly lower systemic toxicity than did bare MNPs, as well as doxorubicin encapsulation efficiency of 72%, and significantly higher doxorubicin release at 41°C compared with 37°C, demonstrating their temperature sensitivity. Released drugs were also active in destroying prostate cancer cells (JHU31). Furthermore, the nanoparticle uptake by JHU31 cells was dependent on dose and incubation time, reaching saturation at 500 μg/mL and 4 hours, respectively. In addition, magnetic resonance imaging capabilities of the particles were observed using agarose platforms containing cells incubated with nanoparticles. Future work includes investigation of targeting capability and effectiveness of these nanoparticles in vivo using animal models. In this paper, previously uncharacterized magnetic nanoparticles were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Various properties of these nanoparticles were evaluated in vitro for targeted drug delivery. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Evaluation of drug-excipient interaction in the formulation of celecoxib tablets.

    Science.gov (United States)

    Bozdağ-Pehlivan, Sibel; Subaşi, Birsel; Vural, Imran; Unlü, Nurşen; Capan, Yilmaz

    2011-01-01

    In the present study, the possible interactions between celecoxib and some excipients (colloidal silicon dioxide (Aerosil), microcrystalline cellulose (Avicel PH 102), lactose anhydrous, magnesium stearate, cross-povidone and talc) were evaluated by examining the pure drug or drug-excipient powder mixtures which were stored under different conditions (25 +/- 2 degrees C, 60% RH +/- 5% RH or 40 + 2 degrees C, 75% RH +/- 5% RH) and different period (30 or 60 days) using DSC, FT-IR and HPLC. In order to investigate the possibility of celecoxib-excipient interaction in aqueous medium, dispersions of the pure drug or drug in physical powder mixture (1:1 w/w) in water (1%, w/v) were also prepared and evaluated by FT-IR and HPLC at day 0 and day 7 (40 +/- 2 degrees C). The interaction between celecoxib and magnesium stearate or colloidal silicon dioxide were determined in the aqueous dispersions by FT-IR. Different tablet formulations with or without excipients tested were prepared, and assessed for drug dissolution and permeability.

  17. Development and evaluation of gastroretentive floating tablets of an antidepressant drug by thermoplastic granulation technique

    Directory of Open Access Journals (Sweden)

    Harshal Ashok Pawar

    2014-06-01

    Full Text Available The present study was undertaken with an aim to formulate, develop and evaluate gastroretentive floating tablets of an antidepressant drug, Venlafaxine HCl (hydrochloride, which release the drug in a sustained manner over a period of 24 h. Three different hydrophobic retardants namely hydrogenated cottonseed oil, carnauba wax, cetyl alcohol and a hydrophilic polymer Methocel® (hydroxy propyl methyl cellulose (HPMC K15M were used in different combinations at different ratios for the preparation of tablets. The tablets were prepared by Hot Melt or Thermoplastic granulation method and evaluated for tablet thickness, hardness, weight variation, friability, floating lag time and in vitro drug release. Formulation F8 with hydrophilic polymer (Methocel® K15M and hydrophobic retardant (carnauba wax in the ratio 1:2.6 (approx. was considered as an optimized formulation. The optimized formulation showed satisfactory sustained drug release and remained buoyant on the surface of the medium for more than 24 h and its release profile was comparable with the marketed formulation (VENTAB-XL 37.5. It can also be concluded that floating drug delivery system of Venlafaxine HCl can be successfully formulated as an approach to increase gastric residence time and thereby improving its bioavailability.

  18. Coping with problematic drug use in the family: An evaluation of the Stepping Stones program.

    Science.gov (United States)

    Gethin, Anni; Trimingham, Tony; Chang, Theo; Farrell, Michael; Ross, Joanne

    2016-07-01

    Problematic substance use by an individual is often highly destructive to their family, creating emotional turmoil and destroying healthy family functioning. The aim of this study was to evaluate the impact of participation in the Stepping Stones family support program on the coping capacity of family members affected by another's substance use. A pre and post study of the Stepping Stones intervention for families was conducted, involving 108 participants recruited from March 2013 to March 2014. Significant improvement in coping across all domains was observed post course and at follow up on both outcome measures (Coping Questionnaire and the Family Drug Support Questionnaire). Improvements for participants were either increased or sustained at 3 months follow up. Participants recorded high satisfaction ratings. The findings from this study demonstrate that participation in the Stepping Stones program assists family members to cope better with problematic substance use of a family member, as indicated by reductions in negative coping strategies, such as over-engagement, making excuses for the drug user or hopelessly tolerating the problem, and improvements in positive coping strategies such as self-care and engagement with their own activities and interests. [Gethin A, Trimingham T, Chang T, Farrell M, Ross J. Coping with problematic drug use in the family: An evaluation of the Stepping Stones program. Drug Alcohol Rev 2016;35:470-476]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

  19. Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

    Science.gov (United States)

    Pentak, Danuta

    2016-05-01

    Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70-150 nm. The analyzed compounds were 1-β- d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC).

  20. Development and evaluation of 'Pure Rush': An online serious game for drug education.

    Science.gov (United States)

    Stapinski, Lexine A; Reda, Bill; Newton, Nicola C; Lawler, Siobhan; Rodriguez, Daniel; Chapman, Catherine; Teesson, Maree

    2017-10-06

    Learning is most effective when it is active, enjoyable and incorporates feedback. Past research demonstrates that serious games are prime candidates to utilise these principles, however the potential benefits of this approach for delivering drug education are yet to be examined in Australia, a country where drug education in schools is mandatory. The serious game 'Pure Rush' was developed across three stages. First, formative consultation was conducted with 115 students (67% male, aged 15-17 years), followed by feasibility and acceptability testing of a prototype of the game (n = 25, 68% male). In the final stage, 281 students (62% female, aged 13-16 years) were randomly allocated to receive a lesson involving Pure Rush or an active control lesson. The lessons were compared in terms of learning outcomes, lesson engagement and future intentions to use illicit drugs. Students enjoyed playing Pure Rush, found the game age-appropriate and the information useful to them. Both the Pure Rush and the active control were associated with significant knowledge increase from pre to post-test. Among females, multi-level mixed-effects regression showed knowledge gain was greater in the Pure Rush condition compared to control (β = 2.36, 95% confidence interval 0.36-4.38). There was no evidence of between condition differences in lesson engagement or future intentions to use illicit drugs. Pure Rush is an innovative online drug education game that is well received by students and feasible to implement in schools. [Stapinski LA, Reda B, Newton NC, Lawler S, Rodriguez D, Chapman C, Teesson M. Development and evaluation of 'Pure Rush': An online serious game for drug education. Drug Alcohol Rev 2017]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

  1. Evaluation of angiotensin II receptor blockers for drug formulary using objective scoring analytical tool

    Directory of Open Access Journals (Sweden)

    Lim TM

    2012-09-01

    Full Text Available Drug selection methods with scores have been developed and used worldwide for formulary purposes. These tools focus on the way in which the products are differentiated from each other within the same therapeutic class. Scoring Analytical Tool (SAT is designed based on the same principle with score and is able to assist formulary committee members in evaluating drugs either to add or delete in a more structured, consistent and reproducible manner. Objective: To develop an objective SAT to facilitate evaluation of drug selection for formulary listing purposes. Methods: A cross-sectional survey was carried out. The proposed SAT was developed to evaluate the drugs according to pre-set criteria and sub-criteria that were matched to the diseases concerned and scores were then assigned based on their relative importance. The main criteria under consideration were safety, quality, cost and efficacy. All these were converted to questionnaires format. Data and information were collected through self-administered questionnaires that were distributed to medical doctors and specialists from the established public hospitals. A convenient sample of 167 doctors (specialists and non-specialists were taken from various disciplines in the outpatient clinics such as Medical, Nephrology and Cardiology units who prescribed ARBs hypertensive drugs to patients. They were given a duration of 4 weeks to answer the questionnaires at their convenience. One way ANOVA, Kruskal Wallis and post hoc comparison tests were carried out at alpha level 0.05. Results: Statistical analysis showed that the descending order of ARBs preference was Telmisartan or Irbesartan or Losartan, Valsartan or Candesartan, Olmesartan and lastly Eprosartan. The most cost saving ARBs for hypertension in public hospitals was Irbesartan. Conclusion: SAT is a tool which can be used to reduce the number of drugs and retained the most therapeutically appropriate drugs in the formulary, to determine most

  2. An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy.

    Science.gov (United States)

    Bank, Claudia; Renzette, Nicholas; Liu, Ping; Matuszewski, Sebastian; Shim, Hyunjin; Foll, Matthieu; Bolon, Daniel N A; Zeldovich, Konstantin B; Kowalik, Timothy F; Finberg, Robert W; Wang, Jennifer P; Jensen, Jeffrey D

    2016-11-01

    The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population genetic method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

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

    Science.gov (United States)

    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. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  4. [The use of pharmacological criteria in the toxicological evaluation of veterinary drugs].

    Science.gov (United States)

    van Leeuwen, F X

    1990-09-01

    The toxicological evaluation of residues of veterinary drugs in foods of animal origin, which is done within the framework of the Netherlands Veterinary Drugs Act, is based on an EEC guide line in which, in addition to the clinical and analytical criteria, the requirements regarding the pharmacological and toxicological evaluation are laid down. In principle, this evaluation is based on classical toxicological criteria. As veterinary drugs have a specific pharmacological action, it is essential that these pharmacological effects should be in included in the toxicological evaluation in view of an adequate protection of public health. The selected starting point is that a pharmacological effect desired in a target animal is regarded as an undesirable effect in consumers. In this presentation, two examples are referred to, viz. the bèta agonist clenbuterol and the bèta-blocking agent carazolol; the approach is compared with a 'classical' toxicological evaluation. This shows that the acceptable daily intake in human individuals (ADI), based on pharmacological criteria is lower by a factor of approximately 50 than is the ADI on the basis of 'classical' toxicological criteria. This clearly illustrates the value of this approach in protecting the health of consumers.

  5. Evaluation of rational drug use based on World Health Organization core drug use indicators in selected public hospitals of eastern Ethiopia: a cross sectional study.

