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Sample records for evaluate anti-malarial drug

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

    PubMed Central

    Mukherjee, Avinaba; Sadhukhan, Gobinda Chandra

    2016-01-01

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

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

    PubMed Central

    2011-01-01

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

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

    PubMed

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

    2015-10-19

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

  4. The biological and clinical activity of anti-malarial drugs in autoimmune disorders.

    PubMed

    Taherian, Elham; Rao, Anshul; Malemud, Charles J; Askari, Ali D

    2013-01-01

    Chloroquine and hydroxychloroquine are 4-aminoquinoline compounds commonly employed as anti-malarial drugs. Chloroquine and its synthetic analogue, hydroxychloroquine also belong to the disease-modifying anti-rheumatic drug class because these drugs are immunosuppressive. The immunosuppressive activity of chloroquine and hydroxychloroquine is likely to account for their capacity to reduce T-cell and B-cell hyperactivity as well as pro-inflammatory cytokine gene expression. This review evaluated experimental and clinical trials results as well as clinical response data relative to the use of chloroquine and/or hydroxychloroquine as first-line medical therapies in systemic lupus erythematosus, rheumatoid arthritis, primary Sjogren's syndrome, the anti-phospholipid syndrome and in the treatment of sarcoidosis. A primary outcomes measure in these clinical trials was the extent to which chloroquine and/or hydroxychloroquine reduced disease progression or exacerbations and/or the use and dosage of corticosteroids. The relative efficacy of chloroquine and hydroxychloroquine in modifying the clinical course of these autoimmune disorders is balanced against evidence that these drugs induce adverse effects which may reduce their use and effectiveness in the therapy of autoimmune disorders.

  5. Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids

    PubMed Central

    2013-01-01

    Background Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. Methods In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 – 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. Results Hybrids 1 – 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os. Conclusions These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated. PMID:23433124

  6. Repurposing the anti-malarial drug, quinacrine: new anti-colitis properties

    PubMed Central

    Chumanevich, Alexander A.; Witalison, Erin E.; Chaparala, Anusha; Chumanevich, Anastasiya; Nagarkatti, Prakash; Nagarkatti, Mitzi; Hofseth, Lorne J.

    2016-01-01

    Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with an increased risk of colorectal cancer in 8-10 years after disease onset. Current colitis treatment strategies do not offer a cure for the disease, but only treat the symptoms with limited success and dangerous side-effects. Also, there is no preventive treatment for either UC or colorectal cancer. Quinacrine is an anti-malarial drug with versatile use in the treatment of diseases involving inflammatory response such as rheumatoid arthritis and lupus erythematosus. It also has putative anti-cancer effect. Quinacrine's anti-inflammatory, anti-oxidant properties, and anti-tumorigenic properties make it a potential small molecule preventive agent for both UC and associated colorectal cancer. Results There were obvious changes in the CDI, histology, and inflammatory load in quinacrine-treated groups in a dose and time dependent manner in both models of UC, induced by chemical or haptenating agent. Methods We tested quinacrine at two different doses as a colitis treatment agent in two mouse models of UC - the dextran sulfate sodium and oxazolone. The clinical disease index (CDI), histological changes of the colon, levels of inflammatory markers (Cox-2, iNOS, p53) and overall health vitals were evaluated. Conclusions We demonstrate that quinacrine successfully suppresses colitis without any indication of toxicity or side-effects in two mouse models of UC. PMID:27447967

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

    PubMed

    Achan, Jane; Talisuna, Ambrose O; Erhart, Annette; Yeka, Adoke; Tibenderana, James K; Baliraine, Frederick N; Rosenthal, Philip J; D'Alessandro, Umberto

    2011-05-24

    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.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Boulton, Ian C; Nwaka, Solomon; Bathurst, Ian; Lanzer, Michael; Taramelli, Donatella; Vial, Henri; Doerig, Christian; Chibale, Kelly; Ward, Steve A

    2010-07-13

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

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

    PubMed

    Marrelli, Mauro Toledo; Brotto, Marco

    2016-11-02

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

  11. Co-treatment with the anti-malarial drugs mefloquine and primaquine highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition.

    PubMed

    Kim, Ju-Hwa; Choi, Ae-Ran; Kim, Yong Kee; Yoon, Sungpil

    2013-11-22

    The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs.

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

    PubMed

    Kalani, Komal; Agarwal, Jyoti; Alam, Sarfaraz; Khan, Feroz; Pal, Anirban; Srivastava, Santosh Kumar

    2013-01-01

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

  13. Synthesis and evaluation of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane, and benzodioxaphosphininamine sulfides and related compounds as potential anti-malarial agents.

    PubMed

    Mara, Christine; Dempsey, Enda; Bell, Angus; Barlow, James W

    2013-06-15

    A series of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane and benzodioxaphosphininamine sulfides and related cyclic organophosphorus compounds based on the lead anti-tubulin herbicides amiprophos methyl and butamifos were synthesised and evaluated for anti-malarial activity. Of these compounds, while none of the phenoxyoxazaphospholidines, phenoxyoxazaphosphinanes or benzodioxaphosphininamine sulphides were more potent than APM, phosphorothioamidate 30, a dual compound also bearing an aminoquinoline motif, showed promising activity against Plasmodium falciparum (IC50 0.038 μM) and warrants further study.

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

    PubMed Central

    2011-01-01

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

  15. Recent progress in the development of anti-malarial quinolones.

    PubMed

    Beteck, Richard M; Smit, Frans J; Haynes, Richard K; N'Da, David D

    2014-08-30

    Available anti-malarial tools have over the ten-year period prior to 2012 dramatically reduced the number of fatalities due to malaria from one million to less than six-hundred and thirty thousand. Although fewer people now die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones are a promising class of compounds, with some demonstrating potent in vitro activity against the malaria parasite. This review summarizes the progress made in the development of potential anti-malarial quinolones since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed.

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

    2013-01-01

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

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

    PubMed

    Amoa Onguéné, Pascal; Ntie-Kang, Fidele; Lifongo, Lydia Likowo; Ndom, Jean Claude; Sippl, Wolfgang; Mbaze, Luc Meva'a

    2013-12-13

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    2011-01-01

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

  1. Slowing down glioblastoma progression in mice by running or the anti-malarial drug dihydroartemisinin? Induction of oxidative stress in murine glioblastoma therapy

    PubMed Central

    Lemke, Dieter; Pledl, Hans-Werner; Zorn, Markus; Jugold, Manfred; Green, Ed; Blaes, Jonas; Löw, Sarah; Hertenstein, Anne; Ott, Martina; Sahm, Felix; Steffen, Ann-Catherine; Weiler, Markus; Winkler, Frank; Platten, Michael

    2016-01-01

    Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer. Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy. PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species. PMID:27447560

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

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

    2008-01-01

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

  4. Repurposing the anti-malarial drug dihydroartemisinin suppresses metastasis of non-small-cell lung cancer via inhibiting NF-κB/GLUT1 axis

    PubMed Central

    Jiang, Jie; Geng, Guojun; Yu, Xiuyi; Liu, Hongming; Gao, Jing; An, Hanxiang; Cai, Chengfu; Li, Ning; Shen, Dongyan; Wu, Xiaoqiang; Zheng, Lisheng; Mi, Yanjun; Yang, Shuyu

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is an aggressive malignancy and long-term survival remains unsatisfactory for patients with metastatic and recurrent disease. Repurposing the anti-malarial drug dihydroartemisinin (DHA) has been proved to possess potent antitumor effect on various cancers. However, the effects of DHA in preventing the invasion of NSCLC cells have not been studied. In the present study, we determined the inhibitory effects of DHA on invasion and migration and the possible mechanisms involved using A549 and H1975 cells. DHA inhibited in vitro migration and invasion of NSCLC cells even in low concentration with little cytotoxicity. Additionally, low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA. Our results suggested that DHA can inhibit metastasis of NSCLC by targeting glucose metabolism via inhibiting NF-κB signaling pathway and DHA may deserve further investigation in NSCLC treatment. PMID:27895313

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

    PubMed Central

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

    2012-01-01

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

  6. Prescribing Pattern of Anti-malarial Drugs with Particular Reference to the use of Artesunate in Complicated Plasmodium Vivax Cases

    PubMed Central

    Singh, Ashutosh Kumar; Khan, Mohd Sajid

    2014-01-01

    Background: In developing countries, Malaria has been found to be one of the most common cause of fever and morbidity, particularly among infants and young children. Therefore, its drug utilization studies should be carried out to know the rationality of treatment. Aim: To evaluate the use of antimalarial agents in children with a diagnosis of Malaria and visited to OPD & IPD Paediatric department of a tertiary care teaching hospital. Materials and Methods: This was a prospective six months study based on a Medication Utilization Form, which has been designed in consultation with the paediatrician. One hundred eighty three children <12 y of age were selected on the basis of inclusion and exclusion criteria. Results: Out of 183 patients, 110 were infected with Plasmodium falciparum (60.10%) and 73 with Plasmodium vivax (39.89%). Most of the patients were male, 56.83% and 43.16% were female patients. Most of the complicated cases were found from Plasmodium falciparum (n = 110) than Plasmodium vivax (n=15). In prescriptions with monotherapy, Artesunate (n=101) was found to be the most commonly prescribed drug and in prescriptions containing more than one drug, Artesunate – lumefantrine (n=125) combinations were frequently used. Most of the drugs were prescribed by oral route (n=285), than the parenteral route (n=140). The average number of drugs per encounter was 2.32 and only 4.50% drugs were prescribed by generic name. Average drug cost per prescription in complicated cases was found to be higher (185.5 INR) than uncomplicated cases (115 INR). Conclusion: Artemisinin were used as first line drugs irrespective of the causative agent for malaria, which is not recommended, however has been found to be effective in complicated cases of Plasmodium vivax also. The cost of the prescription was higher. Interventions to rectify over prescription of injectables necessary to further improve rational drug use in our facility. Also, there should be an awareness program

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

    PubMed Central

    Souares, Aurélia; Lalou, Richard; Sene, Ibra; Sow, Diarietou; Le Hesran, Jean-Yves

    2009-01-01

    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. PMID:19497103

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

    PubMed

    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 < 0.05) in the concentrations of serum albumin, urea, creatinine, cholesterol and triglyceride of rabbits administered SP, A and SPA for 4 weeks, except in serum total protein. No significant differences existed in the activities of AST, ALT and ALP, except in creatine kinase which was elevated in the control. The brain serotonin 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.

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

    PubMed Central

    2012-01-01

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

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

    PubMed

    Diap, Graciela; Amuasi, John; Boakye, Isaac; Sevcsik, Ann-Marie; Pecoul, Bernard

    2010-04-23

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

  11. Anti-malarial Activities of Two Soil Actinomycete Isolates from Sabah via Inhibition of Glycogen Synthase Kinase 3β

    PubMed Central

    Dahari, Dhiana Efani; Salleh, Raifana Mohamad; Mahmud, Fauze; Chin, Lee Ping; Embi, Noor; Sidek, Hasidah Mohd

    2016-01-01

    Exploiting natural resources for bioactive compounds is an attractive drug discovery strategy in search for new anti-malarial drugs with novel modes of action. Initial screening efforts in our laboratory revealed two preparations of soil-derived actinomycetes (H11809 and FH025) with potent anti-malarial activities. Both crude extracts showed glycogen synthase kinase 3β (GSK3β)-inhibitory activities in a yeast-based kinase assay. We have previously shown that the GSK3 inhibitor, lithium chloride (LiCl), was able to suppress parasitaemia development in a rodent model of malarial infection. The present study aims to evaluate whether anti-malarial activities of H11809 and FH025 involve the inhibition of GSK3β. The acetone crude extracts of H11809 and FH025 each exerted strong inhibition on the growth of Plasmodium falciparum 3D7 in vitro with 50% inhibitory concentration (IC50) values of 0.57 ± 0.09 and 1.28 ± 0.11 µg/mL, respectively. The tested extracts exhibited Selectivity Index (SI) values exceeding 10 for the 3D7 strain. Both H11809 and FH025 showed dosage-dependent chemo-suppressive activities in vivo and improved animal survivability compared to non-treated infected mice. Western analysis revealed increased phosphorylation of serine (Ser 9) GSK3β (by 6.79 to 6.83-fold) in liver samples from infected mice treated with H11809 or FH025 compared to samples from non-infected or non-treated infected mice. A compound already identified in H11809 (data not shown), dibutyl phthalate (DBP) showed active anti-plasmodial activity against 3D7 (IC50 4.87 ± 1.26 µg/mL which is equivalent to 17.50 µM) and good chemo-suppressive activity in vivo (60.80% chemo-suppression at 300 mg/kg body weight [bw] dosage). DBP administration also resulted in increased phosphorylation of Ser 9 GSK3β compared to controls. Findings from the present study demonstrate that the potent anti-malarial activities of H11809 and FH025 were mediated via inhibition of host GSK3β. In addition

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

    PubMed

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

    2016-02-13

    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 (<8 %) were found in just two of the countries, whilst substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting.

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

    PubMed Central

    2011-01-01

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

  14. Susceptibility of human Plasmodium knowlesi infections to anti-malarials

    PubMed Central

    2013-01-01

    Background Evidence suggests that Plasmodium knowlesi malaria in Sarawak, Malaysian Borneo remains zoonotic, meaning anti-malarial drug resistance is unlikely to have developed in the absence of drug selection pressure. Therefore, adequate response to available anti-malarial treatments is assumed. Methods Here the ex vivo sensitivity of human P. knowlesi isolates in Malaysian Borneo were studied, using a WHO schizont maturation assay modified to accommodate the quotidian life cycle of this parasite. The in vitro sensitivities of P. knowlesi H strain adapted from a primate infection to in vitro culture (by measuring the production of Plasmodium lactate dehydrogenase) were also examined together with some assays using Plasmodium falciparum and Plasmodium vivax. Results Plasmodium knowlesi is uniformly highly sensitive to artemisinins, variably and moderately sensitive to chloroquine, and less sensitive to mefloquine. Conclusions Taken together with reports of clinical failures when P. knowlesi is treated with mefloquine, the data suggest that caution is required if using mefloquine in prevention or treatment of P. knowlesi infections, until further studies are undertaken. PMID:24245918

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

    2014-01-01

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

  17. New developments in anti-malarial target candidate and product profiles.

    PubMed

    Burrows, Jeremy N; Duparc, Stephan; Gutteridge, Winston E; Hooft van Huijsduijnen, Rob; Kaszubska, Wiweka; Macintyre, Fiona; Mazzuri, Sébastien; Möhrle, Jörg J; Wells, Timothy N C

    2017-01-13

    A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

  18. Anti-malarial activity of indole alkaloids isolated from Aspidosperma olivaceum

    PubMed Central

    2014-01-01

    Background Several species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum. Methods The activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled [3H]-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei. Results All six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 μg/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active. Conclusion Using a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to

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

    PubMed Central

    2011-01-01

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

  20. Recent progress in the identification and development of anti-malarial agents using virtual screening based approaches.

    PubMed

    Shah, Priyanka; Tiwari, Sunita; Siddiqi, Mohammad Imran

    2015-01-01

    Malaria has continued to be one of the most perplexing diseases for biological science community around the world due to its prevalent devastating nature and quick developing resistance against the frontline drugs. Artimisinin-based combination therapy (ACT) has been so far found to be among the best therapies against Plasmodium pathogens but alarming emergence of resistance in parasites against every known chemotherapy has prompted the scientific community to step up all the efforts towards development of new and affordable anti-malarial drugs. Computer-aided approaches have received enormous attention in recent years in the field of identification and design of novel drugs. In this review, we summarize recently published research concerning the identification and development of anti-malarial compounds using virtual screening approaches. It would be admirable to discern the successful application of in silico studies for anti-malarial drug discovery hitherto and would certainly help in generating new avenues for pursuing integrated studies between the experimentalists and computational chemists in a systematic manner as a time and cost efficient alternative for future antimalarial drug discovery projects.

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

    PubMed Central

    2012-01-01

    Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure. PMID:22877082

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

    PubMed Central

    2010-01-01

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

  3. Fourier transform infrared spectroscopy as a tool for identification of crude microbial extracts with anti-malarial potential.

    PubMed

    Sankarganesh, P; Joseph, Baby

    2016-01-01

    Fourier transform infrared (FT-IR) spectroscopy is an indispensable tool for identifying biologically active functional groups in uncharacterized crude samples. Here, using FT-IR spectrum analysis, we identified crude extracts of Streptomyces that have anti-malarial activities and conducted a statistical analysis of their spectra. Among the three crude microbial extracts tested herein, an aromatic amine C-N stretching functional group was observed in the spectra of Streptomyces sp. BJSG1 and BJSG4 crude extracts. These extracts showed promising activity against Plasmodium falciparum in vitro cultures with IC50 values of 0.5 for BJSG1 and 0.4μg/mL for BJSG4. The present results showed that FT-IR analysis is necessary for the primary analysis of unknown samples in anti-malarial drug development.

  4. CoMFA, CoMSIA, and docking studies on thiolactone-class of potent anti-malarials: identification of essential structural features modulating anti-malarial activity.

    PubMed

    Roy, Kuldeep K; Bhunia, Shome S; Saxena, Anil K

    2011-09-01

    The integrated ligand- and structure-based drug design techniques have been applied on a homogeneous dataset of thiolactone-class of potent anti-malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum. Developed CoMFA (q(2) = 0.716) and CoMSIA (q(2) = 0.632) models well explained structure-activity variation in both the training (CoMFA R(2) = 0.948 & CoMSIA R(2) = 0.849) and test set (CoMFA R(2) (pred) = 0.789 & CoMSIA R(2) (pred) = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high-resolution (2.35 Å) structure of FabB-TLM binary complex (PDB-ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H-bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein-ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone-class of compounds that could furnish improved anti-malarial activity.

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

    PubMed Central

    2012-01-01

    Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro. PMID:22401346

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

    PubMed

    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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  10. Self-reported data: a major tool to assess compliance with anti-malarial combination therapy among children in Senegal

    PubMed Central

    2009-01-01

    Background Although there are many methods available for measuring compliance, there is no formal gold standard. Different techniques used to measure compliance were compared among children treated by the anti-malarial amodiaquine/sulphadoxine-pyrimethamine (AQ/SP) combination therapy, in use in Senegal between 2004 and 2006. Methods The study was carried out in 2004, in five health centres located in the Thies region (Senegal). Children who had AQ/SP prescribed for three and one day respectively at the health centre were recruited. The day following the theoretical last intake of AQ, venous blood, and urine samples were collected for anti-malarial drugs dosage. Caregivers and children above five years were interviewed concerning children's drug intake. Results Among the children, 64.7% adhered to 80% of the prescribed dose and only 37.7% were strict full adherent to the prescription. There was 72.7% agreement between self-reported data and blood drug dosage for amodiaquine treatment. Concerning SP, results found that blood dosages were 91.4% concordant with urine tests and 90% with self-reported data based on questionnaires. Conclusion Self-reported data could provide useful quantitative information on drug intake and administration. Under strict methodological conditions this method, easy to implement, can be used to describe patients' behaviors and their use of new anti-malarial treatment. Self-reported data is a major tool for assessing compliance in resource poor countries. Blood and urine drug dosages provide qualitative results that confirm any drug intake. Urine assays for SP could be useful to obtain public health data, for example on chemoprophylaxis among pregnant women. PMID:19922609

  11. Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling

    PubMed Central

    2014-01-01

    Background Successful programmatic use of anti-malarials faces challenges that are not covered by standard drug development processes. The development of appropriate pragmatic dosing regimens for low-resource settings or community-based use is not formally regulated, even though these may alter factors which can substantially affect individual patient and population level outcome, such as drug exposure, patient adherence and the spread of drug resistance and can affect a drug’s reputation and its eventual therapeutic lifespan. Methods An in silico pharmacological model of anti-malarial drug treatment with the pharmacokinetic/pharmacodynamic profiles of artemether-lumefantrine (AM-LF, Coartem®) and dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) was constructed to assess the potential impact of programmatic factors, including regionally optimized, age-based dosing regimens, poor patient adherence, food effects and drug resistance on treatment outcome at population level, and compared both drugs’ susceptibility to these factors. Results Compared with DHA-PPQ, therapeutic effectiveness of AM-LF seems more robust to factors affecting drug exposure, such as age- instead of weight-based dosing or poor adherence. The model highlights the sub-optimally low ratio of DHA:PPQ which, in combination with the narrow therapeutic dose range of PPQ compared to DHA that drives the weight or age cut-offs, leaves DHA at a high risk of under-dosing. Conclusion Pharmacological modelling of real-life scenarios can provide valuable supportive data and highlight modifiable determinants of therapeutic effectiveness that can help optimize the deployment of anti-malarials in control programmes. PMID:24708571

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

    PubMed Central

    Duffy, Sandra; Avery, Vicky M.

    2012-01-01

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

  13. Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria

    PubMed Central

    Darpo, Borje; Ferber, Georg; Siegl, Peter; Laurijssens, Bart; Macintyre, Fiona; Toovey, Stephen; Duparc, Stephan

    2015-01-01

    Aims The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. Methods Exposure–response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100–800 mg and 160–1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing. Results A significant relation between plasma concentrations and placebo-corrected change from baseline QTcF (ΔΔQTcF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml−1 (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTcF effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml−1) and 1440 mg (281 ng ml−1), respectively, administered in the fasted state. Conclusions Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation. PMID:25966781

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

    PubMed Central

    2014-01-01

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

  15. Synthesis, biophysical, and biological studies of wild-type and mutant psalmopeotoxins--anti-malarial cysteine knot peptides from Psalmopoeus cambridgei.

    PubMed

    Kamolkijkarn, Pacharin; Prasertdee, Thitawan; Netirojjanakul, Chawita; Sarnpitak, Pakornwit; Ruchirawat, Somsak; Deechongkit, Songpon

    2010-04-01

    Psalmopeotoxin I and II (PcFK1 and PcFK2), an anti-malarial peptide first extracted from Psalmopoeus cambridgei was synthesized and characterized. Both peptides belong to the Inhibitor Cystine Knot (ICK) superfamily, containing three disulfide bridges. The six cysteine residues are conserved similar to other members of the ICK superfamily, suggesting their critical role for either folding or function. In this study, the peptides were synthesized using Fmoc solid-phase peptide synthesis (SPPS). The three disulfide bonds of were constructed by regioselective and random oxidative approaches. The resulting disulfide bond patterns were verified by the HPLC-MS analysis of intact peptides and by the disulfide bond mapping using tryptic digestion. Implications of the disulfide bonds on the biophysical and biological properties of PcFKs were studied using three disulfide mutants in which a particular pair of cysteines was replaced with two isosteric serine residues. Structures and biophysical characteristics of all variants were studied using far-UV CD and fluorescence spectroscopy. Biological activities of all variants were evaluated using antiplasmodial assay against the K1 multi-drug-resistant strain of P. falciparum. The experimental results showed that the three disulfide bridges could not be correctly synthesized by the random oxidative strategy. Structural and biophysical analyses revealed that all variants had similar structures to the twisted beta-sheet. However, the studies of disulfide bond removal indicated that each disulfide bond had different effects on both biophysical and biological activities of PcFKs. Correlation of biophysical parameters and biological activities showed that both PcFKs may have different mechanisms of actions for antiplasmodial activity.

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

    PubMed Central

    2012-01-01

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

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

    PubMed Central

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

    2011-01-01

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

  18. Structural characterisation of sporozoite components for a multistage, multi-epitope, anti-malarial vaccine.

    PubMed

    Patarroyo, Manuel E; Cifuentes, Gladys; Rodríguez, Raúl

    2008-01-01

    A totally effective anti-malarial vaccine must contain epitopes derived from multiple proteins found in different stages of the particular parasite involved in invasion. It must therefore include sporozoite molecules able to induce protective immunity thereby blocking the parasite's access to hepatic cells; thrombospondin-related anonymous protein (TRAP) is one of them. Conserved high activity binding peptides (HABPs) attaching themselves to hepatic cells were used in immunisation studies with the highly malaria-susceptible Aotus monkey. However, they had to be modified to render them immunogenic. The changes induced in lead peptide 3D structure were analysed by correlating such substitutions with the induction of high anti-sporozoite antibody levels in the experimental monkey model. The modification induced structural changes in most modified HABPs, changing them from random-coil or distorted type III beta-turn structures to classical type III or III' beta-turn, thereby allowing a better fit into the MHC-II-peptide-TCR complex since they bound with high affinity to purified HLA-DRbeta1* molecules. These are the first (TRAP) conserved HABPs corresponding to functionally active amino acid sequences in sporozoite invasion and mobility which, when modified, were able to induce very high anti-sporozoite antibody responses, leading to suggesting them as components in the first line of defence of a fully-effective, subunit-based, multi-epitope, multi-stage, synthetic anti-malarial vaccine.

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

    PubMed Central

    2014-01-01

    Background Self-medication has been widely practiced worldwide particularly in developing countries including Tanzania. In sub-Saharan Africa high incidences of malaria have contributed to self-medication with anti-malarial drugs. In recent years, there has been a gain in malaria control, which has led to decreased malaria transmission, morbidity and mortality. Therefore, understanding the patterns of self-medication during this period when most instances of fever are presumed to be due to non-malaria febrile illnesses is important. In this study, self-medication practice was assessed among community members and information on the habit of self-medication was gathered from health workers. Methods Twelve focus group discussions (FGD) with members of communities and 14 in-depth interviews (IDI) with health workers were conducted in Kilosa district, Tanzania. The transcripts were coded into different categories by MaxQDA software and then analysed through thematic content analysis. Results The study revealed that self-medication was a common practice among FGD participants. Anti-malarial drugs including sulphadoxine-pyrimethamine and quinine were frequently used by the participants for treatment of fever. Study participants reported that they visited health facilities following failure of self-medication or if there was no significant improvement after self-medication. The common reported reasons for self-medication were shortages of drugs at health facilities, long waiting time at health facilities, long distance to health facilities, inability to pay for health care charges and the freedom to choose the preferred drugs. Conclusion This study demonstrated that self-medication practice is common among rural communities in the study area. The need for community awareness is emphasized for correct and comprehensive information about drawbacks associated with self-medication practices. Deliberate efforts by the government and other stakeholders to improve health care

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

    PubMed Central

    2013-01-01

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

  1. Pharmacologic Inhibition of CXCL10 in Combination with Anti-malarial Therapy Eliminates Mortality Associated with Murine Model of Cerebral Malaria

    PubMed Central

    Wilson, Nana O.; Solomon, Wesley; Anderson, Leonard; Patrickson, John; Pitts, Sidney; Bond, Vincent; Liu, Mingli; Stiles, Jonathan K.

    2013-01-01

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

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

    PubMed

    Hsu, Elisabeth

    2009-01-01

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

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

    SciTech Connect

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

    2010-11-22

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

  4. Strategies for developing multi-epitope, subunit-based, chemically synthesized anti-malarial vaccines.

    PubMed

    Patarroyo, M E; Cifuentes, G; Bermúdez, A; Patarroyo, M A

    2008-10-01

    An anti-malarial vaccine against the extremely lethal Plasmodium falciparum is desperately needed. Peptides from this parasite's proteins involved in invasion and having high red blood cell-binding ability were identified; these conserved peptides were not immunogenic or protection-inducing when used for immunizing Aotus monkeys. Modifying some critical binding residues in these high-activiy binding peptides' (HABPs') attachment to red blood cells (RBC) allowed them to induce immunogenicity and protection against experimental challenge and acquire the ability to bind to specific HLA-DRp1* alleles. These modified HABPs adopted certain characteristic structural configurations as determined by circular dichroism (CD) and 1H nuclear magnetic resonance (NMR) associated with certain HLA-DRbeta1* haplotype binding activities and characteristics, such as a 2-angstroms-distance difference between amino acids fitting into HLA-DRp1 Pockets 1 to 9, residues participating in binding to HLA-DR pockets and residues making contact with the TCR, suggesting haplotype and allele-conscious TCR. This has been demonstrated in HLA-DR-like genotyped monkeys and provides the basis for designing high effective, subunit-based, multi-antigen, multi-stage, synthetic vaccines, for immediate human use, malaria being one of them.