    Science.gov (United States)

    Sisay, Mekonnen; Mengistu, Getnet; Molla, Bereket; Amare, Firehiwot; Gabriel, Tesfaye

    2017-02-23

    Despite the complexity of drug use, a number of indicators have been developed, standardized and evaluated by the World Health Organization (WHO). These indicators are grouped in to three categories namely: prescribing indicators, patient care indicators and facility indicators. The study was aimed to evaluate rational drug use based on WHO-core drug use indicators in Dilchora referral hospital, Dire Dawa; Hiwot Fana specialized university hospital, Harar and Karamara general hospital, Jigjiga, eastern Ethiopia. Hospital based quantitative cross sectional study design was employed to evaluate rational drug use based on WHO core drug use indicators in selected hospitals. Systematic random sampling for prescribing indicators and convenient sampling for patient care indicators was employed. Taking WHO recommendations in to account, a total of 1,500 prescription papers (500 from each hospitals) were investigated. In each hospital, 200 outpatient attendants and 30 key essential drugs were also selected using the WHO recommendation. Data were collected using retrospective and prospective structured observational check list. Data were entered to EPI Data Version 3.1, exported and analyzed using SPSS version 16.0. Besides, the data were evaluated as per the WHO guidelines. Statistical significance was determined by one way analysis of variance (ANOVA) for some variables. P-value of less than 0.05 was considered statistically significant. Finally, tabular presentation was used to present the data. Mean, 2.34 (±1.08) drugs were prescribed in the selected hospitals. Prescriptions containing antibiotics and that of injectables were 57.87 and 10.9% respectively. The average consultation and dispensing time were 276.5 s and 61.12 s respectively. Besides, 75.77% of the prescribed drugs were actually dispensed. Only 3.3% of prescriptions were adequately labeled and 75.7% patients know about the dosage of the prescription. Not more than, 20(66.7%) key drugs were available in

  6. Antimonial drugs entrapped into phosphatidylserine liposomes: physicochemical evaluation and antileishmanial activity

    Directory of Open Access Journals (Sweden)

    Samanta Etel Treiger Borborema

    2016-04-01

    Full Text Available Abstract: INTRODUCTION: Leishmaniasis is a disease caused by the protozoan Leishmania that resides mainly in mononuclear phagocytic system tissues. Pentavalent antimonials are the main treatment option, although these drugs have toxic side effects and high resistance rates. A potentially alternative and more effective therapeutic strategy is to use liposomes as carriers of the antileishmanial agents. The aims of this study were to develop antimonial drugs entrapped into phosphatidylserine liposomes and to analyze their biological and physicochemical characteristics. METHODS: Liposomes containing meglumine antimoniate (MA or pentavalent antimony salt (Sb were obtained through filter extrusion (FEL and characterized by transmission electron microscopy. Promastigotes of Leishmania infantum were incubated with the drugs and the viability was determined with a tetrazolium dye (MTT assay. The effects of these drugs against intracellular amastigotes were also evaluated by optical microscopy, and mammalian cytotoxicity was determined by an MTT assay. RESULTS: Liposomes had an average diameter of 162nm. MA-FEL showed inhibitory activity against intracellular L. infantum amastigotes, with a 50% inhibitory concentration (IC50 of 0.9μg/mL, whereas that of MA was 60μg/mL. Sb-FEL showed an IC50 value of 0.2μg/mL, whereas that of free Sb was 9μg/mL. MA-FEL and Sb-FEL had strong in vitro activity that was 63-fold and 39-fold more effective than their respective free drugs. MA-FEL tested at a ten-times higher concentration than Sb-FEL did not show cytotoxicity to mammalian cells, resulting in a higher selectivity index. CONCLUSIONS: Antimonial drug-containing liposomes are more effective against Leishmania-infected macrophages than the non-liposomal drugs.

  7. A controlled evaluation of family behavior therapy in concurrent child neglect and drug abuse.

    Science.gov (United States)

    Donohue, Brad; Azrin, Nathan H; Bradshaw, Kelsey; Van Hasselt, Vincent B; Cross, Chad L; Urgelles, Jessica; Romero, Valerie; Hill, Heather H; Allen, Daniel N

    2014-08-01

    Approximately 50% of child protective service (CPS) referrals abuse drugs; yet, existing treatment studies in this population have been limited to case examinations. Therefore, a family-based behavioral therapy was evaluated in mothers referred from CPS for child neglect and drug abuse utilizing a controlled experimental design. Seventy-two mothers evidencing drug abuse or dependence and child neglect were randomly assigned to family behavior therapy (FBT) or treatment as usual (TAU). Participants were assessed at baseline, 6 months, and 10 months postrandomization. As hypothesized, intent-to-treat repeated measures analyses revealed mothers referred for child neglect not due to their children being exposed to illicit drugs demonstrated better outcomes in child maltreatment potential from baseline to 6- and 10-month postrandomization assessments when assigned to FBT, as compared with TAU mothers and FBT mothers who were referred due to child drug exposure. Similar results occurred for hard drug use from baseline to 6 and 10 months postrandomization. However, TAU mothers referred due to child drug exposure were also found to decrease their hard drug use more than TAU mothers of non-drug-exposed children and FBT mothers of drug-exposed children at 6 and 10 months postrandomization. Although effect sizes for mothers assigned to FBT were slightly larger for marijuana use than TAU (medium vs. large), these differences were not statistically significant. Specific to secondary outcomes, mothers in FBT, relative to TAU, increased time employed from baseline to 6 and 10 months postrandomization. Mothers in FBT, compared to TAU, also decreased HIV risk from baseline to 6 months postrandomization. There were no differences in outcome between FBT and TAU for number of days children were in CPS custody and alcohol intoxication, although FBT mothers demonstrated marginal decreases (p = .058) in incarceration from baseline to 6 months postrandomization relative to TAU mothers

  8. A novel in vitro three-dimensional retinoblastoma model for evaluating chemotherapeutic drugs.

    Science.gov (United States)

    Mitra, Moutushy; Mohanty, Chandana; Harilal, Anju; Maheswari, Uma K; Sahoo, Sanjeeb Kumar; Krishnakumar, Subramanian

    2012-01-01

    Novel strategies are being applied for creating better in vitro models that simulate in vivo conditions for testing the efficacy of anticancer drugs. In the present study we developed surface-engineered, large and porous, biodegradable, polymeric microparticles as a scaffold for three dimensional (3-D) growth of a Y79 retinoblastoma (RB) cell line. We evaluated the effect of three anticancer drugs in naïve and nanoparticle-loaded forms on a 3-D versus a two-dimensional (2-D) model. We also studied the influence of microparticles on extracellular matrix (ECM) synthesis and whole genome miRNA-gene expression profiling to identify 3D-responsive genes that are implicated in oncogenesis in RB cells. Poly(D,L)-lactide-co-glycolide (PLGA) microparticles were prepared by the solvent evaporation method. RB cell line Y79 was grown alone or with PLGA-gelatin microparticles. Antiproliferative activity, drug diffusion, and cellular uptake were studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a yellow tetrazole (MTT) assay, fluorescent microscope, and flow cytometry. Extra cellular matrix (ECM) synthesis was observed by collagenase assay and whole genome miRNA-microarray profiling by using an Agilent chip. With optimized composition of microparticles and cell culture conditions, an eightfold increase from the seeding density was achieved in 5 days of culture. The antiproliferative effect of the drugs in the 3-D model was significantly lower than in the 2-D suspension, which was evident from the 4.5 to 21.8 fold differences in their IC(50) values. Using doxorubicin, the flow cytometry data demonstrated a 4.4 fold lower drug accumulation in the cells grown in the 3-D model at 4 h. The collagen content of the cells grown in the 3-D model was 2.3 fold greater than that of the cells grown in the 2-D model, suggesting greater synthesis of the extracellular matrix in the 3-D model as the extracellular matrix acted as a barrier to drug diffusion. The microarray

  9. Unauthorized drug use in the US Army based on medical review officer evaluations.

    Science.gov (United States)

    Platteborze, Peter L; Kippenberger, Donald J; Martin, Thomas M

    2014-01-01

    This article examines the US Army's Medical Review Officer (MRO) drug positive urinalysis evaluations from 2009 through 2012. We retrospectively analyzed nearly 70,000 MRO results by year, drug and Army component. Of the MRO reviewable positive results, the Army's unauthorized drug positive rate was 22.21%. The component rates were 20.81, 24.17 and 26.09% for the Active Duty, Reserve and National Guard, respectively. By drug, the average unauthorized rates over these 4 years were 13.78% for oxycodone, 24.62% oxymorphone, 18.56% d-amphetamine, 98.04% d-methamphetamine, 21.97% codeine, 45.21% morphine and 100% steroids. In 2012 testing began for hydrocodone and hydromorphone and their unauthorized rates were 12.32 and 15.04%, respectively. The Army's unauthorized drug positive rate peaked in 2012 when it increased over 44% from the previous year. The 2012 rates in decreasing order were steroids > D-methamphetamine > morphine > oxymorphone > oxycodone > codeine > D-amphetamine > hydromorphone > hydrocodone. This comprehensive analysis showed that the majority of the Army's MRO reviews were associated with the use of authorized prescriptions; however, there appears to be significant abuse of oxycodone and D-amphetamine. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  10. Evaluation of the Knowledge of Rural High School Students in Yazd About Drugs

    Directory of Open Access Journals (Sweden)

    Z Kalani

    2010-08-01

    Full Text Available Introduction: Considering high prevalence of addiction, the age range of drug abuse and availability of new synthetic drugs, evaluation of knowledge of adolescents about drugs would be a priority in research. Methods: In this descriptive cross-sectional study, 517 rural high school students were asked to complete a questionnaire and through SPSS soft ware version 13, collected data was analyzed by chi-square and analysis of variance tests. Results: 7.1% of rural families with at least one boy in high school had an addict family member. 70.2% of high school students had had a contact with an addict and 42.5% knew an adolescent addict. Also, 17.5% had been offered drugs and 37.9% of high school students claimed that there was at least one addict in their family or relations. Conclusion: Considering the frequency of addiction in families and rate of invitation to drug abuse in students, there is a high risk of increment of addiction in high schools and therefore real and urgent need to do an intervention.

  11. Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

    Science.gov (United States)

    Boche, Mithila; Pokharkar, Varsha

    2017-04-01

    To evaluate the possibility of improved drug delivery of quetiapine fumarate (QTP), a nanoemulsion system was developed for intranasal delivery. Effects of different HLBs of Emalex LWIS 10, PEG 400 and Transcutol P, as co-surfactants, were studied on isotropic region of pseudoternary-phase diagrams of nanoemulsion system composed of capmul MCM (CPM) as oil phase, Tween 80 as surfactant and water. Phase behaviour, globule size, transmission electron microscope (TEM) photographs and brain-targeting efficiency of quetiapine nanoemulsion were investigated. In vitro dissolution study of optimised nanoemulsion formulation, with mean diameter 144 ± 0.5 nm, showed more than twofold increase in drug release as compared with pure drug. According to results of in vivo tissue distribution study in Wistar rats, intranasal administration of QTP-loaded nanoemulsion had shorter T max compared with that of intravenous administration. Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion. The nanoemulsion system may be a promising strategy for brain-targeted delivery of QTP.

  12. Feasibility of abdominal plain film images in evaluation suspected drug smuggler

    Energy Technology Data Exchange (ETDEWEB)

    Sormaala, Markus J., E-mail: markus.sormaala@welho.com [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland); Salonen, Hanna-Mari, E-mail: hanna-mari.salonen@hus.fi [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland); Mattila, Ville M., E-mail: ville.mattila@uta.fi [Department of Orthopedic Surgery and Trauma, Tampere University Hospital, Tampere (Finland); Kivisaari, Arto, E-mail: arto.kivisaari@hus.fi [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland); Autti, Taina, E-mail: taina.autti@hus.fi [Medical Imaging Center, Helsinki University Central Hospital, Helsinki (Finland)

    2012-09-15

    Objective: Drug smuggling in the gastrointestinal tract has soared within the last 20 years. Though illegal substances in the gastrointestinal tract can be visualized with ultrasound, MRI and CT, the abdominal radiograph has by far remained the most frequently used way of detecting smuggled drugs. The purpose of the study was to evaluate the inter-radiologist interpretation error and the reliability of the abdominal radiograph in detecting smuggled drugs. Materials and methods: A total of 279 abdominal radiographs of suspected smugglers were classified by three radiologists as clearly positive or negative for drug smuggling. All available information about the cases was collected from the customs officers and police. Results: Out of these cases 203 (73%) were interpreted as negative and 35 (13%) as positive by all three radiologists. In 86% of the cases there was, therefore, an inter-radiological agreement in interpreting the images. In 41 (14%) cases, however, there was an inter-radiologist disagreement. Kappa-value for inter-observer variability was 0.70. Conclusions: In up to a seventh of the abdominal radiographs the interpretation can be challenging even for an experienced radiologist. False positive interpretation can lead to innocent passengers being detained in vain. As negatively interpreted images usually result in releasing of the suspect, there is no way of knowing how many false negative occur. This makes the abdominal radiograph a suboptimal examination, and low dose CT should be considered as the screening modality for gastrointestinal drug smugglers.