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

    PubMed

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

    2014-01-01

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

  6. The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice

    PubMed Central

    2014-01-01

    Background Malaria is one of the most lethal and life-threatening killer infectious diseases in the world, and account for the deaths of more than half a million people annually. Despite the remarkable achievement made in preventing and eradicating malaria, it still remains a threat to the public health and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. Therefore, the need to develop new anti-malarial drugs is crucial. The chemistry department at the University of Cape Town synthesized a number of new CQ-like derivatives (TK-series), and evaluated them for in vitro activity against both CQ-sensitive and -resistant Plasmodium falciparum strains, and for general cytotoxicity against a Chinese Hamster Ovarian (CHO) mammalian cell line. The lead compounds from the TK-series were selected for a comprehensive pharmacokinetic (PK) evaluation in a mouse model. Methods A sensitive LC-MS/MS assay was developed for the quantitative determination of TK900D. Multiple reaction monitoring (MRM) in the positive ionization mode was used for detection. The analyte and the internal standard (TK900E) were isolated from blood samples by liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved with a Phenomenex® Kinetex C18 (100 × 2.0 mm id, 2.6 μm) analytical column, using a mixture of 0.1% formic acid and acetonitrile (50:50; v/v) as the mobile phase. The method was fully validated over concentrations that ranged from 3.910 to 1000 ng/ml, and used to evaluate the PK properties of the lead compounds in a mouse model. Results The assay was robust, with deviation not exceeding 11% for the intra- and inter-run precision and accuracy. Extraction recovery was consistent and more than 60%. PK evaluation showed that TK900D and TK900E have moderate oral bioavailability of 30.8% and 25.9%, respectively. The apparent half-life ranged between 4 to 6 h for TK900D and 3.6 to 4 h for TK900E. Conclusion The assay was

  7. From fever to anti-malarial: the treatment-seeking process in rural Senegal

    PubMed Central

    2010-01-01

    Background Currently less than 15% of children under five with fever receive recommended artemisinin-combination therapy (ACT), far short of the Roll Back Malaria target of 80%. To understand why coverage remains low, it is necessary to examine the treatment pathway from a child getting fever to receiving appropriate treatment and to identify critical blockages. This paper presents the application of such a diagnostic approach to the coverage of prompt and effective treatment of children with fever in rural Senegal. Methods A two-stage cluster sample household survey was conducted in August 2008 in Tambacounda, Senegal, to investigate treatment behaviour for children under five with fever in the previous two weeks. The treatment pathway was divided in to five key steps; the proportion of all febrile children reaching each step was calculated. Results were stratified by sector of provider (public, community, and retail). Logistic regression was used to determine predictors of treatment seeking. Results Overall 61.6% (188) of caretakers sought any advice or treatment and 40.3% (123) sought any treatment promptly within 48 hours. Over 70% of children taken to any provider with fever did not receive an anti-malarial. The proportion of febrile children receiving ACT within 48 hours was 6.2% (19) from any source; inclusion of correct dose and duration reduced this to 1.3%. The proportion of febrile children receiving ACT within 48 hours (not including dose & duration) was 3.0% (9) from a public provider, 3.0% (9) from a community source and 0.3% (1) from the retail sector. Inclusion of confirmed diagnosis within the public sector treatment pathway as per national policy increases the proportion of children receiving appropriate treatment with ACT in this sector from 9.4% (9/96) to an estimated 20.0% (9/45). Conclusions Process analysis of the treatment pathway for febrile children must be stratified by sector of treatment-seeking. In Tambacounda, Senegal, interventions

  8. Skeletal hybridization and PfRIO-2 kinase modeling for synthesis of α-pyrone analogs as anti-malarial agent.

    PubMed

    Parveen, Afsana; Chakraborty, Arnish; Konreddy, Ananda Kumar; Chakravarty, Harapriya; Sharon, Ashoke; Trivedi, Vishal; Bal, Chandralata

    2013-01-01

    The pharmacophoric hybridization and computational design approach were applied to generate a novel series of α-pyrone analogs as plausible anti-malarial lead candidate. A putative active site in flexible loop close to wing-helix domain of PfRIO2 kinase was explored computationally to understand the molecular basis of ligand binding. All the synthesized molecules (3a-g) exhibited in vitro antimalarial activity. Oxidative stress induced by 3a-d were calculated and found to be significantly higher in case of 3b. Therefore, 3b, which shown most significant result was identified as promising lead for further SAR study to develop potent anti-malarials.

  9. Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774.

    PubMed

    Efferth, Thomas; Ramirez, Tzutzuy; Gebhart, Erich; Halatsch, Marc-Eric

    2004-05-01

    New drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC(50) values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone.

  10. Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort

    PubMed Central

    Pons-Estel, Guillermo J.; Alarcón, Graciela S.; Hachuel, Leticia; Boggio, Gabriela; Wojdyla, Daniel; Pascual-Ramos, Virginia; Soriano, Enrique R.; Saurit, Verónica; Cavalcanti, Fernando S.; Guzman, Renato A.; Guibert-Toledano, Marlene; Sauza del Pozo, Maria J.; Amigo, Mary-Carmen; Alva, Magaly; Esteva-Spinetti, Maria H.

    2012-01-01

    Objective. To examine the role of ethnicity and the use of anti-malarials (protective) on lupus renal disease. Methods. A nested case–control study (1:2 proportion, n = 265 and 530) within GLADEL's (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort was carried out. The end-point was ACR renal criterion development after diagnosis. Cases and controls were matched for follow-up time (end-point or a comparable time, respectively). Renal disease predictors were examined by univariable and multivariable analyses. Additional analyses were done to determine if the protective effect of anti-malarials persisted after adjusting for intake-associated confounders. Results. Of the cases, 233 (87.9%) were women; their mean (s.d.) age at diagnosis was 28.0 (11.9) years and their median (Q3–Q1 interquartile range) follow-up time for cases and controls was 8.3 months (Q3–Q1: 23.5); 56.6% of the cases and 74.3% of the controls were anti-malarial users. Mestizo ethnicity [odds ratio (OR) 1.72, 95% CI 1.19, 2.48] and hypertension (OR 2.26, 95% CI 1.38, 3.70) were independently associated with a higher risk of renal disease, whereas anti-malarial use (OR 0.39, 95% CI 0.26, 0.58), older age at disease onset (OR 0.98, 95% CI 0.96, 0.99) and female gender (OR 0.56, 95% CI 0.32, 0.99) were negatively associated with such occurrence. After adjusting for variables associated with their intake, the protective effect of anti-malarials on renal disease occurrence persisted (OR 0.38, 95% CI 0.25, 0.58). Conclusion. Mestizo patients are at increased risk of developing renal disease, whereas anti-malarial use protects patients from such an occurrence. PMID:22389125

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

    PubMed Central

    2010-01-01

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

  12. A Systematic Review of Anti-malarial Properties, Immunosuppressive Properties, Anti-inflammatory Properties, and Anti-cancer Properties of Artemisia Annua

    PubMed Central

    Alesaeidi, Samira; Miraj, Sepide

    2016-01-01

    Artemisia annua belongs to the asteraceae family, indigenous to the mild climate of Asia. The aim of this study was to overview its anti-malarial properties, immunosuppressive properties, anti-inflammatory properties and anti-cancer properties. This systematic review was carried out by searching studies in PubMed, Medline, Web of Science, and IranMedex databases. The initial search strategy identified approximately ninety eight references. In this study, forty six studies were accepted for further screening and met all of our inclusion. The search terms were “Artemisia annua”, “therapeutic properties”, “and pharmacological effects”. Artemisia annua is commonly used for its anti-malarial, immunosuppressive anti-inflammatory properties. Artemisia annua contributes to the treatment of various diseases such as diabetes, heart diseases, arthritis and eczema and possesses various effects such as antibacterial, antioxidant, anticoccidial, and antiviral effects. Furthermore, it was said to be good for cancer treatment. In this study, anti-malarial, immunosuppressive, anti-inflammatory properties of this plant are presented using published articles in scientific sites. PMID:27957318

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

    PubMed Central

    2013-01-01

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

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

    PubMed Central

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

    2009-01-01

    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 absence of an obvious

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

    PubMed Central

    2014-01-01

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

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

    PubMed

    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

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

    PubMed

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

    2016-02-17

    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.

  18. Drugs use pattern for uncomplicated malaria in medicine retail outlets in Enugu urban, southeast Nigeria: implications for malaria treatment policy

    PubMed Central

    2014-01-01

    Background Malaria treatment policy recommends regular monitoring of drug utilization to generate information for ensuring effective use of anti-malarial drugs in Nigeria. This information is currently limited in the retail sector which constitutes a major source of malaria treatment in Nigeria, but are characterized by significant inappropriate use of drugs. This study analyzed the use pattern of anti-malarial drugs in medicine outlets to assess the current state of compliance to policy on the use of artemisinin-based combination therapy (ACT). Methods A prospective cross-sectional survey of randomly selected medicine outlets in Enugu urban, southeast Nigeria, was conducted between May and August 2013, to determine the types, range, prices, and use pattern of anti-malarial drugs dispensed from pharmacies and patent medicine vendors (PMVs). Data were collected and analyzed for anti-malarial drugs dispensed for self-medication to patients, treatment by retail outlets and prescription from hospitals. Results A total of 1,321 anti-malarial drugs prescriptions were analyzed. ACT accounted for 72.7%, while monotherapy was 27.3%. Affordable Medicines Facility-malaria (AMFm) drugs contributed 33.9% (326/961) of ACT. Artemether-lumefantrine (AL), 668 (50.6%) was the most used anti-malarial drug, followed by monotherapy sulphadoxine-pyrimethamine (SP), 248 (18.8%). Median cost of ACT at $2.91 ($0.65-7.42) per dose, is about three times the median cost of monotherapy, $0.97 ($0.19-13.55). Total cost of medication (including co-medications) with ACT averaged $3.64 (95% CI; $3.53-3.75) per prescription, about twice the mean cost of treatment with monotherapy, $1.83 (95% CI; $1.57-2.1). Highest proportion 46.5% (614), of the anti-malarial drugs was dispensed to patients for self-treatment. Treatment by retail outlets accounted for 35.8% while 17.7% of the drugs were dispensed from hospital prescriptions. Self-medication, 82%, accounted for the highest source of monotherapy and

  19. Mining of miRNAs and potential targets from gene oriented clusters of transcripts sequences of the anti-malarial plant, Artemisia annua.

    PubMed

    Pérez-Quintero, Alvaro L; Sablok, Gaurav; Tatarinova, Tatiana V; Conesa, Ana; Kuo, Jimmy; López, Camilo

    2012-04-01

    miRNAs involved in the biosynthesis of artemisinin, an anti-malarial compound form the plant Artemisia annua, have been identified using computational approaches to find conserved pre-miRNAs in available A. annua UniGene collections. Eleven pre-miRNAs were found from nine families. Targets predicted for these miRNAs were mainly transcription factors for conserved miRNAs. No target genes involved in artemisinin biosynthesis were found. However, miR390 was predicted to target a gene involved in the trichome development, which is the site of synthesis of artemisinin and could be a candidate for genetic transformation aiming to increase the content of artemisinin. Phylogenetic analyses were carried out to determinate the relation between A. annua and other plant pre-miRNAs: the pre-miRNA-based phylogenetic trees failed to correspond to known phylogenies, suggesting that pre-miRNA primary sequences may be too variable to accurately predict phylogenetic relations.

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

    PubMed

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

    2011-02-01

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

  1. 3D structure and immunogenicity of Plasmodium falciparum sporozoite induced associated protein peptides as components of fully-protective anti-malarial vaccine.

    PubMed

    Alba, Martha P; Almonacid, Hannia; Calderón, Dayana; Chacón, Edgar A; Poloche, Luis A; Patarroyo, Manuel A; Patarroyo, Manuel E

    2011-12-16

    SIAP-1 and SIAP-2 are proteins which are implicated in early events involving Plasmodium falciparum infection of the Anopheles mosquito vector and the human host. High affinity HeLa and HepG2 cell binding conserved peptides have been previously identified in these proteins, i.e. SIAP-1 34893 ((421)KVQGLSYLLRRKNGTKHPVY(440)) and SIAP-1 34899 ((541)YVLNSKLLNSRSFDKFKWIQ(560)) and SIAP-2 36879 ((181)LLLYSTNSEDNLDISFGELQ(200)). When amino acid sequences have been properly modified (replacements shown in bold) they have induced high antibody titres against sporozoites in Aotus monkeys (assessed by IFA) and in the corresponding recombinant proteins (determined by ELISA and Western blot). (1)H NMR studies of these conserved native and modified high activity binding peptides (HABPs) revealed that all had α-helical structures in different locations and lengths. Conserved and corresponding modified HABPs displayed different lengths between the residues fitting into MHCII molecule pockets 1-9 and different amino acid orientation based on their different HLA-DRβ1(∗) binding motifs and binding registers, suggesting that such modifications were associated with making them immunogenic. The results suggested that these modified HAPBs could be potential targets for inclusion as components of a fully-effective, minimal sub-unit based, multi-epitope, and multistage anti-malarial vaccine.

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

    PubMed Central

    Kjær, Anders; Grevsen, Kai; Jensen, Martin

    2012-01-01

    Background and aims 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. Methodology 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), H2O2 (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. Principal results 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. Conclusions 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. PMID:22833781

  3. Communicating the AMFm message: exploring the effect of communication and training interventions on private for-profit provider awareness and knowledge related to a multi-country anti-malarial subsidy intervention

    PubMed Central

    2014-01-01

    Background The Affordable Medicines Facility - malaria (AMFm), implemented at national scale in eight African countries or territories, subsidized quality-assured artemisinin combination therapy (ACT) and included communication campaigns to support implementation and promote appropriate anti-malarial use. This paper reports private for-profit provider awareness of key features of the AMFm programme, and changes in provider knowledge of appropriate malaria treatment. Methods This study had a non-experimental design based on nationally representative surveys of outlets stocking anti-malarials before (2009/10) and after (2011) the AMFm roll-out. Results Based on data from over 19,500 outlets, results show that in four of eight settings, where communication campaigns were implemented for 5–9 months, 76%-94% awareness of the AMFm ‘green leaf’ logo, 57%-74% awareness of the ACT subsidy programme, and 52%-80% awareness of the correct recommended retail price (RRP) of subsidized ACT were recorded. However, in the remaining four settings where communication campaigns were implemented for three months or less, levels were substantially lower. In six of eight settings, increases of at least 10 percentage points in private for-profit providers’ knowledge of the correct first-line treatment for uncomplicated malaria were seen; and in three of these the levels of knowledge achieved at endline were over 80%. Conclusions The results support the interpretation that, in addition to the availability of subsidized ACT, the intensity of communication campaigns may have contributed to the reported levels of AMFm-related awareness and knowledge among private for-profit providers. Future subsidy programmes for anti-malarials or other treatments should similarly include communication activities. PMID:24495691

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

    SciTech Connect

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

    2012-06-19

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

  5. Crystallization, X-Ray Structure Determination and Structure-Based Drug Design for Targeted Malarial Enzymes

    DTIC Science & Technology

    1998-07-01

    COOPERATIVE AGREEMENT NUMBER DAMD17-95-2-5007 TITLE: Crystallization, X-ray Structure Determination and Structure-Based Drug Design for...approach for the develpment of anti-malarial agent using structure-based drug design . This technique will enable us to identify active site inhibitors...based drug design project high resolution three domensional structure of the enzyme - inhibitor complex provides the basis for further modifications

  6. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    DTIC Science & Technology

    2016-06-01

    the Plasmodium mammalian cycle . Identifying parasite proteins that are required for liver infection can lead to novel drugs against malaria. For the...mammalian cycle . Inhibiting this step can block malaria at an early step. However, few anti-malarials target liver infection by sporozoites. Our goal is...methods to synthesize TSP and TSP derivatives, we demonstrated that we could append a propargyl group to the piperidine ring nitrogen and that this

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

    PubMed Central

    Hassali, Mohamed Azmi Ahmad; Shafie, Asrul Akmal; Hussain, Azhar

    2013-01-01

    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. PMID:24223321

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

    NASA Astrophysics Data System (ADS)

    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.

  9. Experimental study and evaluation of radioprotective drugs

    NASA Technical Reports Server (NTRS)

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

    1968-01-01

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

  10. Characterization of two malaria parasite organelle translation elongation factor G proteins: the likely targets of the anti-malarial fusidic acid.

    PubMed

    Johnson, Russell A; McFadden, Geoffrey I; Goodman, Christopher D

    2011-01-01

    Malaria parasites harbour two organelles with bacteria-like metabolic processes that are the targets of many anti-bacterial drugs. One such drug is fusidic acid, which inhibits the translation component elongation factor G. The response of P. falciparum to fusidic acid was characterised using extended SYBR-Green based drug trials. This revealed that fusidic acid kills in vitro cultured P. falciparum parasites by immediately blocking parasite development. Two bacterial-type protein translation elongation factor G genes are identified as likely targets of fusidic acid. Sequence analysis suggests that these proteins function in the mitochondria and apicoplast and both should be sensitive to fusidic acid. Microscopic examination of protein-reporter fusions confirm the prediction that one elongation factor G is a component of parasite mitochondria whereas the second is a component of the relict plastid or apicoplast. The presence of two putative targets for a single inhibitory compound emphasizes the potential of elongation factor G as a drug target in malaria.

  11. Population genetics and drug resistance markers: an essential for malaria surveillance in Pakistan.

    PubMed

    Raza, Afsheen; Beg, Mohammad Asim

    2013-12-01

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

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

    PubMed Central

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

    2015-01-01

    The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established. PMID:25717373

  13. North Carolina Drug Education School Evaluation Instrument.

    ERIC Educational Resources Information Center

    Kim, Sewhan; And Others

    1985-01-01

    Describes the theoretical framework, measurement properties, predictive power, and reliability and validity of the Drug Education School Evaluation Instrument (DESEI), used to determine the effectiveness of the North Carolina Drug Education Schools. The DESEI is included. (BH)

  14. Students' Evaluations of Their Psychoactive Drug Use.

    ERIC Educational Resources Information Center

    Goldstein, Joel W.

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

  15. Plasmodium falciparum drug resistance in Angola.

    PubMed

    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.

  16. Evaluation of a Flipped Drug Literature Evaluation Course

    PubMed Central

    Moser, Lynette R.

    2016-01-01

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

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

    SciTech Connect

    Petzold, Christopher; Keasling, Jay

    2011-07-18

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

  18. Drug interaction microcomputer software evaluation: Drug Master 89.

    PubMed

    Poirier, T I; Giudici, R A

    1989-12-01

    Drug Master 89 was evaluated using general and specific criteria. The installation process, ease of learning, and ease of use were rated excellent. The technical support, scope of coverage, and overall clinical performance were rated good. The quality of the clinical documentation and frequency of updates were fair, while the quality of the user documentation was poor. The program is valuable to the clinical dietician because of the comprehensiveness of its dietary and food interactions data base. For the practicing pharmacist, it performs reasonably well but other available programs are better values.

  19. Development and Evaluation of Artesunate-Loaded Chitosan-Coated Lipid Nanocapsule as a Potential Drug Delivery System Against Breast Cancer.

    PubMed

    Tran, Tuan Hiep; Nguyen, Tuan Duc; Poudel, Bijay Kumar; Nguyen, Hanh Thuy; Kim, Jong Oh; Yong, Chul Soon; Nguyen, Chien Ngoc

    2015-12-01

    Artesunate (ART)--a well-known hydrophobic anti-malarial agent was incorporated in a polymer-lipid hybrid nanocolloidal system for anti-cancer therapeutic. The lipid negatively charged nanoemulsion was formulated by modified hot homogenization method then covered with positively charged chitosan via electrostatic interaction to obtain chitosan-coated lipid nanocapsule (ART-CLN). Physical properties of the system were characterized in terms of size, charge, morphology, drug loading capacity, and physical state. In addition, anti-cancer activities were confirmed by conducting MTT assay for ART and ART-CLN on different cancer cell lines. Obtained ART-CLN after coating chitosan revealed positive charge (13.2 ± 0.87 mV), small particle size (160.9 ± 3.5 nm), and spherical shape. High drug entrapment efficiency (95.49 ± 1.13%) and sustained release pattern were observed. Moreover, the good cellular uptake was recorded by flow cytometry as well as confocal image. Finally, ART-CLN exhibited stronger anti-cancer activity than free ART on breast cancer cell lines (MCF-7, MDA-MB-231). These results suggested that by loading ART into lipid core of polymer-lipid hybrid carrier, the activity and physical stability of ART can be significantly increased for cancer chemotherapy.

  20. 76 FR 45268 - Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-28

    ... HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research, Approach to... approach of the Center for Drug Evaluation and Research (CDER) to addressing drug shortages. This public... address drug shortage issues. Date and Time: The public workshop will be held on September 26, 2011,...

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

    PubMed

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

    2013-10-15

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

  2. Veterinary drugs: disposition, biotransformation and risk evaluation.

    PubMed

    Fink-Gremmels, J; van Miert, A S

    1994-12-01

    Veterinary drugs may only be produced, distributed and administered after being licensed. This implies that, prior to marketing, a critical evaluation of the pharmaceutical quality, the clinical efficacy and the over-all pharmacological and toxicological properties of the active substances will be performed by national and/or supranational authorities. However, despite a sophisticated legal (harmonized) framework, a number of factors involved in residue formation and safety assessment remain unpredictable or dependant on the current 'state of the art' in the understanding of molecular pharmacology and toxicology. For example, drug disposition and residue formation in the target animal species may be influenced by a broad variety of physiological parameters including age, sex and diet, as well as by pathological conditions especially the acute phase response to infection. These factors affect both drug disposition and metabolite formation. Furthermore, current thinking in toxicological risk assessment is influenced by recent developments in molecular toxicology and thus by an increased but still incomplete understanding of the interaction of a toxic compound with the living organism. General recognized principles in the evaluation of potential toxicants are applied in the recommendation of withdrawal times and the establishment of maximum residue limits (MRL values). Apart from toxicological-based assessment, increasing awareness is directed to other than toxicological responses, especially the potential risk of effects of antimicrobial residues on human gastrointestinal microflora. Thus, the methodology of risk assessment is discussed in the context of the recently established legal framework within the European Union.

  3. 76 FR 60505 - Center for Drug Evaluation and Research, Approach to Addressing Drug Shortage; Public Workshop...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ... 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...

  4. New Insight into Isoprenoids Biosynthesis Process and Future Prospects for Drug Designing in Plasmodium

    PubMed Central

    Saggu, Gagandeep S.; Pala, Zarna R.; Garg, Shilpi; Saxena, Vishal

    2016-01-01

    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. PMID:27679614

  5. Hospital pharmacists' evaluation of drug wholesaler services.

    PubMed

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

    1983-10-01

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

  6. Leachables evaluation for bulk drug substance.

    PubMed

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

    2009-01-01

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

  7. Evaluation of resources for analyzing drug interactions*†

    PubMed Central

    Patel, Risha I.; Beckett, Robert D.

    2016-01-01

    Objective The research sought to evaluate seven drug information resources, specifically designed for analyzing drug interactions for scope, completeness, and ease of use, and determine the consistency of content among the seven resources. Methods A cross-sectional study was conducted where 100 drug-drug and drug-dietary supplement interactions were analyzed using 7 drug information resources: Lexicomp Interactions module, Micromedex Drug Interactions, Clinical Pharmacology Drug Interaction Report, Facts & Comparisons eAnswers, Stockley's Drug Interactions (10th edition), Drug Interactions Analysis and Management (2014), and Drug Interaction Facts (2015). The interaction sample was developed based on published resources and peer input. Two independent reviewers gathered data for each interaction from each of the 7 resources using a common form. Results Eighty-two drug-drug and 18 drug-dietary supplement interactions were analyzed. Scope scores were higher for Lexicomp Interactions (97.0%), Clinical Pharmacology Drug Interaction Report (97.0%), and Micromedex Drug Interactions (93.0%) compared to all other resources (p<0.05 for each comparison). Overall completeness scores were higher for Micromedex Drug Interactions (median 5, interquartile range [IQR] 4 to 5) compared to all other resources (p<0.01 for each comparison) and were higher for Lexicomp Interactions (median 4, IQR 4 to 5), Facts & Comparisons eAnswers (median 4, IQR 4 to 5), and Drug Interaction Facts (4, IQR 4 to 5) compared to all other resources, except Micromedex (p<0.05 for each comparison). Ease of use, in terms of time to locate information and time to gather information, was similar among resources. Consistency score was higher for Micromedex (69.9%) compared to all other resources (p<0.05 for each comparison). Conclusions Clinical Pharmacology Drug Interaction Report, Lexicomp Interactions, and Micromedex Drug Interactions scored highest in scope. Micromedex Drug Interactions and Lexicomp

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

    PubMed

    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.

  9. Evaluation of drug information for cardiology patients.

    PubMed Central

    Baker, D; Roberts, D E; Newcombe, R G; Fox, K A

    1991-01-01

    1. Cardiologists and pharmacists at the University Hospital of Wales collaborated to write 20 individual leaflets incorporating guidelines for a range of drugs used in the treatment of cardiology patients. The Plain English Campaign advised on the intelligibility and presentation of the information. 2. One hundred and twenty-five patients from the Regional Cardiology Unit, University Hospital of Wales were randomly allocated to receive usual verbal counselling about their drug treatment with or without an individualised drug information wallet. Two weeks after discharge from hospital patients completed a postal questionnaire to determine their satisfaction with the information about their drug treatment and their understanding of it. Forty-nine questionnaires were returned from the leaflet group and 52 from the control group. 3. The provision of written guidelines resulted in significant improvements in patients' satisfaction with their drug treatment (chi 2 = 33.3, P less than 0.001) and their understanding of it (P less than 0.001, Mann-Whitney test). Overall, patients who received leaflets were more likely to be aware of the potential side effects of their drugs but less likely to be apprehensive about them. Succinct guidelines concerning drug therapy can be assimilated by cardiology patients and provide them with a permanent record for future reference. PMID:1888619

  10. Evaluation of efficacy and safety of a herbal medicine used for the treatment of malaria.

    PubMed

    Ankrah, Nii-Ayi; Nyarko, Alexander K; Addo, Phyllis G A; Ofosuhene, Mark; Dzokoto, Comfort; Marley, Ethel; Addae, Michael M; Ekuban, Frederick A

    2003-06-01

    Resistance of Plasmodium falciparum to chloroquine has been reported in several countries. Other anti-malarial drugs in use are expensive and not readily accessible to most people in malaria endemic countries. This has led to renewed interest in the development of herbal medicines that have the potential to treat malaria with little or no side effects. This study obtained a preliminary information on the safety and effectiveness of a plant decoction (AM-1), used in treating malaria. The AM-1 is formulated from Jatropha curcas, Gossypium hirsutum, Physalis angulata and Delonix regia. Patients with suspected malaria attending a herbal clinic were enrolled in the study on voluntary basis. They were hospitalized for treatment, clinical observation, biochemical and haematological monitoring, and parasite clearance while on AM-1. In addition male and female Sprague Dawley rats were used to evaluate the acute and subchronic toxicity effects of AM-1. The AM-1 eliminated malaria parasites (Plasmodium falciparum and Plasmodium malarie) from the peripheral blood of patients with malaria. In addition the AM-1 did not show any undesired effects in the patients as well as in laboratory rats. The AM-1, however, showed differential effect on the activities of selected cytochrome P450 isozymes (7-pentoxyresorufin-O-depentylation, 7-ethoxyresorufin-O-deethylation and p-nitrophenol hydroxylase) in relation to sex of the laboratory rats. These results indicate that AM-1 could be used to treat malaria. However, it could precipitate interactions with other drugs via their biotransformation and elimination. The obtained data warrant further studies in a large number of malaria subjects with monitoring for possible drug interactions.

  11. Clinical evaluation of hypnotic drugs: contributions from sleep laboratory studies.

    PubMed

    Kales, A; Scharf, M B; Soldatos, C R; Bixler, E O

    1979-07-01

    The most thorough and clinically relevant approach to hypnotic drug evaluation is one that balances the strengths and weaknesses of clinical trials and sleep laboratory evaluations. Advantages of clinical trials include the ability to evaluate large numbers of subjects and specific target groups and to thoroughly assess and quantify a drug's side effects, whereas sleep laboratory studies are very limited in all of these areas. Sleep laboratory studies however provide a rigorous, precise, and comprehensive profile of a drug's activity since there is more control over experimental variables and measurements are objective as well as continuous throughout the night. These benefits offset the shortcomings of clinical trials, which include a lack of objective measurements, less control over experimental variables, failure to evaluate a drug's effectiveness with continued use, and inattention to drug interaction and withdrawal effect. Several basic principles derived from sleep laboratory findings have been incorporated into both the clinical trials and sleep laboratory evaluations recommended in the new FDA Guidelines for the Clinical Evaluation of Hypnotic Drugs. These principles include provision for adequate baseline and withdrawal periods, use of multiple consecutive drug nights to assess a drug's effectiveness with continued use, and inclusion of an adequate washout period when a cross-over design is used. The guidelines do not emphasize either clinical trials or sleep laboratory studies at the expense of each other, but rather stress their complementary utilization.

  12. Anti-malarial, anti-algal, anti-tubercular, anti-bacterial, anti-photosynthetic, and anti-fouling activity of diterpene and diterpene isonitriles from the tropical marine sponge Cymbastela hooperi.

    PubMed

    Wright, Anthony D; McCluskey, Adam; Robertson, Mark J; MacGregor, Kylie A; Gordon, Christopher P; Guenther, Jana

    2011-01-21

    In an investigation into their potential ecological role(s), a group of mainly diterpene isonitriles, nine in total, isolated from the tropical marine sponge Cymbastela hooperi, and the sesquiterpene axisonitrile-3, isolated from the tropical marine sponge Acanthella kletra, were evaluated in a series of bioassays including anti-fouling, anti-algal, anti-photosynthetic, anti-bacterial (Gram +ve and -ve), anti-fungal, and anti-tubercular. The results of these assays showed that all of the tested compounds, with the exception of diterpene 9, were active in at least two of the applied test systems, with axisonitrile-3 (10) and diterpene isonitrile 1 being the two most active compounds overall, closely followed by diterpene isonitrile 3. Based on the results of the photosynthetic study a molecular modelling investigation was undertaken with all of the compounds used in that study. The results showed a positive correlation between reduction in photosynthetic activity and the interaction of the modelled compounds with a potential enzyme active site.