  13. Delayed cerebellar ataxia: A rare self limiting complication of plasmodium falciparum malaria

    Directory of Open Access Journals (Sweden)

    Amit K Sakaria

    2013-01-01

    Full Text Available The classic presentation of malaria with paroxysms of fever is seen only in 50-70% of the patients. The development of immunity, the increasing resistance to anti-malarial drugs, and the indiscriminate use of anti-malarial drugs have led to malaria with the presentation of unusual features. Cerebellar ataxia, extrapyramidal rigidity and various psychiatric symptoms have been described either as early manifestations of cerebral malaria or as a part of post malaria neurological syndrome. In this case report, we will discuss one such patient of falciparum malaria infection who developed midline cerebellar signs, and responded to anti-malarial treatment.

  14. Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations.

    Science.gov (United States)

    Gorgulho, Rita; Jacinto, Raquel; Lopes, Susana S; Pereira, Sofia A; Tranfield, Erin M; Martins, Gabriel G; Gualda, Emilio J; Derks, Rico J E; Correia, Ana C; Steenvoorden, Evelyne; Pintado, Petra; Mayboroda, Oleg A; Monteiro, Emilia C; Morello, Judit

    2018-01-01

    Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes ("donuts", "pancakes" and "rods"), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI.

  15. Design and in vitro evaluation of effervescent gastric floating drug delivery systems of propanolol HCl.

    Science.gov (United States)

    Meka, Venkata Srikanth; Songa, Ambedkar Sunil; Nali, Sreenivasa Rao; Battu, Janaki Ram; Kolapalli, Venkata Ramana Murthy

    2012-03-01

    Abstract. The purpose of this research was to develop and evaluate effervescent gastric floating tablets of propranolol HCl. The oral delivery of antihypertensive propranolol HCl was facilitated by preparing an effervescent floating dosage form which could increase its absorption in the stomach by increasing the drug's gastric residence time. In the present work, effervescent floating tablets were prepared with a hydrophilic carrier such as polyethylene oxide (PEO WSR N 60K and PEO WSR 303) as a release retarding agent and sodium bicarbonate as a gas generating agent. The prepared tablets were evaluated for all their physicochemical properties, in vitro buoyancy, drug release and rate order kinetics. From the results, P9 was selected as an optimized formulation based on their 12 h drug release, minimal floating lag time and maximum total floating time. The optimized formulation followed first order rate kinetics with erosion mechanism. The optimized formulation was characterized with FTIR studies and no interaction between the drug and the polymers were observed.

  16. Evaluation of hydroxypropyl methylcellulose matrix systems as swellable gastro-retentive drug delivery systems (GRDDS).

    Science.gov (United States)

    Matharu, Amol S; Motto, Michael G; Patel, Mahendra R; Simonelli, Anthony P; Dave, Rutesh H

    2011-01-01

    Utilizing gastro-retentive drug delivery systems (GRDDS) to increase absorption of weakly basic drugs by extending their transit time is a promising approach. Swellable systems were evaluated for this purpose. Such systems demonstrate dual mechanism of release-diffusion and erosion. GRDDS requires maintaining its dimensions, which demands diffusion as a predominant mechanism of release (Fickian). In this work, dypyridamole, a weakly basic drug, together with various grades of hydroxypropyl methylcellulose and different excipients were evaluated for release and swelling properties. Dissolution data were analyzed by curve fitting to various models to estimate predominant release mechanism. It was found that matrices containing a swellable diluent like microcrystalline cellulose demonstrated predominantly Fickian mechanism of release, whereas soluble diluents (lactose and mannitol) contributed to a mixed mechanism of release. Addition of copovidone increased the swelling and survivability, whereas sodium chloride altered the erosion behavior. A correlation between matrix weight loss and drug release was obtained, which further consolidated the analysis. Correlation for the soluble excipients was linear, whereas that for the swellable excipient was nonlinear, implying predominance of Fickian release mechanism for the latter. Hence, the selection of excipients can influence matrix survivability and release kinetics, which can be used for developing GRDDS. Copyright © 2010 Wiley-Liss, Inc. and the American Pharmacists Association

  17. Illicit drug exposure in patients evaluated for alleged child abuse and neglect.

    Science.gov (United States)

    Oral, Resmiye; Bayman, Levent; Assad, Abraham; Wibbenmeyer, Lucy; Buhrow, Jakob; Austin, Andrea; Bayman, Emine O

    2011-06-01

    Substantiation of drug exposure in cases with alleged maltreatment is important to provide proper treatment and services to these children and their families. A study performed at University of Iowa Hospitals and Clinics showed that 30% of pediatric patients with burn injuries, which were due to child maltreatment, were also exposed to illicit drugs. The children presenting to the University of Iowa Hospitals and Clinics with alleged maltreatment have been tested for illicit substances since 2004. The objective of this study was to analyze the presence of illicit drug exposure in the pediatric subpopulation admitted to pediatric inpatient and outpatient units for an evaluation for abuse/neglect. The study design is a retrospective chart review. Using hospital databases, every pediatric chart with a child abuse/neglect allegation was retrieved. The association between risk factors and clinical presentation and illicit drug test result was assessed. Excel and SAS were used for statistical analysis. Institutional review board approval was obtained to conduct this study. Six hundred sixty-five charts met study inclusion criteria for child abuse/neglect allegation. Of those, 232 cases were tested for illicit drugs between 2004 and 2008 per the testing protocol. Thirty-four cases (14.7%) tested positive on a drug test. Positive test rates based on clinical presentation were 28.6% (18/63) in neglect cases, 16.1% (5/31) in cases with soft tissue injuries, 14.3% (4/28) in burn injuries, 10.0% (2/20) in cases with sexual abuse, 7.1% (2/28) in cases with fractures, and 4.8% (3/62) in abusive head trauma cases. There were long-term abuse findings in 129 children (55.6%). Logistic regression analysis revealed that positive drug testing was most significantly associated with clinical symptoms suggesting physical abuse or neglect versus sexual abuse (odds ratio [OR] = 6.70; 95% confidence interval [CI], 1.26-35.49; P = 0.026), no or public health insurance versus those with

  18. A replication and methodological critique of the study "Evaluating drug trafficking on the Tor Network"

    DEFF Research Database (Denmark)

    Munksgaard, Rasmus; Demant, Jakob Johan; Branwen, Gwern

    2016-01-01

    The development of cryptomarkets has gained increasing attention from academics, including growing scientific literature on the distribution of illegal goods using cryptomarkets. Dolliver's 2015 article “Evaluating drug trafficking on the Tor Network: Silk Road 2, the Sequel” addresses this theme...... by evaluating drug trafficking on one of the most well-known cryptomarkets, Silk Road 2.0. The research on cryptomarkets in general—particularly in Dolliver's article—poses a number of new questions for methodologies. This commentary is structured around a replication of Dolliver's original study....... The replication study is not based on Dolliver's original dataset, but on a second dataset collected applying the same methodology. We have found that the results produced by Dolliver differ greatly from our replicated study. While a margin of error is to be expected, the inconsistencies we found are too great...

  19. Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

    Science.gov (United States)

    Paciotti, Giulio F; Zhao, Jielu; Cao, Shugeng; Brodie, Peggy J; Tamarkin, Lawrence; Huhta, Marja; Myer, Lonnie D; Friedman, Jay; Kingston, David G I

    2016-11-16

    The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented.

  20. Evaluation of parenteral drugs for anesthesia in the blue crab (Callinectes sapidus).

    Science.gov (United States)

    Quesada, Rolando J; Smith, Christopher D; Heard, Darryl J

    2011-06-01

    The objective of this study was to evaluate the efficacy and safety of several parenteral anesthetics in blue crabs (Callinectes sapidus). Thirty-one animals were administered one or more of the following drugs by injection into the hemolymph (i.v.) through an arthrodial membrane: etomidate, ketamine, lidocaine, pentobarbital, propofol, tiletamine-zolazepam, xylazine, and ketamine-xylazine. A subset of crabs received intracardiac ketamine. Etomidate had no effect. Lidocaine effects were ultrashort (sapidus as well as in other crab species.

  1. COMPARATIVE IN VITRO QUALITY EVALUATION OF SOME PARACETAMOL TABLETS, COMMERCIALLY AVAILABLE IN BANGLADESH DRUG MARKET

    OpenAIRE

    Jannatul Farhana, Md. Najem Uddin*, Md. Robiul Islam

    2018-01-01

    Paracetamol is a widely used non-prescription analgesic and antipyretic medicine. It is one of the most commonly used drugs worldwide with non-prescription sales exceeding 25 thousand million doses per year in the United States of America. The study was conducted to assess the comparative in-vitro quality control parameters through the evaluation of weight variation, hardness, friability, disintegration time and dissolution profile among the commercially available tablet brands of paracetamol...

  2. A useful tool for drug interaction evaluation: The University of Washington Metabolism and Transport Drug Interaction Database

    Directory of Open Access Journals (Sweden)

    Hachad Houda

    2010-10-01

    Full Text Available Abstract The Metabolism and Transport Drug Interaction Database (http://www.druginteractioninfo.org is a web-based research and analysis tool developed in the Department of Pharmaceutics at the University of Washington. The database has the largest manually curated collection of data related to drug interactions in humans. The tool integrates information from the literature, public repositories, reference textbooks, guideline documents, product prescribing labels and clinical review sections of new drug approval (NDA packages. The database's easy-to-use web portal offers tools for visualisation, reporting and filtering of information. The database helps scientists to mine kinetics information for drug-metabolising enzymes and transporters, to assess the extent of in vivo drug interaction studies, as well as case reports for drugs, therapeutic proteins, food products and herbal derivatives. This review provides a brief description of the database organisation, its search functionalities and examples of use.

  3. Evaluation of health plan member use of an online prescription drug price comparison tool.

    Science.gov (United States)

    Carroll, Norman V; Mitchell, Matthew P; Cannon, H Eric; York, Bryan W York; Oscar, Robert S

    2010-01-01

    Health plans have implemented tiered copayment systems to incentivize members to use less expensive medications. However, members need drug price information to make comparisons among therapeutic alternatives. Many health plans and pharmacy benefit management companies have implemented online prescription drug price comparison tools to provide such information. There has been little published evaluation of these tools. To evaluate use of an online price comparison tool- MyPharmacyTools (MPT)- by the measures of (a) the extent to which the tool was used, (b) changes in use over the first year after implementation, and (c) the types of members who were most likely to use the tool. Data were provided by a 500,000-member integrated health plan with approximately 156,250 enrolled families. The sample included only families with continuous eligibility for all members from July 1, 2006, through June 30, 2008; use of 1 of 7 common copayment structures; and use of the pharmacy benefit in every quarter of the study period. Data collected on each member, using pharmacy claims for the time period July 1, 2007, through June 30, 2008, included annual drug costs (total, out-of-pocket, plan-paid, and mail order) and number of unique drugs and unique generic drugs taken during the third quarter of 2007. Data collected also included whether the member had each of several selected chronic diseases (as inferred from drug claims for the third quarter of 2007) and demographics. Age, gender, and family size were taken from eligibility files. Other demographic data were imputed to members from the demographics of the ZIP code in which they resided. MPT was made available to members on July 1, 2007. Use of MPT was measured as the number of times members logged into the site for each quarter during the subsequent year. Statistical analyses were conducted at the family rather than at the individual level, and families were defined as users if any family member used MPT at least once during

  4. Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers.

    Science.gov (United States)

    Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina

    2016-01-01

    To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers. An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods. Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively. These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

  5. Evaluation of the potential for a pharmacokinetic drug-drug interaction between armodafinil and ziprasidone in healthy adults.