  13. Drug Evaluation in the Plasmodium Falciparum-Aotus Model

    DTIC Science & Technology

    1996-03-01

    with. drug resistant P. falciparum, chloroquine resist ance-l R) was reversed by chlorpromazine and prochlorperazine. Both water-insoluble and soluble...Animals of the Institute of Laboratory Resources, National Research Council (NIH Publication No. 86-23, Revised 1985) For the protection of human sub...new drugs be evaluated in the preclinical Aotus model for their potential usefulness against human infections. Initially, antimalarial drug studies

  14. An evaluation of protein assays for quantitative determination of drugs.

    PubMed

    Williams, Katherine M; Arthur, Sarah J; Burrell, Gillian; Kelly, Fionnuala; Phillips, Darren W; Marshall, Thomas

    2003-07-31

    We have evaluated the response of six protein assays [the biuret, Lowry, bicinchoninic acid (BCA), Coomassie Brilliant Blue (CBB), Pyrogallol Red-Molybdate (PRM), and benzethonium chloride (BEC)] to 21 pharmaceutical drugs. The drugs evaluated were analgesics (acetaminophen, aspirin, codeine, methadone, morphine and pethidine), antibiotics (amoxicillin, ampicillin, gentamicin, neomycin, penicillin G and vancomycin), antipsychotics (chlorpromazine, fluphenazine, prochlorperazine, promazine and thioridazine) and water-soluble vitamins (ascorbic acid, niacinamide, pantothenic acid and pyridoxine). The biuret, Lowry and BCA assays responded strongly to most of the drugs tested. The PRM assay gave a sensitive response to the aminoglycoside antibiotics (gentamicin and neomycin) and the antipsychotic drugs. In contrast, the CBB assay showed little response to the aminoglycosides and gave a relatively poor response with the antipsychotics. The BEC assay did not respond significantly to the drugs tested. The response of the protein assays to the drugs was further evaluated by investigating the linearity of the response and the combined response of drug plus protein. The results are discussed with reference to drug interference in protein assays and the development of new methods for the quantification of drugs in protein-free solution.

  15. Evaluation of Temple University's Drug Abuse Prevention Program.

    ERIC Educational Resources Information Center

    Swisher, John D.; Horman, Richard E.

    Temple University's concern for the problem of drug abuse culminated in a Retreat on the Hazards of Drug Abuse. Participants were undergraduates, graduates, and staff. An evaluation design, involving pre- and post-testing, had previously been designed to test for information gains and attitude changes. A followup was designed to focus on…

  16. Evaluation of the NexScreen and DrugCheck Waive RT urine drug detection cups.

    PubMed

    Lin, Chia-Ni; Nelson, Gordon J; McMillin, Gwendolyn A

    2013-01-01

    Urine drug testing is an important tool that is commonly used to assess patient compliance with prescription regimens. Point-of-collection immunoassay devices allow for timely availability of laboratory test results to guide therapy during the same office visit. Two waived immunoassay-based urine drug screen cups were evaluated in this study. The NexScreen cup and the DrugCheck Waive RT cup claim to detect 10-12 drug classes of commonly used and/or abused drugs. This study included a sensitivity and precision challenge with 4-6 replicates at concentrations 0-150% of the manufacture's claimed cutoff, using drug-free urine spiked with purified reference standards. The stability of test results was evaluated by reading the results at intervals between five and 1,440 min. Specificity was evaluated by parallel comparison of pooled patients' specimens, representing 56 patients and 41 known drug compounds. When comparing results to validated liquid chromatography-mass spectrometry results, false positives were observed in the NexScreen cups for benzodiazepine, methamphetamine, methadone, opiates and tricyclic antidepressant tests, but there were no false negatives. The DrugCheck Waive RT cups showed false negative results for barbiturates and opiates, but no false positives. Overall, the NexScreen cup demonstrated better sensitivity than claimed, whereas the sensitivity of the DrugCheck Waive RT cup did not meet claims.

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

    PubMed

    Tren, Richard; Hess, Kimberly; Bate, Roger

    2009-12-22

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

  18. Malaria in South America: a drug discovery perspective

    PubMed Central

    2013-01-01

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

  19. Drug Evaluation in the Plasmodium Falciparum - Aotus Model.

    DTIC Science & Technology

    1992-03-23

    AOTUS MODEL PRINCIPAL INVESTIGATOR: Richard N. Rossan, Ph.D. CONTRACTING ORGANIZATION: PROMED TRADING, S.A. P.O. Box 025426, PTY-051 Miami, Florida...91 - 2/28/92) 4. TITLE AND SUBTITLE S. FUNDING NUMBERS DRUG EVALUATION IN THE PLASMODIUM FALCIPARUM - Contract No. AOTUS MODEL DAMD17-91-C-1072 6C...words) Tne Panamanian Autus - PLasmodium falciparum model was used to evaluate potential antimalaria drugs. Neither protriptylene nor tetrandrine, each

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

    PubMed Central

    Miller, Laurence L.

    2014-01-01

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

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

    ERIC Educational Resources Information Center

    Magura, Stephen

    2010-01-01

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

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

  3. Formulation and evaluation of transdermal drug delivery of topiramate

    PubMed Central

    Cherukuri, Suneetha; Batchu, Uma Rajeswari; Mandava, Kiranmai; Cherukuri, Vidhyullatha; Ganapuram, Koteswara Rao

    2017-01-01

    Background: Transdermal drug delivery system (TDDS) was designed to sustain the release and improve the bioavailability of drug and patient compliance. Among the various types of transdermal patches, matrix dispersion type systems disperse the drug in the solvent along with the polymers and solvent is allowed to evaporate forming a homogeneous drug-polymer matrix. The objective of the present study was to design and formulate TDDS of topiramate (TPM) and to evaluate their extended release in vitro and ex vivo. Materials and Methods: In the present study, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising TPM with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent casting technique. Results: The physicochemical compatibility of the drug and the polymers was studied by Fourier transform infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the ex vivo permeation studies using pig ear skin. Conclusions: On the basis of results obtained from the physical evaluation and ex vivo studies the patches containing the polymers, that is, Eudragit L 100 and polyvinylpyrrolidone, with oleic acid as the penetration enhancer were considered as the best formulations for the transdermal delivery of TPM.

  4. Hepatocytes as a tool in drug metabolism, transport and safety evaluations in drug discovery.

    PubMed

    Sahi, Jasminder; Grepper, Susan; Smith, Cornelia

    2010-09-01

    The liver is the primary site of metabolism for most drugs. Its major roles include detoxification of the systemic and portal blood, and production and secretion of critical blood and biliary components. A number of liver-derived in vitro systems, such as slices, primary and immortalized hepatocytes, microsomes and S9 fractions are used to assess the metabolism and potential toxicity of new chemical entities. Over the past decade, primary hepatocytes have become a standard in vitro tool to evaluate hepatic drug metabolism, cytochrome P450 (P450) induction, and drug interactions affecting hepatic metabolism. While earlier, hepatocytes were used in suspension for metabolic stability evaluations, more recent studies have demonstrated the added value of using these over longer terms in primary culture. Primary hepatocyte cultures are particularly useful in the evaluation of low turn-over compounds. Hepatic transporter studies are recommended for drug candidates that are predominantly eliminated through the bile. An appropriate strategy is to use primary hepatocytes to assess uptake, followed by singly transfected cell lines to identify the specific transporter(s) involved. Primary hepatocytes can also be used to assess biliary clearance to enable improved hepatic clearance predictions. Newer technologies such as siRNA can be used to knock out specific transporters for more predictive evaluations of potential clinically-based drug-drug interactions. In vitro safety (toxicology) studies have historically been conducted using cell lines. There is increasing evidence that co-cultures of primary hepatocytes and Kupffer cells would be more predictive of the in vivo outcome, as this system provides the complete complement of drug metabolizing enzymes, transcription factors and cytokines necessary to get a more in vivo-like toxicological response. In this review, we will discuss standard and novel in vitro approaches for using primary hepatocytes to extrapolate clinical

  5. An evaluation of the drug calculation skills of registered nurses.

    PubMed

    Fleming, Sandra; Brady, Anne-Marie; Malone, Anne-Marie

    2014-01-01

    Mathematical skill and proficiency underpin a number of nursing activities, with the most common application being in relation to drug dosage calculation and administration. Medication errors have been identified as the most common type of error affecting patient safety and the most common single preventable cause of adverse events and they can occur as a result of mathematical calculation error and or conceptual error. The purpose of this study was to evaluate the drug calculation skills of registered nurses (n = 124) on commencement of employment. The findings of this study indicate that there are inconsistencies in the amount of pharmacology content and drug calculation skills delivered within nursing curricula. The most frequent type of drug calculation errors are attributed to conceptual errors and participants identified ward based education on drug calculation as a pathway for improving the drug calculation skills of registered nurses. The study recommends that medication education, encompassing mathematical and conceptual drug calculation skills should be identified as a distinct competency in nursing curricula and continuing education programme.

  6. Evaluation of a drug abuse prevention program: a field experiment.

    PubMed

    LoSciuto, L; Ausetts, M A

    1988-01-01

    The central aim of this study was to evaluate Project PRIDE, a school-based affective education program offered in select schools since 1970 and throughout the entire Philadelphia Public School System since 1981. The primary purpose of the program is to increase youth's resistance to drug use and abuse through weekly small group counseling sessions. The 12 weekly student sessions focused on developing self-awareness, life skills, knowledge, and appropriate attitudes about drugs. Project PRIDE also developed training modules for teachers and parents. Evaluation was by means of a true experimental pretest-posttest design, with random assignment to treatment and control groups. Measures of attitudes, self-reported drug use, and behavioral intentions were administered to students, teachers, and parents; process evaluation measures of the student component were collected throughout the treatment period as well. Data analyses indicate that, while a few of the broad aims of the prevention program were not met, there were reliable changes in the intended direction in many of the students' attitudes and intentions. Student attitudes toward drug use and knowledge about drugs both improved. Project PRIDE participation was associated with a relative decrease in willingness to experiment with drugs, even though all groups showed strongly negative attitudes toward drug use. Treatment interacted with sex of student and/or SES on a number of items. Generally, effects were more pronounced for girls and for low SES students. All groups of participants felt they gained significant knowledge and skills from the program. Other effects for parents and teachers were infrequent and inconsistent.

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

    ERIC Educational Resources Information Center

    Betros, Emeel S.; And Others

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

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

    PubMed Central

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

    2015-01-01

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

  9. Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

    NASA Astrophysics Data System (ADS)

    Howard, Brittany L.; Thompson, Philip E.; Manallack, David T.

    2011-08-01

    The similarity between Plasmodium falciparum phosphodiesterase enzymes ( PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDEα. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

  10. 77 FR 35689 - Guidance for Industry on Irritable Bowel Syndrome-Clinical Evaluation of Drugs for Treatment...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-14

    ... Evaluation of Drugs for Treatment; Availability; Correction AGENCY: Food and Drug Administration, HHS. ACTION... guidance for industry entitled ``Irritable Bowel Syndrome--Clinical Evaluation of Drugs for...

  11. Drug-usage evaluation by disease state: developing protocols.

    PubMed

    Enlow, M L

    1996-07-01

    The Joint Commission definition of drug-usage evaluation (DUE) also applies to DUE by disease state. The criteria for disease process selection, key processes being evaluated, methods to develop initial DUE protocols, and DUE validation and approval processes are reviewed. The treatment of community-acquired pneumonia is a disease state DUE performed at Saint Joseph Health Center in Kansas City, Missouri. The preliminary protocol was developed by a collaborative network of clinical pharmacists in the metropolitan area. Outcome measures were included in the evaluation. The results were used as baseline data in the development of a pneumonia clinical pathway.

  12. Evaluation of Factors Affecting Powdered Drug Reconstitution in Microgravity

    NASA Technical Reports Server (NTRS)

    Schaffner, Grant; Johnston, Smith; Marshburn, Tom

    1999-01-01

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

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

    PubMed

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

    2010-03-12

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Kodadová, Alexandra; Vitková, Zuzana; Herdová, Petra

    2013-10-01

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

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

    PubMed

    Marshall, Valerie; Baylor, Norman W

    2011-05-01

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

  17. Drug Evaluation in the Plasmodium Falciparum-Aotus Model

    DTIC Science & Technology

    1996-03-01

    liver and erythrocytic stages of P. falciparum. If successful, it will establish for the first time that DNA vaccines can protect non- human primates, a...of the Institute of Laboratory Resources, National Research Council (NIH Publication No. 86-23, Revised 1985). For the protection of human subjects...essential that new drugs be evaluated in the preclinical Aotus model for their potential usefulness against human infections. Initially, antimalarial

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

    SciTech Connect

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

    2010-03-01

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

  19. Drug interactions evaluation: an integrated part of risk assessment of therapeutics.

    PubMed

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

    2010-03-01

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

  20. Cellular Tests for the Evaluation of Drug Hypersensitivity.

    PubMed

    Ariza, Adriana; Montanez, Maria I; Fernandez, Tahia D; Perkins, James R; Mayorga, Cristobalina

    2016-01-01

    The diagnosis of drug hypersensitivity reactions (DHR) is complex, with many potential pitfalls. Although the use of clinical history and skin testing can be valuable, drug provocation testing (DPT) remains the gold standard for many DHR. However, DPT carries some potential risk and should not be performed for severe reactions. There is therefore a general consensus on the need to improve in vitro tests to achieve safe and accurate diagnosis of DHR. A range of in vitro approaches can be applied depending on the type of reaction and the immunological mechanism involved, i.e. IgE- or T-cell-mediated. However, commercially available tests only exist for a handful of drugs, and only for drugs that provoke IgEmediated DHR. Of the cellular tests that focus on the identification of the culprit drug, the best validated is the basophil activation test used for evaluating IgE-mediated reactions. For T-cell-mediated DHR, the lymphocyte transformation test and enzyme-linked immunosorbent spot appear to be the most promising. However, these tests often show low sensitivity. Despite their current drawbacks, in vitro tests can complement in vivo testing and further work in this area will be crucial to improve our current arsenal of tools for the detection and assessment of DHR. For this, the use of appropriate and relevant drug metabolites as well as other factors that can amplify the cell response as well as the use of multiple tests in concert key to improving in vitro diagnosis. Such improvements will be crucial to diagnose patients with severe reactions for whom DPT cannot be performed.

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

    PubMed

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

    2010-03-01

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

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

    PubMed Central

    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

  3. Animal models to evaluate anti-atherosclerotic drugs.

    PubMed

    Priyadharsini, Raman P

    2015-08-01

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

  4. Evaluation of SMS reminder messages for altering treatment adherence and health seeking perceptions among malaria care-seekers in Nigeria

    PubMed Central

    Liu, Jenny X.; Modrek, Sepideh

    2016-01-01

    In Nigeria, access to malaria diagnostics may be expanded if drug retailers were allowed to administer malaria rapid diagnostic tests (RDTs). A 2012 pilot intervention showed that short message service (SMS) reminder messages could boost treatment adherence to RDT results by 10–14% points. This study aimed to replicate the SMS intervention in a different population, and additionally test the effect of an expanded message about anticipated RDT access policy change on customers’ acceptability for drug retailers’ administration of RDTs. One day after being tested with an RDT, participants who purchased malaria treatment from drug shops were randomized to receive (1) a basic SMS reminder repeating the RDT result and appropriate treatment actions, (2) an expanded SMS reminder additionally saying that the ‘government might allow pharmacists/chemists to do RDTs’ or (3) no SMS reminders (i.e. control). Using regression analysis, we estimate intent-to-treat (ITT) and treatment effects on the treated for 686 study participants. Results corroborate previous findings that a basic SMS reminder increased treatment adherence [odds ratio (OR) = 1.53, 95% CI 0.96–2.44] and decreased use of unnecessary anti-malarials for RDT-negative adults [OR = 0.63, 95% CI 0.39–1.00]. The expanded SMS also increased adherence for adults [OR = 1.42, 95% CI 0.97–2.07], but the effects for sick children differed—the basic SMS did not have any measurable impact on treatment adherence [OR = 0.87, 95% CI 0.24–3.09] or use of unnecessary anti-malarials [OR = 1.27, 95% CI 0.32–1.93], and the expanded SMS actually led to poorer treatment adherence [OR = 0.26, 95% CI 0.10–0.66] and increased use of unnecessary anti-malarials [OR = 4.67, 95% CI 1.76–12.43]. Further, the targeted but neutral message in the expanded SMS lowered acceptance for drug retailers' administration of RDTs [OR = 0.55, 95% CI 0.10–2.93], counter to what we hypothesized. Future

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

    PubMed

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

    1998-04-01

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

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

    PubMed Central

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

    1998-01-01

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

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

    PubMed

    Kondo, Ayumi; Satou, Yoshitaka; Matsumoto, Toshihiko

    2016-02-01

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

  8. [Evaluation of pharmacokinetic drug-drug-interactions. Critical considerations of the relevance of pharmacokinetic drug-drug interactions of proton pump inhibitors in self medication].

    PubMed

    Petersen, Karl-Uwe

    2011-08-01

    Mechanisms and evaluation of pharmacokinetic drug interactions are discussed in general, including mechanisms beyond the hepatic phase-I reactions, and especially for the example of proton pump inhibitors (PPI), preferentially omeprazole. Particular attention is paid to the use of PPI as self-prescribed drugs. The sequelae of pharmacokinetic drug interactions can be serious. However, only the evidence of clinical consequences will convert such an interaction from a laboratory finding into a possible adverse effect. Without this, interacting drugs can still be co-administered if the specific characteristics of the concerned drugs, quantitative aspects of the interaction, and especially severity and frequency of possible clinical correlates are taken into consideration. It is encouraging that the laboratory findings reported for the PPI--in vitro or ex vivo from volunteer studies--have hardly found equivalents in clinical consequences. As of today, this is also true of the widely discussed interaction with clopidogrel. Regarding the safety of use of PPI as self-prescribed drugs, it also needs to be emphasized that a sizable number of interactions reported for omeprazole and/or pantoprazole were observed at higher dose levels than the 20 mg licensed for self medication. In conjunction with the temporal limitation of PPI self-prescription (14 days), it can be expected that pharmacokinetic drug interactions will generally be no critical factor in the usage of PPI in self-medication. However clinically relevant interactions can occur, e.g. when PPI are combined with extracts from St. John's wort, methotrexat or some inhibitors of HIV-protease with pH-dependent absorption.

  9. 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

    PubMed Central

    2013-01-01

    Background 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. Methods 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. Results 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

  10. Evaluation of antibiotic allergy: the role of skin tests and drug challenges.

    PubMed

    Solensky, Roland; Khan, David A

    2014-09-01

    Antibiotic allergies are frequently reported in both adult and pediatric populations. While a detailed drug history is essential in the evaluation of antibiotic allergy, the history is typically insufficient to determine the presence of a drug allergy. The most readily available diagnostic testing for evaluating antibiotic allergies are drug skin testing and drug challenges. This review will focus on updates in the evaluation of antibiotic allergy utilizing immediate skin tests, delayed intradermal testing, drug patch tests, and drug challenges for both adults and children with histories of antibiotic allergies.

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

    PubMed Central

    2013-01-01

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

  12. Evaluating Melanoma Drug Response and Therapeutic Escape with Quantitative Proteomics*

    PubMed Central

    Rebecca, Vito W.; Wood, Elizabeth; Fedorenko, Inna V.; Paraiso, Kim H. T.; Haarberg, H. Eirik; Chen, Yi; Xiang, Yun; Sarnaik, Amod; Gibney, Geoffrey T.; Sondak, Vernon K.; Koomen, John M.; Smalley, Keiran S. M.

    2014-01-01

    The evolution of cancer therapy into complex regimens with multiple drugs requires novel approaches for the development and evaluation of companion biomarkers. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) is a versatile platform for biomarker measurement. In this study, we describe the development and use of the LC-MRM platform to study the adaptive signaling responses of melanoma cells to inhibitors of HSP90 (XL888) and MEK (AZD6244). XL888 had good anti-tumor activity against NRAS mutant melanoma cell lines as well as BRAF mutant cells with acquired resistance to BRAF inhibitors both in vitro and in vivo. LC-MRM analysis showed HSP90 inhibition to be associated with decreased expression of multiple receptor tyrosine kinases, modules in the PI3K/AKT/mammalian target of rapamycin pathway, and the MAPK/CDK4 signaling axis in NRAS mutant melanoma cell lines and the inhibition of PI3K/AKT signaling in BRAF mutant melanoma xenografts with acquired vemurafenib resistance. The LC-MRM approach targeting more than 80 cancer signaling proteins was highly sensitive and could be applied to fine needle aspirates from xenografts and clinical melanoma specimens (using 50 μg of total protein). We further showed MEK inhibition to be associated with signaling through the NFκB and WNT signaling pathways, as well as increased receptor tyrosine kinase expression and activation. Validation studies identified PDGF receptor β signaling as a potential escape mechanism from MEK inhibition, which could be overcome through combined use of AZD6244 and the PDGF receptor inhibitor, crenolanib. Together, our studies show LC-MRM to have unique value as a platform for the systems level understanding of the molecular mechanisms of drug response and therapeutic escape. This work provides the proof-of-principle for the future development of LC-MRM assays for monitoring drug responses in the clinic. PMID:24760959

  13. The Screening and Evaluation of Experimental Antiparasitic Drugs

    DTIC Science & Technology

    1990-08-04

    Chemotherapy of Drug-Sensitive African Trypanosomiasis 33 INTRODUCTION 33 METHODS 34 Animals Hosts 34 Inoculation of Parasites 34 Drug... Chemotherapy of Drug-Resistant African Trypanosomiasis 38 INTRODUCTION 38 METHODS 39 Aninals Hosts 39 Inoculation of Parasites 39 Drug Administration 39 Cross...malaria situation. Vector control problems have continuously failed leaving malaria to be controlled by chemotherapy . Attempts to control Plasmodium

  14. 78 FR 16679 - Center for Drug Evaluation and Research Medical Policy Council; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-18

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

  15. Interchangeability Evaluation of Multisource Ibuprofen Drug Products Using Biowaiver Procedure

    PubMed Central

    Shohin, I. E.; Kulinich, J. I.; Vasilenko, G. F.; Ramenskaya, G. V.

    2011-01-01

    The WHO biowaiver procedure for BCS Class II weak acids was evaluated by running two multisource IR ibuprofen drug products (Ibuprofen, 200 mg tablets, Tatchempharmpreparaty, Russia and Ibuprofen, 200 mg tablets, Biosintez, Russia) with current Marketing Authorizations (i.e. in vivo bioequivalent) through that procedure. Risks associated with excipients interaction and therapeutic index were considered to be not critical. In vitro dissolution kinetic studies were carried out according WHO Guidance (WHO Technical Report Series, No. 937, Annexes 7 and 8) using USP Apparatus II (paddle method) at 75 rpm. Dissolution profiles of test and reference ibuprofen tablets were considered equivalent in pH 4.5 using factors f1 (13) and f2 (72) and not equivalent in pH 6.8 (factor f1 was 26 and f2 was 24). Drug release of ibuprofen at pH 1.2 was negligible due to its weak acid properties. Therefore, two in vivo bioequivalent tablets were declared bioinequivalent by this procedure, indicating that procedure seems to be over-discriminatory. PMID:22707831

  16. The Screening and Evaluation of Experimental Antiparasitic Drugs

    DTIC Science & Technology

    1990-03-01

    Chemotherapy of Drug-Sensitive African Trypanosomiasis 30 Introduction 30 Methods 31 Animals Hosts 31 Inoculation of Parasites 32 Drug Administration 32...06 D3 rug-resistant malaria, Chloroquine-resistant malaria, Calciu 06 03 Channel Blockers, Vitamin E, African trypanosomiasis , (OVER) 19. NEBSTRACT...Drug Activity 33 Results 33 Controls 33 Compounds Tested 34 Table XI Summary of Drug-Sensitive Trypanosoma rhodesiense Results 35 Chemotherapy of Drug

  17. The role of quantitative safety evaluation in regulatory decision making of drugs.

    PubMed

    Chakravarty, Aloka G; Izem, Rima; Keeton, Stephine; Kim, Clara Y; Levenson, Mark S; Soukup, Mat

    2016-01-01

    Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general.

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

    SciTech Connect

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

    2010-03-01

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

  19. Evaluation of drug-related hypersensitivity reactions in children.

    PubMed

    Martín-Muñoz, F; Moreno-Ancillo, A; Domínguez-Noche, C; Díaz-Pena, J M; García-Ara, C; Boyano, T; Ojeda, J A

    1999-01-01

    Patients with drug reactions are often referred to allergists for "allergy". Skin testing and clinical history seem to have a good negative predictive value, however, although drug challenge could be dangerous, it is the only way to confirm the diagnosis. We aimed to demonstrate that most children with a history of non-life-threatening drug reactions do not have a true drug allergy and examined the use of drug challenge in childhood. Patients with reactions were referred to our clinic by pediatricians. In 1 year, 354 reactions were studied in 239 children. Patients were classified according to their positive or negative history of drug allergy. Skin prick testing was done in all cases. Exclusion criteria for challenge included drug anaphylaxis, Stevens-Johnson syndrome, systemic reactions with severe concomitant illness, beta-inhibitor drug therapy or positive skin test to the implicated drug with a positive history. It was found that the beta-lactam antibiotics were involved in 50% of suspected reactions, aspirin in 10% and sulfonamides in 9%. Histories were considered positive only in 25%. Drug challenges confirmed only 4% of all reactions. It was concluded that drug challenge may be the gold standard for most childhood reactions that are considered to be allergic, non-life-threatening and drug-related. Only 4% of these suspected reactions were exclusively caused by drug allergy.

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

    PubMed Central

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

    2015-01-01

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

  1. A regulatory perspective on the abuse potential evaluation of novel stimulant drugs in the United States.

    PubMed

    Calderon, Silvia N; Klein, Michael

    2014-12-01

    In the United States of America (USA), the abuse potential assessment of a drug is performed as part of the safety evaluation of a drug under development, and to evaluate if the drug needs to be subject to controls that would minimize the abuse of the drug once on the market. The assessment of the abuse potential of new drugs consists of a scientific and medical evaluation of all data related to abuse of the drug. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, in general, including novel stimulants. The role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs, and its role in drug control are also discussed. A definition of abuse potential, an overview of the currently accepted approaches to evaluating the abuse potential of a drug, as well as a description of the criteria that applies when recommending a specific level of control (i.e., a Schedule) for a drug under the Controlled Substances Act (CSA). This article is part of the Special Issue entitled 'CNS Stimulants'.

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

    ERIC Educational Resources Information Center

    Silva, Roberta K.

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

  3. Summary of the Evaluation of the Phoenix Pilot Drug Program.

    ERIC Educational Resources Information Center

    Emrich, Robert L.; Green, Patricia

    The goal of the Phoenix Pilot Drug Program is to provide a drug/alcohol free educational environment which will enable students to reduce their drug/alcohol usage and function in a regular school program. To determine the degree to which the program is accomplishing these short-term goals, and also to examine the adequacy of the counseling…

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

    PubMed

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

    2014-07-23

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

  5. Assessing Treatment: The Conduct of Evaluation within Drug Abuse Treatment Programs. Treatment Research Report.

    ERIC Educational Resources Information Center

    Tims, Frank M.

    The need for evaluation of drug abuse treatment programs has been generally recognized and mandated by law since 1976. To learn to what extent such evaluations are actually performed and to obtain information about those evaluations, drug abuse treatment programs receiving federal funds in 1979 were surveyed. Questionnaires were sent to a random…

  6. The Nation's Toughest Drug Law: Evaluating the New York Experience. Final Report of the Joint Committee on New York Drug Law Evaluation.

    ERIC Educational Resources Information Center

    1978

    This volume presents the results of a three-year study of the impact of New York State's strict drug law, which was enacted in 1973. The study was undertaken by the Joint Committee on New York Drug Law Evaluation, established by the Association of the Bar of the City of New York and the Drug Abuse Council, Inc. The volume has three main sections.…

  7. [Pharmacovigilance idea should be introduced sufficiently into the safety monitoring and evaluation process of Chinese drugs].

    PubMed

    Zhang, Li; Yang, Xiao-Hui

    2009-09-01

    Along with the general improving of public consciousness on drugs' safety and the increasing of new Chinese drugs' manufacture and application, the safety of Chinese drugs has become a more prominent concern and a focus of attention. The scientific identification, analysis and evaluation of this affairs greatly impacts the scientific decision-making for ensuring the public use of drugs in security, also influences the healthy development of Chinese medicine industry. In this paper, the different meanings of "adverse reaction" and "adverse events" of Chinese drugs were introduced from pharmacovigilance idealistic view, and the influencing factors on safety of Chinese drugs were analyzed from the perspective of pharmacovigilance. The authors proposed that "Chinese medicine safety monitoring and evaluation" is a much more practical concept in consistency with the current situation. They pointed out that introducing sufficiently the concept of pharmaco vigilance idea into the safety monitoring and evaluation process is the basis for overall evaluation and effective risk controlling of Chinese drugs.

  8. [Significance of re-evaluation and development of Chinese herbal drugs].

    PubMed

    Gao, Yue; Ma, Zengchun; Zhang, Boli

    2012-01-01

    The research of new herbal drugs involves in new herbal drugs development and renew the old drugs. It is necessary to research new herbal drugs based on the theory of traditional Chinese medicine (TCM). The current development of famous TCM focuses on the manufacture process, quality control standards, material basis and clinical research. But system management of security evaluation is deficient, the relevant system for the safety assessment TCM has not been established. The causes of security problems, security risks, target organ of toxicity, weak link of safety evaluation, and ideas of safety evaluation are discussed in this paper. The toxicology research of chinese herbal drugs is necessary based on standard of good laboratory practices (GLP), the characteristic of Chinese herbal drugs is necessary to be fully integrated into safety evaluation. The safety of new drug research is necessary to be integrated throughout the entire process. Famous Chinese medicine safety research must be paid more attention in the future.

  9. 76 FR 72422 - Draft Guidance for Industry on Evaluating the Effectiveness of Anticoccidial Drugs in Food...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ... clinical effectiveness studies, and describes criteria that the Center for Veterinary Medicine (CVM) thinks... represent the Agency's current thinking on evaluating the effectiveness of anticoccidial drugs in...

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

    PubMed

    Zhang, Q I; Wang, Shanshan; Yang, Dexuan; Pan, Kevin; Li, Linna; Yuan, Shoujun

    2016-05-01

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

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

    PubMed Central

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

    2016-01-01

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

  12. Comparative evaluation of humic substances in oral drug delivery

    PubMed Central

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

    2011-01-01

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

  13. [Current evaluation of teratogenic and fetotoxic effects of psychotropic drugs].