    Science.gov (United States)

    Darwish, Mona; Bond, Mary; Yang, Ronghua; Hellriegel, Edward T; Robertson, Philmore

    2014-10-01

    Armodafinil has been studied as adjunctive therapy for major depressive episodes associated with bipolar I disorder. This open-label, single-centre, 2-period study evaluated the effect of armodafinil, a moderate inducer of cytochrome-P450 (CYP) isoenzyme CYP3A4, on the pharmacokinetics and safety of ziprasidone, an atypical antipsychotic used to treat bipolar I disorder and metabolized in part by CYP3A4. Thirty-five healthy subjects received ziprasidone (20 mg) alone and after armodafinil pretreatment (titrated to 250 mg/day); of those, 25 were evaluable for pharmacokinetics. Pharmacokinetic parameters were derived from plasma concentrations of ziprasidone collected prior to and over the 48 h after each ziprasidone administration. Plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone, were also obtained after repeated daily dosing of armodafinil alone. Safety and tolerability were assessed. Systemic exposure to ziprasidone was similar following administration alone or after pretreatment with armodafinil, as assessed by mean peak plasma concentration (C max, 52.1 vs 50.4 ng/mL) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞, 544.6 vs 469.1 ng·h/mL). Geometric mean ratios of systemic exposure (ziprasidone alone: ziprasidone after pretreatment with armodafinil) were close to unity, with associated 90 % confidence intervals (CIs) within the range of 0.80-1.25 (C max, 0.97; 90 % CI, 0.87-1.08; AUC0-∞, 0.86; 90 % CI, 0.82-0.91). Adverse events were consistent with the known safety profiles of each agent. Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.

  6. The law on the streets: Evaluating the impact of mexico's drug decriminalization reform on drug possession arrests in Tijuana, Mexico.

    Science.gov (United States)

    Arredondo, J; Gaines, T; Manian, S; Vilalta, C; Bañuelos, A; Strathdee, S A; Beletsky, L

    2018-01-04

    In 2009, Mexican Federal Government enacted "narcomenudeo" reforms decriminalizing possession of small amounts of drugs, delegating prosecution of retail drug sales to the state courts, and mandating treatment diversion for habitual drug users. There has been insufficient effort to formally assess the decriminalization policy's population-level impact, despite mounting interest in analagous reforms across the globe. Using a dataset of municipal police incident reports, we examined patterns of drug possession, and violent and non-violent crime arrests between January 2009 and December 2014. A hierarchical panel data analysis with random effects was conducted to assess the impact of narcomenudeo's drug decriminalization provision. The reforms had no significant impact on the number of drug possession or violent crime arrests, after controlling for other variables (e.g. time trends, electoral cycles, and precinct-level socioeconomic factors). Time periods directly preceding local elections were observed to be statistically associated with elevated arrest volume. Analysis of police statistics parallel prior findings that Mexico's reform decriminalizing small amounts of drugs does not appear to have significantly shifted drug law enforcement in Tijuana. More research is required to fully understand the policy transformation process for drug decriminalization and other structural interventions in Mexico and similar regional and international efforts. Observed relationship between policing and political cycles echo associations in other settings whereby law-and-order activities increase during mayoral electoral campaigns. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Menard Sandie

    2012-04-01

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

  8. Efficacy evaluation of the school program Unplugged for drug use prevention among Brazilian adolescents

    Directory of Open Access Journals (Sweden)

    Zila M. Sanchez

    2016-11-01

    Full Text Available Abstract Background Most Brazilian schools do not have a continuous program for drug use prevention and do not conduct culturally adapted activities for that purpose. This study evaluated the impact of the Unplugged program on drug use prevention among children and adolescents in public middle schools of Brazil. Methods A non-randomized controlled trial was conducted in 2013 with 2185 students in 16 public schools from 3 Brazilian cities. The intervention group attended 12 weekly classes of the Unplugged program for drug use prevention, and the control group did not attend to any school prevention programs in the same year. Multilevel analyses were used to evaluate temporal and between group changes in the consumption of each drug. Results The study suggested that there was no evidence that Unplugged effected 11- to 12-year-old students. However, the program seemed to stimulate a decrease in recent marijuana use (transition from use to non-use in 85.7% of intervention cases and 28.6% of control cases, OR = 17.5, p = 0.039 among 13- to 15-year-old students. In addition, students in this age range who received the Unplugged program had similar drug consumption levels to those observed before the program began. However, students in the control group presented a significant tendency to increase marijuana use and binge drinking. Conclusions This study adds to the evidence of program efficacy among Brazilian middle school students by presenting marginal effects on binge drinking and marijuana use. An 18-month randomized controlled trial is recommended for a future study.

  9. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

    Science.gov (United States)

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

    2015-06-01

    Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

  10. Drug coated microneedles for minimally-invasive treatment of oral carcinomas: development and in vitro evaluation.

    Science.gov (United States)

    Ma, Yunzhe; Boese, Seth E; Luo, Zhen; Nitin, Nitin; Gill, Harvinder S

    2015-04-01

    Treatment of recurring oral cancers is challenging as common surgical approaches are not feasible for these patients. In addition, these patients do not respond well to systemic chemotherapy. Localized intratumoral injection of anti-cancer drugs is considered to be an attractive alternative treatment approach for these patients. However, conventional hypodermic injections result in poor distribution of the drug in the tumor and leakage of the drug from the injection site to systemic circulation, in addition to causing pain to the patient. The objective of this study was to develop coated microneedles as a novel device for direct and minimally invasive intratumoral delivery of anti-cancer drugs. Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulating doxorubicin (DOX) were prepared and coated on inplane (1D) microneedles. Microscopic evaluation of 3D tissue phantoms and porcine cadaver buccal tissues that were treated with 1D microneedle arrays coated with DOX-PLGA nanoparticles demonstrated that DOX could diffuse both laterally and vertically in to the tissues and produced cellular cytotoxicity. Out of plane (2D) microneedle arrays measuring 1 cm x 1 cm with 57 microneedles coated with free DOX could produce uniform distribution of DOX in a porcine cadaver buccal tissue up to a depth greater than 3 mm. Hypodermic injection of different volumes in to a porcine buccal tissue confirmed significant leakage of the injected volume (about 25% of the injected 80 μl). In summary, this study demonstrates that drug coated microneedles is an attractive microscale device that can uniformly and effectively deliver drugs to localized oral cancers. This microscale device has potential to impact the treatment of oral cancer patients.

  11. Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

    Energy Technology Data Exchange (ETDEWEB)

    Pentak, Danuta, E-mail: danuta.pentak@us.edu.pl [University of Silesia, Department of Materials Chemistry and Chemical Technology, Institute of Chemistry (Poland)

    2016-05-15

    Vesicle size and composition are a critical parameter for determining the circulation half-life of liposomes. Size influences the degree of drug encapsulation in liposomes. The geometry, size, and properties of liposomes in an aqueous environment have to be described to enable potential applications of liposome systems as drug carriers. The characteristics of multiple thermotropic phase transitions are also an important consideration in liposomes used for analytical and bioanalytical purposes. The aim of this study was to evaluate the physicochemical properties of liposomes which accommodate hydrophilic and amphiphilic drugs used in cancer therapy. The studied liposomes were prepared with the involvement of the modified reverse-phase evaporation method (mREV). The prepared liposomes had a diameter of 70–150 nm. The analyzed compounds were 1-β-d-arabinofuranosylcytosine, cyclophosphamide, and ifosfamide. In literature, there is no information about simultaneous incorporation of cytarabine, ifosfamide, and cyclophosphamide, in spite of the fact that these drugs have been used for more than 30 years. A combination of the examined drugs is used in CODOX-M/IVAC therapy. CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) is one of the currently preferred intensive-dose chemotherapy regimens for Burkitt lymphoma (BL). The present research demonstrates the pioneering studies of incorporation of ifosfamide into liposome vesicles, location of and competition between the analyzed drugs and liposome vesicles. The applied methods were nuclear magnetic resonance (NMR), atomic force microscopy (AFM), differential scanning calorimetry (DSC).Graphical Abstract.

  12. Evaluation of a needle social marketing strategy to control HIV among injecting drug users in China.

    Science.gov (United States)

    Wu, Zunyou; Luo, Wei; Sullivan, Sheena G; Rou, Keming; Lin, Peng; Liu, Wei; Ming, Zhongqiang

    2007-12-01

    To evaluate the effectiveness of a needle social marketing strategy to reduce needle sharing and hepatitis C Virus (HCV)/HIV transmission among injecting drug users (IDU) in China. Two-armed, prospective, community-randomized prevention trial. Four counties/townships in Guangxi and Guangdong provinces; one randomized to intervention the other to control in each province. Injecting drug users: 823 (443 intervention, 382 control) at baseline and 852 (415 intervention, 407 control) at the second cross-sectional survey 12 months later. A needle social marketing programme, including promotion of safe injection norms and increased access to clean needles over a 12 month period. Cross sectional surveys at baseline and follow-up compared changes in drug using behaviours and HIV and HCV rates in the intervention and control communities. Needle sharing behaviours were similar in the two groups at baseline (68.4 vs. 67.8%), and dropped significantly to 35.3% in the intervention community and remained relatively stable in the control community (62.3%; P marketing can reduce risky injecting behaviour and HIV/HCV transmission among injecting drug users in China and should be expanded.

  13. Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds.

    Science.gov (United States)

    Martin, Baptiste; Brouillet, Fabien; Franceschi, Sophie; Perez, Emile

    2017-05-01

    The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.

  14. Evaluation of the functionality of biodegradable polymeric platforms for drug delivery systems

    Energy Technology Data Exchange (ETDEWEB)

    Gioti, M., E-mail: mgiot@physics.auth.gr; Karagkiozaki, V.; Basgiouraki, A.; Karagiannidis, P.G.; Logothetidis, S.

    2013-09-15

    We present the development of a drug-loaded triple-layer platform consisting of thin film biodegradable polymers, in a properly designed form for the desired gradual degradation. Poly(DL-lactide-co-glycolide) (PLGA (65:35), PLGA (75:25)) and polycaprolactone (PCL) were grown by spin coating technique, to synthesize the platforms with the order PCL/PLGA (75:25)/PLGA (65:35) that determine their degradation rates. The outer PLGA (65:35) layer was loaded with dipyridamole, an antiplatelet drug. Spectroscopic ellipsometry (SE) in the Vis-far UV range was used to determine the nanostructure, as well as the content of the incorporated drug in the as-grown platforms. In situ and real-time SE measurements were carried out using a liquid cell for the dynamic evaluation of the fibrinogen and albumin protein adsorption processes. Atomic force microscopy studies justified the SE results concerning the nanopores formation in the polymeric platforms, and the dominant adsorption mechanisms of the proteins, which were defined by the drug incorporation in the platforms.

  15. An in-vivo evaluation of a MEMS drug delivery device using Kunming mice model.

    Science.gov (United States)

    Liu, Yaqian; Song, Peiyi; Liu, Jianwei; Tng, Danny Jian Hang; Hu, Rui; Chen, Hongyan; Hu, Yazhuo; Tan, Cher Heng; Wang, Jianhua; Liu, Jing; Ye, Ling; Yong, Ken-Tye

    2015-02-01

    The use of MEMS implantable drug delivery pump device enables one to program the desired drug delivery profile in the device for individualized medicine treatment to patients. In this study, a MEMS drug delivery device is prepared and employed for in vivo applications. 12 devices are implanted subcutaneously into Kunming mice for evaluating their long term biocompatibility and drug-delivery efficiency in vivo. All the mice survived after device implantation surgery procedures. Histological analysis result reveals a normal wound healing progression within the tissues-to-device contact areas. Serum analysis shows that all measured factors are within normal ranges and do not indicate any adverse responses associated with the implanted device. Phenylephrine formulation is chosen and delivered to the abdominal cavity of the mice by using either the implanted MEMS device (experimental group) or the syringe injection method (control group). Both groups show that they are able to precisely control and manipulate the increment rate of blood pressure in the small animals. Our result strongly suggests that the developed refillable implantable MEMS devices will serve as a viable option for future individualized medicine applications such as glaucoma, HIV-dementia and diabetes therapy.

  16. In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery

    Science.gov (United States)

    Rahimi, Maham; Wadajkar, Aniket; Subramanian, Khaushik; Yousef, Monet; Cui, Weina; Hsieh, Jer-Tsong; Nguyen, Kytai

    2010-01-01

    Previously uncharacterized poly(N-isopropylacrylamide-acrylamide-allylamine)-coated magnetic nanoparticles (MNPs) were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Properties of these nanoparticles such as size, biocompatibility, drug loading efficiency, and drug release kinetics were evaluated in vitro for targeted and controlled drug delivery. Spherical core-shell nanoparticles with a diameter of 100 nm showed significantly lower systemic toxicity than did bare MNPs, as well as doxorubicin encapsulation efficiency of 72%, and significantly higher doxorubicin release at 41°C compared with 37°C, demonstrating their temperature sensitivity. Released drugs were also active in destroying prostate cancer cells (JHU31). Furthermore, the nanoparticle uptake by JHU31 cells was dependent on dose and incubation time, reaching saturation at 500 μg/mL and 4 hours, respectively. In addition, magnetic resonance imaging capabilities of the particles were observed using agarose platforms containing cells incubated with nanoparticles. Future work includes investigation of targeting capability and effectiveness of these nanoparticles in vivo using animal models. PMID:20172050

  17. New anticoagulant drugs versus warfarin in atrial fibrillation: economic evaluation and cost-effectiveness analysis

    Directory of Open Access Journals (Sweden)

    Mauro Silingardi

    2013-12-01

    Full Text Available Health care resources available for medical procedures, including pharmaceuticals, are limited worldwide. Health economic evidence is now accepted as an essential component of health technology appraisal, realizing the importance of value for money considerations for a more efficient (cost-effective prescribing. Regulatory agencies in more and more countries perform economic evaluation and cost-effectiveness analysis in order to decide about reimbursement of a new and almost always more expensive drug. Pharmacoeconomy is now acknowledged as a science. Cost-effective analysis is just one of its approaches, measuring cost in money and benefit in terms of Quality Adjusted Life Year, a new outcome measure which combines quantity/quality of additional life-years gained with the new drug/technology. A growing body of pharmacoeconomic evidence about new anticoagulant drugs (dabigatran, rivaroxaban, apixaban for stroke prevention in atrial fibrillation is now available. Most of this evidence comes from the National Institute of Health and Clinical Excellence (NICE in the United Kingdom, the most referenced regulatory agency in the world. Compared to current standard therapies (warfarin, dabigatran, rivaroxaban and apixaban are cost-effective treatments for the whole population of patients with atrial fibrillation, independently of poor/good international normalized ratio control (time in therapeutic range and risk stratification for stroke (CHADS2 score. Significant innovation and the lower rate of intracranial hemorrhage/hemorrhagic stroke coupled with the new drugs are the key drivers of these results.

  18. Attenuation of Plasmodium falciparum in vitro drug resistance phenotype following culture adaptation compared to fresh clinical isolates in Cambodia.

    Science.gov (United States)

    Chaorattanakawee, Suwanna; Lanteri, Charlotte A; Sundrakes, Siratchana; Yingyuen, Kritsanai; Gosi, Panita; Chanarat, Nitima; Wongarunkochakorn, Saowaluk; Buathong, Nillawan; Chann, Soklyda; Kuntawunginn, Worachet; Arsanok, Montri; Lin, Jessica T; Juliano, Jonathan J; Tyner, Stuart D; Char, Mengchuor; Lon, Chanthap; Saunders, David L

    2015-12-02

    There is currently no standardized approach for assessing in vitro anti-malarial drug susceptibility. Potential alterations in drug susceptibility results between fresh immediate ex vivo (IEV) and cryopreserved culture-adapted (CCA) Plasmodium falciparum isolates, as well as changes in parasite genotype during culture adaptation were investigated. The 50 % inhibitory concentration (IC50) of 12 P. falciparum isolates from Cambodia against a panel of commonly used drugs were compared using both IEV and CCA. Results were compared using both histidine-rich protein-2 ELISA (HRP-2) and SYBR-Green I fluorescence methods. Molecular genotyping and amplicon deep sequencing were also used to compare multiplicity of infection and genetic polymophisms in fresh versus culture-adapted isolates. IC50 for culture-adapted specimens were significantly lower compared to the original fresh isolates for both HRP-2 and SYBR-Green I assays, with greater than a 50 % decline for the majority of drug-assay combinations. There were correlations between IC50s from IEV and CCA for most drugs assays. Infections were nearly all monoclonal, with little or no change in merozoite surface protein 1 (MSP1), MSP2, glutamate-rich protein (GLURP) or apical membrane antigen 1 (AMA1) polymorphisms, nor differences in P. falciparum multidrug resistance 1 gene (PfMDR1) copy number or single nucleotide polymorphisms following culture adaptation. The overall IC50 reduction combined with the correlation between fresh isolates and culture-adapted drug susceptibility assays suggests the utility of both approaches, as long as there is consistency of method, and remaining mindful of possible attenuation of resistance phenotype occurring in culture. Further study should be done in higher transmission settings where polyclonal infections are prevalent.

  19. Medication Reconciliation and Evaluation of Drug Discrepancies by a Pharmacist in Omid Hospital, Lali, Khouzestan

    Directory of Open Access Journals (Sweden)

    Leila Kouti

    2017-09-01

    Full Text Available Background: Medication discrepancies occur at the time of medicine prescription in inpatient and outpatient settings, especially at patient transfer and discharge. Pharmacists can prevent these medication errors by reconciliation of the patients’ medications. In this study, medication discrepancies of the only hospital of a small town are assessed by a pharmacist.Methods:A medication reconciliation form was designed to fully record all patients’ drug history and current therapies. All admitted patients during a six month interval were evaluated by a pharmacist and their medical records were compared to the detailed data form.Results:150 admitted patients were evaluated in this study from September 2015 to February 2016. 51% of the patients were male and 49% female. 56% of the patients had medication discrepancies when discharged. Interestingly none of the patients had documented drug history in their medical records.Conclusion:More than half of the patients developed a medication discrepancy at the time of discharge. We think that a drug review of the patients at the time of admission and discharge and establishing medication reconciliation processes may be helpful in improvement of health care.

  20. Comparative evaluation of polymersome versus micelle structures as vehicles for the controlled release of drugs

    Energy Technology Data Exchange (ETDEWEB)

    Alibolandi, Mona [Mashhad University of Medical Sciences, Biotechnology Research Center, School of Pharmacy (Iran, Islamic Republic of); Ramezani, Mohammad; Abnous, Khalil [Mashhad University of Medical Sciences, Pharmaceutical Research Center, School of Pharmacy (Iran, Islamic Republic of); Sadeghi, Fatemeh, E-mail: sadeghif@mums.ac.ir [Mashhad University of Medical Sciences, Targeted Drug Delivery Research Center, School of Pharmacy (Iran, Islamic Republic of); Hadizadeh, Farzin, E-mail: hadizadehf@mums.ac.ir [Mashhad University of Medical Sciences, Biotechnology Research Center, School of Pharmacy (Iran, Islamic Republic of)

    2015-02-15

    Di-block copolymers composed of two biocompatible polymers, poly(ethylene glycol) and poly(d,l-lactide), were synthesized by ring-opening polymerization for the preparation of doxorubicin-loaded self-assembled nanostructures, including polymeric vesicles (polymersomes) and micelles. The capability and stability of the nanostructures prepared for the controlled release of DOX are discussed in this paper. The in vitro drug release at 37 °C was evaluated up to 6 days at pH 7.4 and 5.5 and in the presence of 50 % FBS. The cellular uptake and cytotoxicity effect of both formulations were also evaluated in the MCF-7 cell line. The SEM and AFM images confirmed the hollow spherical structure of the polymersomes and the solid round structures of the micelles. The TEM results also revealed the uniformity in size and shape of the drug-loaded micelle and polymersome nanostructures. The DOX-loaded micelles and polymersomes presented efficient anticancer performance, as verified by flow cytometry and MTT assay tests. The most important finding of this study is that the prepared nanopolymersomes presented significant increases in the doxorubicin encapsulation efficiency and the stability of the formulation in comparison with the micelle formulation. In vitro studies revealed that polymersomes may be stable in the blood circulation and meet the requirements for an effective drug delivery system.

  1. Evaluation of the drug solubility and rush ageing on drug release performance of various model drugs from the modified release polyethylene oxide matrix tablets.

    Science.gov (United States)

    Shojaee, Saeed; Nokhodchi, Ali; Maniruzzaman, Mohammed

    2017-02-01

    Hydrophilic matrix systems are currently some of the most widely used drug delivery systems for controlled-release oral dosage forms. Amongst a variety of polymers, polyethylene oxide (PEO) is considered an important material used in pharmaceutical formulations. As PEO is sensitive to thermal oxidation, it is susceptible to free radical oxidative attack. The aim of this study was to investigate the stability of PEO based formulations containing different model drugs with different water solubility, namely propranolol HCl, theophylline and zonisamide. Both polyox matrices 750 and 303 grade were used as model carriers for the manufacture of tablets stored at 40 °C. The results of the present study suggest that the drug release from the matrix was affected by the length of storage conditions, solubility of drugs and the molecular weight of the polymers. Generally, increased drug release rates were prevalent in soluble drug formulations (propranolol) when stored at the elevated temperature (40 °C). In contrast, it was not observed with semi soluble (theophylline) and poorly soluble (zonisamide) drugs especially when formulated with PEO 303 polymer. This indicates that the main parameters controlling the drug release from fresh polyox matrices are the solubility of the drug in the dissolution medium and the molecular weight of the polymer. DSC traces indicated that that there was a big difference in the enthalpy and melting points of fresh and aged PEO samples containing propranolol, whereas the melting point of the aged polyox samples containing theophylline and zonisamide was unaffected. Graphical abstract ᅟ.

  2. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Kejian, E-mail: kejian.wang.bio@gmail.com [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai (China); Weng, Zuquan [Japan National Institute of Occupational Safety and Health, Kawasaki (Japan); Sun, Liya [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai (China); Sun, Jiazhi; Zhou, Shu-Feng [Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL (United States); He, Lin, E-mail: helin@Bio-X.com [Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai (China)

    2015-02-13

    Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. In the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.

  3. Evaluation of chemically modified hydrophobic sago starch as a carrier for controlled drug delivery.

    Science.gov (United States)

    Singh, Akhilesh Vikram; Nath, Lila Kanta

    2013-04-01

    The present investigation deals with the development of controlled release tablets of lamivudine using acetylated sago starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated sago starch was tested for acute toxicity and drug-excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, % friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in the case of higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion processes. There was a significant difference in the pharmacokinetic parameters (T max, C max, AUC, V d, T 1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir® which proves the controlled release property of acetylated sago starch.