    PubMed

    Watanabe, Omi

    2014-01-01

    Psychiatric disorders are equally common among pregnant and non-pregnant women, and many of these conditions are treated with psychotropic medications. The use of psychotropic medicines during pregnancy, especially antidepressants, became increasingly prevalent in the early 2000's, although many physicians prefer not to prescribe drugs for pregnant women due to concerns about teratogenicity. Current data on the risks of in utero exposure to psychotropic medications are limited, leaving women and physicians to make difficult decisions regarding the initiation or maintenance of treatment during pregnancy without a complete knowledge of the risks. Of all the psychotropics, antidepressant use in pregnancy has been relatively well studied. However, available studies have not yet adequately controlled for other factors that may influence birth outcomes, including maternal illness or problematic health-related behaviors such as smoking and alcohol use during pregnancy. This review focuses on the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, the antidepressants most commonly used to treat depression. In the evaluation of medication during pregnancy, teratogenicity and fetotoxicity must be considered. Most studies on the use of SSRIs during the first trimester of pregnancy have not shown an increase in the overall risk of major malformations, although several studies have suggested that SSRIs may be associated with a small increased risk of cardiovascular malformations, mainly involving ventricular and atrial septal defects. In addition to structural malformations, drugs were also observed to induce other adverse effects. Since SSRIs readily cross the placenta, concern has been raised about the short- or long-term effects of prenatal exposure to SSRIs on the developing offspring. Epidemiological studies have documented that 10-30% of neonates exposed to SSRIs near term had poor neonatal adaptation syndrome (PNAS). Some studies reported that

  14. Drugs for treating urinary schistosomiasis

    PubMed Central

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

    2014-01-01

    , another anti-malarial mefloquine has been evaluated in two small trials with inconsistent effects. Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality. Authors' conclusions Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base. Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures. Plain Language summary Drugs for treating urinary schistosomiasis What is urinary schistosomiasis and how is it treated? Urinary schistosomiasis is a disease caused by infection of people with the parasitic worm Schistosoma haematobium. These worms live in blood vessels around the infected person's bladder and the worm releases eggs which are released in the person's urine. If the urine is passed into ponds or lakes, the eggs can hatch and infect people that are washing or swimming there. Infection can cause blood in the urine and if left untreated can eventually lead to anaemia, malnutrition, kidney failure, or bladder cancer. Urinary schistosomiasis is diagnosed by looking for worm eggs in the urine. The disease occurs mainly in school-aged children and young adults in sub-Saharan Africa. The drug currently recommended for treatment is praziquantel, which can be given as a single dose, but other drugs such as metrifonate, artesunate, and mefloquine have also been evaluated. After examining the research published up to 23th May 2014, we included 30 randomized controlled trials, enrolling 8165 children and adults. What does the research say? On average, the standard dose of praziquantel cures around 60% of people at one to two months after treatment (high quality

  15. Drug evaluation: ADI-PEG-20--a PEGylated arginine deiminase for arginine-auxotrophic cancers.

    PubMed

    Shen, Li-Jiuan; Shen, Wei-Chiang

    2006-06-01

    Pheonix is developing ADI-PEG-20, a PEGylated arginine deiminase for the potential treatment of hepatocellular carcinoma, for which the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products have granted the drug Orphan Drug status, and melanoma, for which the FDA has also awarded ADI-PEG-20 Orphan Drug status. ADI-PEG-20 is also being investigated for the potential treatment of influenza virus infection and hepatitis C virus infection.

  16. A Process Evaluation of a Comprehensive Drug Education Training Package.

    ERIC Educational Resources Information Center

    Dewit, David J.; And Others

    1996-01-01

    Examined effects of a comprehensive drug education training package on the planning, development, and implementation of drug education lessons. Results based on 205 teacher questionnaires indicate a high approval rating. A majority of teachers reported that they would recommend the program to their colleagues; one-quarter reported using it to…

  17. Evaluation of postmortem redistribution phenomena for commonly encountered drugs.

    PubMed

    Han, Eunyoung; Kim, Eunmi; Hong, Hyojeong; Jeong, Sujin; Kim, Jihyun; In, Sangwhan; Chung, Heesun; Lee, Sangki

    2012-06-10

    We described the findings of a study into the post-mortem redistribution (PMR) of 76 drugs found in 129 drug-related cases between 2006 and 2009. Seventy six drugs (psychotropic drugs (n=14), antidepressants (n=9), sedatives (n=6) and so on) were simultaneously quantified in cardiac and peripheral blood by gas chromatography-mass spectrometry (GC/MS) or liquid chromatography-tandem mass spectrometry (LC/MS/MS). The absence, possibility or presence of PMR of drugs was determined according to the ratios of cardiac to femoral blood concentrations (C/P ratios). Proxyphylline (C/P ratio: 0.85) showed no PMR; carbamazepine was not subject to PMR; a potential for PMR of lorazepam and mirtrazapine cannot be excluded; chlordiazepoxide is subject to PMR; acetaminophen and alprazolam exhibit minimal PMR; amitriptyline and benztropine exhibit PMR. Codeine (C/P ratio: 4.9), zolpidem (C/P ratio: 3.74), chlorpromazine (C/P ratio: 2.97), fluoxetine (C/P ratio: 2.83) and propranolol (C/P ratio: 2.72) had the largest C/P ratios. Postmortem drug concentrations showed variations depending on sampling sites and characteristics of the drugs. It is continuously necessary to analyze commonly used or abused drugs in simultaneously collected cardiac and peripheral blood to establish significant reference values for PMR. These findings can be used to reach a conclusion about the cause and manner of death.

  18. The Screening and Evaluation of Experimental Antiparasitic Drugs.

    DTIC Science & Technology

    1983-12-01

    a.o & % Nb...I- V. THE CHEMOTHERAPY OF EXPERIMENTALLY INDUCED DRUG- r RESISTANT AFRICAN TRYPANOSOMIASIS (I. JLEJNE) IN MICE. A. Introduction 31 B...Methods 31 C. Results 33 D. Summary of compounds tested (Table VII). 35 VI. THE CHEMOTHERAPY OF EXPERIMENTALLY INDUCED AMERICAN TRYPANOSOMIASIS (_T...rhodesiense Plasmodium berghei Prophylactic African trypanosomiasis P. yoelii Repository American trypanosomiasis Drug-sensitive Suppressive

  19. [Medical economics evaluation of 5-HT3 receptor antagonist drugs].

    PubMed

    Utsunomiya, Junpei; Hirano, Shigeki; Fukui, Aiko; Funabashi, Kazuaki; Deguchi, Yuko; Yamada, Susumu; Naito, Kazuyuki

    2010-10-01

    At Komaki City Hospital, the drug cost in connection with cancer chemotherapy was re-examined as part of improved management along with the introduction of DPC in July 2008. With due attention to the 5-HT3 receptor antagonists, both the change from injections to oral drugs and the change from brand-name drugs to generic drugs were tried between July 2008 and June 2009. After that, in order to examine the economic impact of these changes, we investigated and analyzed the number of medications, the cost of medicine purchased, and the average drug cost per medication of the 5-HT3 receptor antagonists between April 2008 and September 2009. As a result, the cost of 5-HT3 receptor antagonists purchased decreased greatly, and the impact of the improvement was mainly due to the change to oral drugs, and partially to the change to generic drugs. Therefore, from the viewpoint of hospital economic improvement in DPC, it was thought that the change to oral drugs(5-HT3 receptor antagonists)is given top priority.

  20. A critical evaluation of drug interactions with Echinacea spp.

    PubMed

    Freeman, Camille; Spelman, Kevin

    2008-07-01

    Accurate information concerning drug-herb interactions is vital for both healthcare providers and patients. Unfortunately, many of the reviews on drug-herb interactions contain overstated or inaccurate information. To provide accurate information on drug-herb interactions healthcare providers must account for product verification, dosage, medicinal plant species, and plant part used. This critical review assessed the occurrence of drug interactions with one of the top selling botanical remedies, echinacea including Echinacea angustifolia, E. pallida, and E. purpurea. Only eight papers containing primary data relating to drug interactions were identified. Herbal remedies made from E. purpurea appear to have a low potential to generate cytochrome P450 (CYP 450) drug-herb interactions including CYP 450 1A2 (CYP1A2) and CYP 450 3A4 (CYP3A4). Currently there are no verifiable reports of drug-herb interactions with any echinacea product. However, further pharmacokinetic testing is necessary before conclusive statements can be made about echinacea drug-herb interactions. Given our findings, the estimated risk of taking echinacea products (1 in 100,000), the number of echinacea doses consumed yearly (> 10 million), the number of adverse events (< 100) and that the majority of use is short term, E. purpurea products (roots and/or aerial parts) do not appear to be a risk to consumers.

  1. Evaluation of drug administration errors in a teaching hospital

    PubMed Central

    2012-01-01

    Background Medication errors can occur at any of the three steps of the medication use process: prescribing, dispensing and administration. We aimed to determine the incidence, type and clinical importance of drug administration errors and to identify risk factors. Methods Prospective study based on disguised observation technique in four wards in a teaching hospital in Paris, France (800 beds). A pharmacist accompanied nurses and witnessed the preparation and administration of drugs to all patients during the three drug rounds on each of six days per ward. Main outcomes were number, type and clinical importance of errors and associated risk factors. Drug administration error rate was calculated with and without wrong time errors. Relationship between the occurrence of errors and potential risk factors were investigated using logistic regression models with random effects. Results Twenty-eight nurses caring for 108 patients were observed. Among 1501 opportunities for error, 415 administrations (430 errors) with one or more errors were detected (27.6%). There were 312 wrong time errors, ten simultaneously with another type of error, resulting in an error rate without wrong time error of 7.5% (113/1501). The most frequently administered drugs were the cardiovascular drugs (425/1501, 28.3%). The highest risks of error in a drug administration were for dermatological drugs. No potentially life-threatening errors were witnessed and 6% of errors were classified as having a serious or significant impact on patients (mainly omission). In multivariate analysis, the occurrence of errors was associated with drug administration route, drug classification (ATC) and the number of patient under the nurse's care. Conclusion Medication administration errors are frequent. The identification of its determinants helps to undertake designed interventions. PMID:22409837

  2. Evaluation of Perioperative Medication Errors and Adverse Drug Events

    PubMed Central

    Nanji, Karen C.; Patel, Amit; Shaikh, Sofia; Seger, Diane L.; Bates, David W.

    2015-01-01

    Background The purpose of this study is to assess the rates of perioperative medication errors (MEs) and adverse drug events (ADEs) as percentages of medication administrations, evaluate their root causes, and formulate targeted solutions to prevent them. Methods In this prospective observational study, anesthesia-trained study staff (anesthesiologists/nurse anesthetists) observed randomly selected operations at a 1,046 bed tertiary care academic medical center to identify MEs and ADEs over eight months. Retrospective chart abstraction was performed to flag events that were missed by observation. All events subsequently underwent review by two independent reviewers. Primary outcomes were the incidence of MEs and ADEs. Results A total of 277 operations were observed with 3,671 medication administrations of which 193 (5.3%, 95% CI 4.5 to 6.0) involved a ME and/or ADE. Of these, 153 (79.3%) were preventable and 40 (20.7%) were non-preventable. The events included 153 (79.3%) errors and 91 (47.2%) ADEs. While 32 (20.9%) of the errors had little potential for harm, 51 (33.3%) led to an observed ADE and an additional 70 (45.8%) had the potential for patient harm. Of the 153 errors, 99 (64.7%) were serious, 51 (33.3%) were significant and 3 (2.0%) were life-threatening. Conclusions One in twenty perioperative medication administrations included an ME and/or ADE. More than one third of the MEs led to observed ADEs, and the remaining two thirds had the potential for harm. These rates are markedly higher than those reported by retrospective surveys. Specific solutions exist which have the potential to decrease the incidence of perioperative MEs. PMID:26501385

  3. Drug and Vaccine evaluation in the Human Aotus Plasmodium falciparum Model

    DTIC Science & Technology

    2011-05-01

    AWARD NUMBER: W81XWH-07-C-0044 TITLE: Drug and Vaccine Evaluation in the Human Aotus...Apr 2010 – 30 Apr 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-07-C-0044 Drug and Vaccine Evaluation in the Human Aotus Plasmodium...The use of Aotus lemurinus lemurinus (Panamanian Aotus monkey), kariotypes VIII and IX (16) as a model to study malaria drug resistance and vaccine

  4. The Screening and Evaluation of Experimental Antiparasitic Drugs.

    DTIC Science & Technology

    1982-06-01

    subcutaneously. Compounds to be administered orally are mixed in an aqueous solution of 0.5% hydroxyethylcellulose-0.1% Tween - 80 . Treatment consists of a...parasites. All drugs are mixed in aqueous 0.5% hydroxyethylcellulose-0.1% Tween - 80 and ultrasonicated when neccesary. Drug doses are prepared using 100% of...is ground with a mortar and pestle and then suspended in 0.5% hydroxyethylcellulose-O.l% Tween - 80 to make the desired drug doses. The percent free

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

    PubMed Central

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

    2007-01-01

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

  6. Evaluating alignment between Canadian Common Drug Review reimbursement recommendations and provincial drug plan listing decisions: an exploratory study

    PubMed Central

    Allen, Nicola; Walker, Stuart R.; Liberti, Lawrence; Sehgal, Chander; Salek, M. Sam

    2016-01-01

    Background: The CADTH Common Drug Review was established in 2002 to prepare national health technology assessment reports to guide listing decisions for 18 participating drug plans. The aim of this study was to compare the nonmandatory recommendations from the Common Drug Review in Canada with the listing decisions of provincial payers to determine alignment. Methods: We identified the recommendations issued by the Common Drug Review from Jan. 1, 2009, to Jan. 1, 2015, and compared these with the listing decisions of 3 provincial public payers (Alberta, British Columbia and Ontario) that participate in the Common Drug Review and the recommendations from Quebec. Results: We identified 174 medicine-indication pairs in CADTH Common Drug Review reports issued from Jan. 1, 2009, to Jan. 1, 2015; 110 of these met the inclusion criterion. Among the 110 medicine-indication pairs, listing decisions were available for 95 in Alberta, 102 in Quebec, 104 in Ontario and 106 in BC. There was moderate to substantial agreement between provincial listing decisions and Common Drug Review recommendations: 74.5% (κ = 0.47, 95% confidence interval [CI] 0.31-0.64) for Quebec, 78.8% (κ = 0.56, 95% CI 0.41-0.72) for Ontario, 78.9% (κ = 0.58, 95% CI 0.42-0.74) for Alberta and 81.1% (κ = 0.62, 95% CI 0.47-0.77) for BC. Interpretation: Our study showed moderate to substantial agreement between Common Drug Review recommendations and provincial listing decisions. Future studies can build on this research by evaluating the concordance between Common Drug Review recommendations and listing decisions of all participating federal, provincial and territorial drug plans. PMID:28018881

  7. Developing a paradigm of drug innovation: an evaluation algorithm.

    PubMed

    Caprino, Luciano; Russo, Pierluigi

    2006-11-01

    Assessment of drug innovation is a burning issue because it involves so many different perspectives, mainly those of patients, decision- and policy-makers, regulatory authorities and pharmaceutical companies. Moreover, the innovative value of a new medicine is usually an intrinsic property of the compound, but it also depends on the specific context in which the medicine is introduced and the availability of other medicines for treating the same clinical condition. Thus, a model designed to assess drug innovation should be able to capture the intrinsic properties of a compound (which usually emerge during R&D) and/or modification of its innovative value with time. Here we describe the innovation assessment algorithm (IAA), a simulation model for assessing drug innovation. IAA provides a score of drug innovation by assessing information generated during both the pre-marketing and the post-marketing authorization phase.