  4. Evaluation of anti-GERD activity of gastro retentive drug delivery system of itopride hydrochloride.

    Science.gov (United States)

    Satapathy, Trilochan; Panda, Prasana K; Goyal, Amit K; Rath, Goutam

    2010-08-01

    The present work describes the formulation and evaluation of the gastroretentive system of Itopride hydrochloride. In this research, we have formulated floating hydrogel-based microspheres employing calcium carbonate (CaCO(3)) as a gas forming agent dispersed in alginate matrix. In vitro characterizations such as drug content, particle size, and drug release were carried out. GI motility was determined by administration of charcoal meal to rats. Results demonstrated that prepared microspheres were spherical in shape with smooth surface, good loading efficiency, and excellent buoyancy. The gastro retentive dosage form of itiopride demonstrated significant antacid, anti-ulcer, and anti-GERD activity after 12 hours in comparison with the conventional dosage form.

  5. Synthesis and Biological Evaluation of 2,4-Diaminopyrimidine-Based Antifolate Drugs against Bacillus anthracis

    Directory of Open Access Journals (Sweden)

    Baskar Nammalwar

    2014-03-01

    Full Text Available Due to the innate ability of bacteria to develop resistance to available antibiotics, there is a critical need to develop new agents to treat more resilient strains. As a continuation of our research in this area, we have synthesized a series of racemic 2,4-diaminopyrimidine-based drug candidates, and evaluated them against Bacillus anthracis. The structures are comprised of a 2,4-diaminopyrimidine ring, a 3,4-dimethoxybenzyl ring, and an N-acryloyl-substituted 1,2-dihydrophthalazine ring. Various changes were made at the C1 stereocenter of the dihydrophthalazine moiety in the structure, and the biological activity was assessed by measurement of the MIC and Ki values to identify the most potent drug candidate.

  6. Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance

    DEFF Research Database (Denmark)

    Gani, Osman A B S M; Narayanan, Dilip; Engh, Richard A

    2013-01-01

    Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space...... for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. 'Dual active' inhibitors against both targets were grouped together with inactive ligands chosen from different...... component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus...

  7. ASSESSING THE PATTERN OF DRUG USE AMONG PREGNANT WOMEN AND EVALUATING THE IMPACT OF COUNSELLING ON MEDICATION ADHERENCE AMONG THEM

    OpenAIRE

    Banda Shalini Reddy; NeelkantReddy Patil; Hinchageri S. S; Swarna kamala

    2011-01-01

    In the present study an attempt is made to assess the pattern of drug use among pregnant women and to evaluate the impact of counseling on medication adherence by providing patient education regarding pregnancy. During the study period pregnant women were enrolled in the study after obtaining consent from them. The prescriptions containing atleast one drug were analyzed and the drugs prescribed were classified according to their pharmacological class. Analysis of prescription patterns did not...

  8. The American Medicine Chest Challenge: Evaluation of a Drug Take-Back and Disposal Campaign.

    Science.gov (United States)

    Yanovitzky, Itzhak

    2016-07-01

    Prescription drug take-back programs provide a safe and convenient way to dispose of expired, unwanted, or unused medications that people store in homes, thus limiting the potential misuse of prescription drugs. This study evaluated public response to a social marketing campaign promoting a community-based drug take-back program, the American Medicine Chest Challenge. A telephone survey was conducted with a representative sample of adults in New Jersey (N = 906) 2 weeks following the conclusion of the statewide collection day event in November 2010. The survey assessed public exposure to the campaign and the extent to which it is associated with public perceptions and behaviors the campaign was designed to influence. The campaign, which relied heavily on community channels for the dissemination of messages, was able to reach directly more than 60% of its target audience. When potential confounders were controlled for, campaign exposure was a strong predictor of a respondent having one or more conversations with others about medicine disposal (odds ratio [OR] = 2.4, 95% CI [1.5, 3.6]); actually disposing of expired, unwanted, or unused medicine in a collection site (OR = 2.14, 95% CI [1.15, 3.9]); and talking to kids about the dangers of prescription drug abuse (OR = 1.65, 95% CI [1.1, 2.45])-all of which were exclusively promoted through the campaign. This case illustrates the potential efficacy of community-based prevention marketing efforts to stimulate community discourse regarding the dangers of prescription drug misuse and to decrease the availability of expired, unwanted, or unused medicine in the community.

  9. Drug solubilization and in vitro toxicity evaluation of lipoamino acid surfactants.

    Science.gov (United States)

    Ménard, Nathalie; Tsapis, Nicolas; Poirier, Cécile; Arnauld, Thomas; Moine, Laurence; Lefoulon, François; Péan, Jean-Manuel; Fattal, Elias

    2012-02-28

    To improve solubilization of a water insoluble anticancer drug, novel surfactants were synthesized. All surfactants derived from lysine, with a so-called nitrilo triacetic acid (NTA) polar head, and differed from the length and saturation degree of their hydrophobic moieties: C19:0-NTA, C20:4-NTA, C25:0-NTA and C25:4-NTA. Self-assembling properties and critical micellar concentration (CMC) values were determined using pyrene fluorescence and cytotoxicity using MTT and LDH assays on endothelial cells. Surfactant haemolytic activity and drug solubilization capacity were also evaluated. All surfactants self-assemble with low CMC values from 0.012 to 0.430 mg/mL. Cytotoxicity assays showed that C20:4-NTA and C25:0-NTA were less cytotoxic than polysorbate 80. Unsaturations and alkane chain length have a marked influence on toxicity. Saturated surfactants had a similar haemolytic activity, explained by their low CMC values and the linear configuration of their hydrophobic tail. C20:4-NTA and C25:4-NTA were less haemolytic than polysorbate 80. Furthermore, C19:0-NTA, C25:0-NTA and C25:4-NTA increased drug solubility from <0.15 μg/mL up to 7 mg/mL, with 46% (w/w) drug loading, due to their linear and flexible hydrophobic chain configuration, as evidenced by molecular modelling. Although these solubilizers are promising, a compromise between drug solubilization and toxicity remains to be found. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics.

    Science.gov (United States)

    Aceves Baldó, Pau; Anzures-Cabrera, Judith; Bentley, Darren

    2013-03-01

    To assess the effect of the UGT inhibitor probenecid on the pharmacokinetics of dalcetrapib, an investigational drug whose pharmacologically active thiol form undergoes glucuronidation (fm UGT ≥ 0.25). A two-way crossover study in 20 healthy subjects. Subjects received a single 600 mg dose of dalcetrapib with or without probenecid (500 mg 4 times daily for 6 days). AUC∞ and Cmax of dalcetrapib thiol were increased by 14% and 21%, respectively, by co-administration of probenecid. This case study illustrates the difficulty in predicting clinically relevant drug-drug interactions for UGT substrates based only on the fraction metabolized by glucuronidation.

  11. Efficacy of sulfadoxine-pyrimethamine for the treatment of ...

    African Journals Online (AJOL)

    pyrimethamine for the treatment of uncomplicated falciparum malaria to enable evidence based policy decisions. Design: The study used the new WHO (2003) protocol for the assessment of the therapeutic efficacy of anti-malarial drugs. Setting: Eleven ...

  12. Evaluation of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs according to the latest classification.

    Science.gov (United States)

    Demir, S; Olgac, M; Unal, D; Gelincik, A; Colakoglu, B; Buyukozturk, S

    2015-11-01

    The consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) proposed by the European Network for Drug Allergy (ENDA) interest group (2011) was revised in 2013. We aimed to evaluate the usability of the latest NSAID hypersensitivity classification of ENDA. A total of 370 patients with a history of hypersensitivity reactions to NSAIDs among the 1250 outpatients referred for suspected drug allergy between July 2013 and June 2014 were evaluated, and 308 patients who were confirmed as having NSAID hypersensitivity were included in this study. After confirming the diagnosis, a single-blind placebo-controlled drug provocation test was performed with aspirin or diclofenac to categorize the patients according to the ENDA classification. The reactions not meeting the ENDA classification criteria were grouped as blended reactions. Among the 308 patients (224 female, mean age 42.12 ± 13.24), the leading cause of hypersensitivity reactions was metamizol (30.5%) followed by aspirin (30.2%). The most common NSAID hypersensitivity subgroup was SNIUAA (46.4%) and the least common type was SNIDR (1.6%). Cross-reactivity was identified in 50.3% of the patients. In five patients (1.6%), the hypersensitivity reactions to NSAIDs did not meet the ENDA classification: Three patients experienced anaphylaxis with different NSAIDs, one patient encountered anaphylaxis with one NSAID and urticaria with other NSAIDs, and the last patient had angioedema with different NSAIDs. The latest ENDA classification for NSAID hypersensitivity is generally a practical and useful instrument for clinicians. We only point out that anaphylaxis with different NSAIDs can be seen in a small group of patients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Implementing a pharmacovigilance program to evaluate cutaneous adverse drug reactions in an antiretroviral access program

    Science.gov (United States)

    Mudzviti, Tinashe; Sibanda, Marvelous; Gavi, Samuel; Maponga, Charles Chiedza; Morse, Gene D.

    2012-01-01

    Background Cutaneous adverse drug reactions (cADRs) can cause significant morbidity and distress in patients especially in the HIV infected population on antiretroviral therapy. Adverse Drug Reaction monitoring and ascertaining causality in resource limited settings still remains a challenge. This study was carried out to evaluate causality and measure incidence of cADRs in HIV infected patients on highly active antiretroviral therapy. The study was also designed to test a 3-step approach in the monitoring and evaluation of ADRs in resource limited settings. Methodology A retrospective patient medical records review was carried out at the Parirenyatwa Family Care Centre, (Harare, Zimbabwe). Cases of cADRs were reported to the Medicines Control Authority of Zimbabwe (Drug regulating body in Zimbabwe) for assessment and causality classification. Results Two hundred and twenty-one patient records were randomly selected and reviewed to determine if any diagnosis of cADRs was made by clinicians. Causality assessment revealed 13.1% of cADRs which were due to an offending agent in the antiretroviral therapy against an initial incidence of 17.6% which had been determined by the physicians. Conclusions cADRs had an incidence of 13.1% within the population under study due to non nucleoside reverse transcriptase inhibitors (NNRTIs). Most reactions were due to the NNRTIs which contributed 72.4 % of all cADRs. A panel of experts from the drug regulatory authority can be used as an implementation based mechanism in ascertaining causality objectively in settings where resources are constrained. PMID:23277506

  14. In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.

    Science.gov (United States)

    Pak, Y Anne; Long, Amanda J; Annes, William F; Witcher, Jennifer W; Knadler, Mary Pat; Ayan-Oshodi, Mosun A; Mitchell, Malcolm I; Leese, Phillip; Hillgren, Kathleen M

    2017-02-01

    Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with K m value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC 50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter. Copyright © 2017 by The Author(s).

  15. [Evaluation of potential drug interactions in primary health care prescriptions in Vitória da Conquista, Bahia (Brazil)].

    Science.gov (United States)

    Leão, Danyllo Fábio Lessa; de Moura, Cristiano Soares; de Medeiros, Danielle Souto

    2014-01-01

    Drug interactions are risk factors for the occurrence of adverse drug reactions. The risk for drug interactions includes factors related to prescription that are intrinsic to the patient. This study sought to evaluate the potential drug interactions in primary care prescriptions in Vitória da Conquista in the state of Bahia to fill the knowledge gap on this topic in Brazil. Information about several variables derived from the primary health care prescriptions was collected and drug interactions were evaluated based on information from Medscape and Micromedex(R) databases. Polypharmacy frequency and its association with the occurrence of drug interactions were also evaluated. Results revealed a 48,9% frequency of drug interactions, 74,9% of moderate or greater severity, 8,6% of prescriptions in polypharmacy that in the chi-square test showed a positive association with the occurrence of drug interactions (p Conquista in the state of Bahia showed a high frequency of drug interactions, however it is necessary to analyze other risk factors for their occurrence at this level of health care.

  16. Challenges in evaluating cancer as a clinical outcome in postapproval studies of drug safety.

    Science.gov (United States)

    Pinheiro, Simone P; Rivera, Donna R; Graham, David J; Freedman, Andrew N; Major, Jacqueline M; Penberthy, Lynne; Levenson, Mark; Bradley, Marie C; Wong, Hui-Lee; Ouellet-Hellstrom, Rita

    2016-11-01

    Pharmaceuticals approved in the United States are largely not known human carcinogens. However, cancer signals associated with pharmaceuticals may be hypothesized or arise after product approval. There are many study designs that can be used to evaluate cancer as an outcome in the postapproval setting. Because prospective systematic collection of cancer outcomes from a large number of individuals may be lengthy, expensive, and challenging, leveraging data from large existing databases are an integral approach. Such studies have the capability to evaluate the clinical experience of a large number of individuals, yet there are unique methodological challenges involved in their use to evaluate cancer outcomes. To discuss methodological challenges and potential solutions, the Food and Drug Administration and the National Cancer Institute convened a two-day public meeting in 2014. This commentary summarizes the most salient issues discussed at the meeting. Published by Elsevier Inc.

  17. A study on regional comprehensive performance evaluation indicator system of rational use of drugs

    Directory of Open Access Journals (Sweden)

    Sun Tongda

    2017-01-01

    Full Text Available The current research presents the design of a 4-degree-3-level performance evaluation indicator system of rational use of drugs for health care institutions accord with the Balanced Score Card (BSC method. Financial index, patient index, professional process index, and development and blazing new trials index are adopted in the light of scientific, guiding, operable and generalizable principles. The index weight is based on the analytic hierarchy process, and comprehensive performance evaluation indicators are calculated by a linear integrated weighting method. Its practical application in 21 state-run health care institutions in Ningbo, from 2008 to 2012, has arrived at the finding that the comprehensive performance evaluation indicator system offers a scientific, practical and effective performance management quantification and is thus worth popularizing.

  18. Diagnostic evaluation and risk factors for drug allergies in children: from clinical history to skin and challenge tests.

    Science.gov (United States)

    Arikoglu, Tugba; Aslan, Gulen; Batmaz, Sehra Birgul; Eskandari, Gulcin; Helvaci, Ilter; Kuyucu, Semanur

    2015-08-01

    Parent or self-reported drug allergy claims frequently overestimate the real incidence of hypersensitivity reactions. A detailed and algorithmic diagnostic evaluation of drug reactions may allow a proper diagnosis. The aim of this study was to determine the confirmation rates and risk factors for confirmed allergic drug reactions in children. Mersin University Hospital in Turkey. The study consisted of children between ages of 8 months and 18 years with the history of suspected drug allergy as reported by the clinician or the patients. Parents were interviewed by a clinician to complete questionnaires that included questions about demographic data and characteristics of index drug reaction. Immediate reactions (IRs) were assessed with immediate-reading skin prick (SPT) and intradermal tests (IDT). Nonimmediate reactions (NIRs) were assessed with SPT, both early and delayed reading of IDT and patch tests. In case of negative skin tests, drug provocation tests were performed. The possible risk factors for confirmed drug allergy in univariate analysis (p Parent or self-reported drug allergy should be evaluated with a standardized diagnostic work-up before strict prohibitions are made. In addition, family and personal histories of drug allergy were significant risk factors related to allergic drug reactions in children.

  19. DRUG COURTS: Better DOJ Data Collection and Evaluation Efforts Needed to Measure Impact of Drug Court Programs

    National Research Council Canada - National Science Library

    2002-01-01

    ...; and prescribe sanctions and rewards as appropriate in collaboration with prosecutors, defense attorneys, treatment providers, and others. While some basic requirements are set at the federal level, most decisions about how a drug court operates are left to local jurisdictions.

  20. Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective.

    Science.gov (United States)

    Bohnert, Tonika; Patel, Aarti; Templeton, Ian; Chen, Yuan; Lu, Chuang; Lai, George; Leung, Louis; Tse, Susanna; Einolf, Heidi J; Wang, Ying-Hong; Sinz, Michael; Stearns, Ralph; Walsky, Robert; Geng, Wanping; Sudsakorn, Sirimas; Moore, David; He, Ling; Wahlstrom, Jan; Keirns, Jim; Narayanan, Rangaraj; Lang, Dieter; Yang, Xiaoqing

    2016-08-01

    Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  1. Development and evaluation of a test program for Y-site compatibility testing of total parenteral nutrition and intravenous drugs

    OpenAIRE

    Staven, Vigdis; Wang, Siri; Gr?nlie, Ingrid; Tho, Ingunn

    2016-01-01

    Background There is no standardized procedure or consensus to which tests should be performed to judge compatibility/incompatibility of intravenous drugs. The purpose of this study was to establish and evaluate a test program of methods suitable for detection of physical incompatibility in Y-site administration of total parenteral nutrition (TPN) and drugs. Methods Eight frequently used methods (dynam...

  2. Intelligence and High Intensity Drug Trafficking Areas (HIDTA’s): A Critical Evaluation of the HIDTA Investigative Support Center (ISC)

    Science.gov (United States)

    2004-09-01

    The purpose of this thesis is to evaluate critically the ongoing reform of the High Intensity Drug Trafficking Area (HIDTA) Investigative Support...or Fusion Center for information sharing between agencies investigating crimes relating to drug trafficking , terrorism, and money laundering.

  3. A Multicenter Evaluation of Off-Label Medication Use and Associated Adverse Drug Reactions in Adult Medical ICUs.

    Science.gov (United States)

    Smithburger, Pamela L; Buckley, Mitchell S; Culver, Mark A; Sokol, Sarah; Lat, Ishaq; Handler, Steven M; Kirisci, Levent; Kane-Gill, Sandra L

    2015-08-01

    Prior research indicates that off-label use is common in the ICU; however, the safety of off-label use has not been assessed. The study objective was to determine the prevalence of adverse drug reactions associated with off-label use and evaluate off-label use as a risk factor for the development of adverse drug reactions in an adult ICU population. Multicenter, observational study : Medical ICUs at three academic medical centers. Adult patients (age ≥ 18 yr old) receiving medication therapy. All administered medications were evaluated for Food and Drug Administration-approved or off-label use. Patients were assessed daily for the development of an adverse drug reaction through active surveillance. Three adverse drug reaction assessment instruments were used to determine the probability of an adverse drug reaction resulting from drug therapy. Severity and harm of the adverse drug reaction were also assessed. Cox proportional hazard regression was used to identify a set of covariates that influenced the rate of adverse drug reactions. Overall, 1,654 patient-days (327 patients) and 16,391 medications were evaluated, with 43% of medications being used off-label. One hundred and sixteen adverse drug reactions were categorized dichotomously (Food and Drug Administration or off-label), with 56% and 44% being associated with Food and Drug Administration-approved and off-label use, respectively. The number of adverse drug reactions for medications administered and the number of harmful and severe adverse drug reactions did not differ for medications used for Food and Drug Administration-approved or off-label use (0.74% vs 0.67%; p = 0.336; 33 vs 31 events, p = 0.567; 24 vs 24 events, p = 0.276). Age, sex, number of high-risk medications, number of off-label medications, and severity of illness score were included in the Cox proportional hazard regression. It was found that the rate of adverse drug reactions increases by 8% for every one additional off-label medication

  4. Drug Utilization Evaluation of Vancomycin in a Referral Infectious Center in Mazandaran Province

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    Ebrahim Salehifar

    2015-10-01

    Full Text Available Background: DUE (Drug Utilization Evaluation studies can help identify and correct problems associated with irrational use of drugs. Considering lack of data regarding how rational vancomycin is being used, we evaluated this DUE study in a referral infectious center to evaluate compliance with guidelines in terms of rational use of this valuable antibiotic.Methods: This retrospective study was done for 6 months from March to September 2012 at Razi hospital, an educational hospital affiliated to Mazandaran University of Medical Sciences. Data including patients’ demographics, vancomycin dose, kidney function assessment, dose adjustments, sampling and culture were collected. Based on the HICPAC (Hospital Infection Control Practices Advisory Committee and Up-to-date 2012 advices, the concordance of practice with standard guidelines was assessed.Results: One hundred and forty six medical records were reviewed in this study. Fever and shortness of breath were the most common symptoms at the time of initiation of vancomycin. Skin infections, lower respiratory tract infection and septicemia were the most common initial diagnosis of patients. Sampling was done in almost one-third of patients. Most of patient with a specific order were received vancomycin in half an hour. Considering the indication, Vancomycin was administered appropriately in 58 percent of patients.Conclusion: Vancomycin was used irrationally in a great proportion of patients. The main observed drawbacks were empiric use of vancomycin without subsequent adjustment of antimicrobial agent according to culture and sensitivity data and lack of paying enough attention to calculation of creatinine clearance and dosage adjustment.

  5. In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions.

    Science.gov (United States)

    Bani-Jaber, Ahmad; Alshawabkeh, Iyad; Abdullah, Samaa; Hamdan, Imad; Ardakani, Adel; Habash, Maha

    2017-07-01

    Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug-protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.

  6. Multicenter evaluation of the nitrate reductase assay for drug resistance detection of Mycobacterium tuberculosis.

    Science.gov (United States)

    Martin, Anandi; Montoro, Ernesto; Lemus, Dihadenys; Simboli, Norberto; Morcillo, Nora; Velasco, Maritza; Chauca, José; Barrera, Lucía; Ritacco, Viviana; Portaels, Françoise; Palomino, Juan Carlos

    2005-11-01

    The performance of the nitrate reductase assay was evaluated in a multicenter laboratory study to detect resistance of Mycobacterium tuberculosis to the first-line anti-tuberculosis drugs rifampicin, isoniazid, ethambutol and streptomycin using a set of coded isolates. Compared with the gold standard proportion method on Löwenstein-Jensen medium, the assay was highly accurate in detecting resistance to rifampicin, isoniazid and ethambutol with an accuracy of 98%, 96.6% and 97.9%, respectively. For streptomycin, discrepant results were obtained with an overall accuracy of 85.3%. The assay proved easy to be implemented in countries with limited laboratory facilities.

  7. Evaluation of a Novel Herbal Immunomodulator Drug (IMOD) in Treatment of Experimental Canine Visceral leishmaniasis.

    Science.gov (United States)

    Malmasi, Abdolali; Ziaie Ardestani, Bijan; Mohebali, Mehdi; Akhoundi, Behnaz; Ziaie, Shadi; Masoudifard, Majid; Khorram Khorshid, Hamidreza; Nasiri, Mehdi; Bayanolhagh, Saeed; Mostafavi, Ehsan; Delrobai, Moin; Siavashi, Vahid

    2014-01-01

    Toxicity and drug resistance against pentavalent antimonials, medications of choice in treatment of leishmaniasis for more than 5 decades, have become important subjects globally. This study was a randomized, open labeled trial that was designed to determine efficacy and safety of IMOD as a novel herbal immunomodulator drug for treatment of canine visceral leishmaniasis (CVL). Twenty healthy mongrel dogs were infected with Iranian strain of L. Infantum amastigotes and randomly divided to 5 groups with four animals for each included on: I: negative control (non-infected) II: Glucantime® III: Glucantime® plus IMOD (immune-chemotherapy) IV: IMOD and V: positive control (non-treated). Physical examination, hematological, biochemical, serological, parasitological, pathological and imaging evaluations were performed pre-/post- interventions every month for 3 months. Comparing with control groups (I&V), immune-chemotherapy group (Glucantime® plus IMOD) showed significantly higher efficacy in resolving the clinical signs and hematobiochemistry factors. Based on our results, using IMOD in combination with meglumine antimoniate (Glucantime®) has significantly improved CVL than the latter drug alone. So, it seems this new herbal medicine is useful as adjuvant therapy for canine visceral leishmaniasis.

  8. Evaluation of immunomodulatory effect of Ranahamsa Rasayanaya - A Sri Lankan classical rasayana drug, on experimental animals.

    Science.gov (United States)

    Somarathna, K Indrajith; Chandola, H M; Ravishankar, B; Pandya, K N; Attanayake, A M P; Ashok, B K

    2010-10-01

    Immunity plays a key role in maintaining the health of an individual. Therefore, the rational modulation of the immunity through psycho-neuro-endocrine-immune (PNI) axis is useful for the prevention as well as for the curing of the diseases. As immunomodulation is a parameter for evaluation of the rasayana effect of a drug, the same has been studied to assess the rasayana effect of Ranahamsa Rasayanaya (RR). Experimental models such as antibody formation against sheep red blood cells (SRBC) and cell mediated immunity (CMI) have been carried out befitting on Wistar strain albino rats to determine the immunomodulatory effect plus rasayana effect of RR. Statistically significant increase in body weight, nonsignificant increase in antibody formation against SRBC, highly significant decrease in CMI were observed in the treatment groups, when compared to the standard control group. These results show the probable immunomodulatory and anabolic activities of the test drug. Outcome of these studies validate the strong rasayana effect of the test drug claimed by the traditional practitioners of Sri Lanka.

  9. Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system.

    Science.gov (United States)

    Abdullah, Ghassan Z; Abdulkarim, Muthanna F; Chitneni, Mallikarjun; Mutee, Ahmed F; Ameer, Omar Z; Salman, Ibrahim M; Noor, Azmin M

    2011-08-01

    Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon.

  10. Blood-Vessel-on-a-Chip Platforms for Evaluating Nanoparticle Drug Delivery Systems.

    Science.gov (United States)

    Li, Yuancheng; Zhu, Kai; Liu, Xiao; Zhang, Y Shrike

    2017-09-24

    Nanoparticle-based drug delivery systems hold great promise for the treatment of major diseases. However, their slow translation from bench to the clinic posts a serious concern. It is mainly attributed to the lack of suitable in vitro platforms for rapid and accurate screening of nanomedicine. Recent developments in microfluidic technologies have provided the possibility to reproduce the biomimetic blood vessel microenvironments outside the body, thus offering a convenient means to characterize the in vivo dynamics and biological responses of nanoparticles. In this review, we discuss the challenges facing the field of nanoparticle drug delivery and highlight the urgent need for construction of blood-vessel-on-a-chip platforms for testing nanomedicine. We subsequently illustrate advances in fabricating various well-controlled blood-vessel-on-a-chip platforms, covering a few examples that have used such models for evaluating nanoparticles behaviors. We then summarize with conclusions and perspectives. We anticipate that, further development of these blood-vessel-on-a-chip platforms with improved biomimetic parameters, tissue specificity, and personalization, will enable their wide applications in drug screening including nanomedicine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

    Science.gov (United States)

    Aflaki, Elma; Stubblefield, Barbara K; Maniwang, Emerson; Lopez, Grisel; Moaven, Nima; Goldin, Ehud; Marugan, Juan; Patnaik, Samarjit; Dutra, Amalia; Southall, Noel; Zheng, Wei; Tayebi, Nahid; Sidransky, Ellen

    2014-06-11

    Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development. Copyright © 2014, American Association for the Advancement of Science.

  12. New Indicators to Compare and Evaluate Harmful Drug Use Among Adolescents in 38 European Countries

    Directory of Open Access Journals (Sweden)

    Mammone Alessia

    2014-10-01

    Full Text Available AIMS – New trends in drug consumption reveal increasing polydrug use. Epidemiological indicators in the current use are based on the prevalence and the associated potential harm of a single “main” substance. We propose new indicators to evaluate frequency and potential harm of poly-drug use. The indicators are used to compare drug use among countries based on survey data on adolescents’ substance use in 38 European countries. METHODS – The approach is based on analysis of the frequency of use in the various population samples: lifetime use, twelve months use or last thirty days, depending on available data, and on the risk of harm for the substances used. Two indicators are provided: the frequency of use score (FUS by summing the frequency of use of each substance, and the polydrug use score (PDS that weight all the substances used by their risk. RESULTS – The indicators FUS and PDS were calculated and the distribution functions were used to characterise substance use across ESPAD countries. The analysis shows important differences in poly-substance use severity among countries presenting similar prevention policies. CONCLUSIONS – Systematic analysis of substance use and the related risk are of paramount interest. The proposed indicators are designed to better monitor and understand consequences of polydrug use and to measure the resulting risk at country or population level. The indicators may also be used to assess the effects of policy interventions.

  13. Mid-Term Assessment of the EU Drugs Strategy 2013–2020 and Final Evaluation of the Action Plan on Drugs 2013–2016

    Science.gov (United States)

    Emilie, Balbirnie; Matthew, Davies; Emma, Disley; Cristina Gonzalez, Monsalve; Stephen, Hartka; Stijn, Hoorens; Kristy, Kruithof; Martin, Sacher; Jirka, Taylor

    2018-01-01

    Abstract The aim of the EU Drugs Strategy 2013–2020 is to contribute to a reduction in drug demand and drug supply within the EU. The Strategy has so far been implemented by an Action Plan covering the period 2013–2016. This article sets out the findings of an evaluation that assesses the degree of implementation of the Strategy and the Action Plan in terms of outputs and, where possible, impacts. It looks at the extent to which the objectives of the Strategy have been achieved. The evaluation aims to provide evidence to support the European Commission's decision about whether to propose a new Action Plan for the period 2017–2020 and, if so, what changes would be needed compared to the current plan. Through applying a mixed-methods approach, the evaluation examined the effectiveness, efficiency, relevance and coherence of the actions undertaken on the basis of the EU Drugs Strategy and the Action Plan, as well as their EU added value. The evaluation makes 20 recommendations, addressed to the European Commission, Member States, the European Council and other stakeholders. The key recommendation for the Commission is that a new Action Plan should be implemented for the period 2017–2020. This should be an updated version of the current Action Plan, rather than taking a new approach or introducing more new actions.

  14. A systematic review of observational studies evaluating costs of adverse drug reactions

    Directory of Open Access Journals (Sweden)

    Batel Marques F

    2016-08-01

    Full Text Available Francisco Batel Marques,1,2 Ana Penedones,1,2 Diogo Mendes,1,2 Carlos Alves,1,2 1CHAD – Centre for Health Technology Assessment and Drug Research, AIBILI – Association for Innovation and Biomedical Research on Light and Image, 2School of Pharmacy, University of Coimbra, Coimbra, Portugal Introduction: The growing evidence of the increased frequency and severity of adverse drug events (ADEs, besides the negative impact on patient’s health status, indicates that costs due to ADEs may be steadily rising. Observational studies are an important tool in pharmacovigilance. Despite these studies being more susceptible to bias than experimental designs, they are more competent in assessing ADEs and their associated costs.Objective: To identify and characterize the best available evidence on ADE-associated costs.Methods: MEDLINE, Cochrane Library, and Embase were searched from 1995 to 2015. Observational studies were included. The methodological quality of selected studies was assessed by Cochrane Collaboration tool for experimental and observational studies. Studies were classified according to the setting analyzed in “ambulatory”, “hospital”, or both. Costs were classified as “direct” and “indirect”. Data were analyzed using descriptive statistics. The total incremental cost per patient with ADE was estimated.Results: Twenty-nine (94% longitudinal observational studies and two (7% cross-sectional studies were included. Twenty-three (74% studies were assessed with the highest methodological quality score. The studies were mainly conducted in the US (61%. Twenty (65% studies evaluated any therapeutic group. Twenty (65% studies estimated costs of ADEs leading to or prolonging hospitalization. The “direct costs” were evaluated in all studies, whereas only two (7% also estimated the “indirect costs”. The “direct costs” in ambulatory ranged from €702.21 to €40,273.08, and the in hospital from €943.40 to €7

  15. The Suitability of P. falciparum Merozoite Surface Proteins 1 and 2 as Genetic Markers for In Vivo Drug Trials in Yemen

    Science.gov (United States)

    Al-abd, Nazeh M.; Mahdy, Mohammed A. K.; Al-Mekhlafi, Abdulsalam M. Q.; Snounou, Georges; Abdul-Majid, Nazia B.; Al-Mekhlafi, Hesham M.; Fong, Mun Y.

    2013-01-01

    Background The accuracy of the conclusions from in vivo efficacy anti-malarial drug trials depends on distinguishing between recrudescences and re-infections which is accomplished by genotyping genes coding P. falciparum merozoite surface 1 (MSP1) and MSP2. However, the reliability of the PCR analysis depends on the genetic markers’ allelic diversity and variant frequency. In this study the genetic diversity of the genes coding for MSP1 and MSP2 was obtained for P. falciparum parasites circulating in Yemen. Methods Blood samples were collected from 511 patients with fever and screened for malaria parasites using Giemsa-stained blood films. A total 74 samples were infected with P. falciparum, and the genetic diversity was assessed by nested PCR targeting Pfmsp1 (Block2) and Pfmsp2 (block 3). Results Overall, 58%, 28% and 54% of the isolates harboured parasites of the Pfmsp1 K1, MAD20 and RO33 allelic families, and 55% and 89% harboured those of the Pfmsp2 FC27 and 3D7 allelic families, respectively. For both genetic makers, the multiplicity of the infection (MOI) was significantly higher in the isolates from the foothills/coastland areas as compared to those from the highland (PYemen Pfmsp1 should not be used for PCR correction of in vivo clinical trials outcomes, and that caution should be exercised when employing Pfmsp2. PMID:23861823

  16. The political and scientific challenges in evaluating compulsory drug treatment centers in Southeast Asia.

    Science.gov (United States)

    Vuong, Thu; Nguyen, Nhu; Le, Giang; Shanahan, Marian; Ali, Robert; Ritter, Alison

    2017-01-11

    In Vietnam, like many countries in Southeast Asia, the commonly used approach of center-based compulsory drug treatment (CCT) has been criticized on human rights ground. Meanwhile, community-based voluntary methadone maintenance treatment (MMT) has been implemented for nearly a decade with promising results. Reform-minded leaders have been seeking empirical evidence of the costs and effectiveness associated with these two main treatment modalities. Conducting evaluations of these treatments, especially where randomization is not ethical, presents challenges. The aim of this paper is to discuss political challenges and methodological issues when conducting cost-effectiveness studies within the context of a non-democratic Southeast Asian country. A retrospective analysis of the political and scientific challenges that were experienced in the study design, sample size determination, government approval and ethics approvals, participant recruitment, data collection, and determination of sources, and quantification of cost and effectiveness data was undertaken. As a consequence of the non-randomized design, analysis of patient characteristics for both treatment types was undertaken to identify the magnitude of baseline group differences. Concordance between self-reported heroin use and urine drug testing was undertaken to determine the reliability of self-report data in a politically challenging environment. We demonstrate that conducting research around compulsory treatment in a non-democratic society is feasible, yet it is politically challenging and requires navigation between science and politics. We also demonstrate that engagement with the government decision makers in the research conception, implementation, and dissemination of the results increases the likelihood of research evidence being considered for change in a contentious drug policy area. Local empirical evidence on the comparative cost-effectiveness of CCT and MMT in a Southeast Asian setting is

  17. In vitro approaches to evaluate placental drug transport by using differentiating JEG-3 human choriocarcinoma cells.

    Science.gov (United States)

    Ikeda, Kenji; Utoguchi, Naoki; Tsutsui, Hidenobu; Yamaue, Satoko;