  8. Drug Evaluation in the Plasmodium falciparum - Aotus Model

    DTIC Science & Technology

    1990-12-12

    Previous editions are obsolete. SECURITY CLASSIFICATION OF THIS PAGE 19. Trials with other drugs, ketotifen, cyproheptadine , combretestatin, and an aryl...regimen. Recent studies of in vivo reversal of chloroquine- resistance have used the following drugs: WR 267634, ketotifen; WR 35917, cyproheptadine ; WR...WR 035917AB (BN:BL 08170), cyproheptadine M. WR 267634AC (BN:BM 01916), ketotifen 25 N. WR 035917AB (BN:BM 08170), cyproheptadine 26 0. WR 268766AA

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

    PubMed

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2005-10-01

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

  11. Evaluation of uncertainties associated with the determination of community drug use through the measurement of sewage drug biomarkers.

    PubMed

    Castiglioni, Sara; Bijlsma, Lubertus; Covaci, Adrian; Emke, Erik; Hernández, Félix; Reid, Malcolm; Ort, Christoph; Thomas, Kevin V; van Nuijs, Alexander L N; de Voogt, Pim; Zuccato, Ettore

    2013-02-05

    The aim of this study was to integrally address the uncertainty associated with all the steps used to estimate community drug consumption through the chemical analysis of sewage biomarkers of illicit drugs. Uncertainty has been evaluated for sampling, chemical analysis, stability of drug biomarkers in sewage, back-calculation of drug use (specific case of cocaine), and estimation of population size in a catchment using data collected from a recent Europe-wide investigation and from the available literature. The quality of sampling protocols and analytical measurements has been evaluated by analyzing standardized questionnaires collected from 19 sewage treatments plants (STPs) and the results of an interlaboratory study (ILS), respectively. Extensive reviews of the available literature have been used to evaluate stability of drug biomarkers in sewage and the uncertainty related to back-calculation of cocaine use. Different methods for estimating population size in a catchment have been compared and the variability among the collected data was very high (7-55%). A reasonable strategy to reduce uncertainty was therefore to choose the most reliable estimation case by case. In the other cases, the highest uncertainties are related to the analysis of sewage drug biomarkers (uncertainty as relative standard deviation; RSD: 6-26% from ILS) and to the back-calculation of cocaine use (uncertainty; RSD: 26%). Uncertainty can be kept below 10% in the remaining steps, if specific requirements outlined in this work are considered. For each step, a best practice protocol has been suggested and discussed to reduce and keep to a minimum the uncertainty of the entire procedure and to improve the reliability of the estimates of drug use.

  12. Finding, evaluating, and managing drug-related risks: approaches taken by the US Food and Drug Administration (FDA).

    PubMed

    Weaver, Joyce; Grenade, Lois La; Kwon, Hyon; Avigan, Mark

    2009-01-01

    Marketed pharmaceuticals are evaluated for safety by the US Food and Drug Administration (FDA) throughout the life cycle of the products. The FDA uses data from controlled clinical trials, from postmarketing case reports reported to the FDA's Adverse Event Reporting System, from epidemiological studies, and from registries to evaluate the safety of approved products. For some products, including some products used in dermatologic medicine, risks become apparent during the postmarketing period that require additional measures beyond product labeling and routine pharmacovigilance. The FDA continues to seek additional tools to assess risk, including pharmacogenomic biomarkers for adverse drug reactions and the use of large medical record and epidemiological databases for the systematic detection and characterization of drug-associated safety outcomes.

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

    NASA Astrophysics Data System (ADS)

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

    2016-08-01

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

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

    PubMed

    Huang, Qin; Wang, Jun

    2015-11-01

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

  15. Liver tissue engineering in the evaluation of drug safety.

    PubMed

    Dash, Ajit; Inman, Walker; Hoffmaster, Keith; Sevidal, Samantha; Kelly, Joan; Obach, R Scott; Griffith, Linda G; Tannenbaum, Steven R

    2009-10-01

    Assessment of drug-liver interactions is an integral part of predicting the safety profile of new drugs. Existing model systems range from in vitro cell culture models to FDA-mandated animal tests. Data from these models often fail, however, to predict human liver toxicity, resulting in costly failures of clinical trials. In vitro screens based on cultured hepatocytes are now commonly used in early stages of development, but many toxic responses in vivo seem to be mediated by a complex interplay among several different cell types. We discuss some of the evolving trends in liver cell culture systems applied to drug safety assessment and describe an experimental model that captures complex liver physiology through incorporation of heterotypic cell-cell interactions, 3D architecture and perfused flow. We demonstrate how heterotypic interactions in this system can be manipulated to recreate an inflammatory environment and apply the model to test compounds that potentially exhibit idiosyncratic drug toxicity. Finally, we provide a perspective on how the range of existing and emerging in vitro liver culture approaches, from simple to complex, might serve needs across the range of stages in drug discovery and development, including applications in molecular therapeutics.

  16. Prediction and evaluation of protein farnesyltransferase inhibition by commercial drugs

    PubMed Central

    DeGraw, Amanda J.; Keiser, Michael J.; Ochocki, Joshua D.; Shoichet, Brian K.; Distefano, Mark D.

    2010-01-01

    The Similarity Ensemble Approach (SEAa) relates proteins based on the set-wise chemical similarity among their ligands. It can be used to rapidly search large compound databases and to build cross-target similarity maps. The emerging maps relate targets in ways that reveal relationships one might not recognize based on sequence or structural similarities alone. SEA has previously revealed cross talk between drugs acting primarily on G-protein coupled receptors (GPCRs). Here we used SEA to look for potential off-target inhibition of the enzyme protein farnesyltransferase (PFTase) by commercially available drugs. The inhibition of PFTase has profound consequences for oncogenesis, as well as a number of other diseases. In the present study, two commercial drugs, Loratadine and Miconazole, were identified as potential ligands for PFTase and subsequently confirmed as such experimentally. These results point towards the applicability of SEA for the prediction of not only GPCR-GPCR drug cross talk, but also GPCR-enzyme and enzyme-enzyme drug cross talk. PMID:20180535

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

    PubMed

    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.

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

    PubMed

    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.

  19. Evaluation of gliadins nanoparticles as drug delivery systems: a study of three different drugs.

    PubMed

    Duclairoir, C; Orecchioni, A-M; Depraetere, P; Osterstock, F; Nakache, E

    2003-03-06

    In this paper, biopolymer nanoparticles are studied, which unlike many synthetic carriers used for controlled release, are biocompatible and biodegradable systems. Gliadins nanoparticles are obtained by a desolvatation method, also known as drawning-out precipitation. These particles have been shown to be interesting as drug release systems for all-trans-retinoic acid. The aim of this paper was to study the influence of the polarity of different drugs on nanoparticle characteristics such as size and drug loading efficiency. Three drugs of three different polarities were studied: the hydrophobic Vitamin E (VE), the slightly polar mixture of linalool and of linalyl acetate (LLA) and the cationic amphiphilic benzalkonium chloride (BZC). This comparative work shows that the amount of the entrapped VE and LLA is higher than that of the cationic BZC, confirming a strong interaction between gliadins and apolar compounds, due to the apolarity of the proteins. This interaction results in a low diffusion coefficient and a partition coefficient in favour of gliadins, resulting in a low permeability coefficient. The drug release kinetics of two substances, LLA and BZC, are observed, in showing a burst effect, then a diffusion process, which can be modelled assuming that the particles are homogeneous spheres.

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

    PubMed

    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.

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

    ERIC Educational Resources Information Center

    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…

  2. 77 FR 32124 - Guidance for Industry on Irritable Bowel Syndrome-Clinical Evaluation of Drugs for Treatment...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-31

    ... Evaluation of Drugs for Treatment; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... entitled ``Irritable Bowel Syndrome--Clinical Evaluation of Drugs for Treatment.'' This guidance is intended to assist the pharmaceutical industry and investigators who are developing drugs for the...

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

    PubMed

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

    2015-08-07

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

  4. Expanded Access of Investigational Drugs: The Experience of the Center of Drug Evaluation and Research Over a 10-Year Period

    PubMed Central

    Jarow, Jonathan P.; Lemery, Steven; Bugin, Kevin; Khozin, Sean; Moscicki, Richard

    2016-01-01

    Background The purpose of this study was to describe the experience of the Center of Drug Evaluation and Research (CDER) with expanded access of investigational drugs. Methods Multiple searches of CDER’s document tracking system were performed to identify the number, type, and indication for all expanded access requests over the 10-year time period of January 2005 through December 2014. An additional search was performed to identify all active commercial investigational drug development programs during that time period and whether or not the clinical program was placed on hold. The two searches were then cross-referenced to identify those commercial investigational drug development programs placed on clinical hold due to serious adverse events occurring within expanded access programs. Results CDER receives over 1000 applications for expanded access each year. The majority are for single patients, roughly evenly split between emergency and nonemergency use. The vast majority, 99.7%, are allowed to proceed. The incidence of clinical holds for all commercial investigational drug development programs is 7.9%, as compared to only 0.2% related to adverse events observed in patients receiving drug treatments under expanded access. Conclusions The expanded access program is viewed as a success from FDA’s perspective based on the large number of applications processed and allowed to proceed each year. However, the actual number of patients and their health care providers that desire drug treatments available under expanded access is not known. It is exceedingly rare for a serious adverse event under expanded access to affect the development program for that drug. PMID:27917324

  5. Evaluation of popular drug information resources on clinically useful and actionable pharmacogenomic information*†

    PubMed Central

    Chang, Jennifer S.; Pham, Duyen-Anh; Dang, Maithao T.; Lu, Yiting; VanOsdol, Sheri

    2016-01-01

    Background Pharmacogenomics is the study of how genes affect a person's response to drugs. This descriptive study assessed whether popular drug information resources provide clinically useful pharmacogenomic (PGx) information. Methods Four resources (package inserts, Lexicomp, Micromedex 2.0, and Epocrates) were evaluated for information about twenty-seven drugs. Results There was wide variability of PGx information. Whereas Lexicomp included relevant PGx biomarker information for all 27 drugs, Epocrates did in less than 50% of the drugs. None of the resources had monographs that fully incorporated Clinical Pharmacogenomics Implementation Consortium (CPIC) recommendations in more than 30% of the drugs. Conclusion Lexicomp appears to be most useful PGx drug information resource, but none of the resources are sufficient. PMID:26807054

  6. Signify ER Drug Screen Test evaluation: comparison to Triage Drug of Abuse Panel plus tricyclic antidepressants.

    PubMed

    Phillips, Jane Ellen; Bogema, Stuart; Fu, Paul; Furmaga, Wieslaw; Wu, Alan H B; Zic, Vlasta; Hammett-Stabler, Catherine

    2003-02-01

    Signify ER Drug Screen Test (Signify ER) and Triage Drug of Abuse Panel plus TCA (Triage DOA Panel) rapid drug screening devices were compared at four laboratories. Both assay systems are point of care immunoassays, measuring phencyclidine, barbiturates, amphetamine, cocaine metabolite, methamphetamine, tricyclic antidepressants, opiates, marijuana metabolite, and benzodiazepines in human urine. The performance of these two assay systems, including a cutoff verification and cross-reactivity using spiked urine specimens and accuracy using clinical urine samples, was investigated. The cutoff verification study showed that the Signify ER had 95.4% precision for all drugs tested at concentrations of 50%, 75%, 125%, 150%, and 200% of cutoffs compared to 90% precision obtained with Triage DOA Panel. Accuracy studies testing 53 negative urine samples demonstrated that both Signify ER and Triage DOA Panel have 100% specificity. Testing of 693 positive urine samples demonstrated that Signify ER and Triage DOA Panel have sensitivities of 99.8% and 99.3%, respectively, with an accuracy of 99.9% and 99.6%. A total of 527 compounds were tested for the cross-reactivity study. Eighty-seven structurally related drugs and metabolites were found to cross-react with at least one of the nine tests of the Signify ER. Four hundred forty structurally unrelated compounds that can be found in human urine were shown not to cross-react with the Signify ER. In terms of operating characteristics, the Signify ER device is simpler since only a single pipetting step is required, and reaction completed within 8 min.

  7. Evaluation of the Discover Drug Education Curriculum for Grades K-4.

    ERIC Educational Resources Information Center

    Adams, Ronald D.; Butler, Joan M.

    A major purpose of this study was to establish and test a procedure for evaluating drug education curricula that allows for a more objective view of the effectiveness of drug education materials and the instructional delivery system. A major focus of the study was to determine the extent to which the Discover Curriculum affected student outcomes.…

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

    ERIC Educational Resources Information Center

    Moon, Melissa M.; Latessa, Edward J.

    1994-01-01

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

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

    ERIC Educational Resources Information Center

    Theriot, Matthew T.

    2006-01-01

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

  10. Local Evaluation of Programs Funded under the Drug-Free Schools and Communities Act. Final Report.

    ERIC Educational Resources Information Center

    Tashjian, Michael D.; Elliott, Barbara

    In September 1993 the U.S. Department of Education (ED) released a handbook to assist school- and community-based practitioners in designing and conducting evaluations of drug- and violence-prevention programs funded under the Drug Free Schools and Communities Act (DFSCA). A study was undertaken to assess the level of customer satisfaction with…

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

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Cervantes, Paige E.

    2013-01-01

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

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

    ERIC Educational Resources Information Center

    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.…

  13. Saginaw Drug and Alcohol Abuse Education and Training Program: Product Evaluation, 1990-1991.

    ERIC Educational Resources Information Center

    Saginaw Public Schools, MI. Dept. of Evaluation Services.

    This report evaluates the Saginaw Drug and Alcohol Abuse Education Training Program conducted in 1990-1991, which provided in-depth training for 94 professionals including 63 teachers and 7 counselors through a workshop lasting 5 days and containing 6 hours of instruction per day. The workshops addressed the identification of both drug abuse…

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

    ERIC Educational Resources Information Center

    Gabriel, Roy M.; Salmon, Jennifer R.

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

  15. In silico evaluation of TERT inhibition by anticancer drugs.

    PubMed

    Mahendar, Porika; Sirisha, Kalam; Kulandaivelu, Umasankar; Shankar, Prakhya Laxmi Jaya; Radhika, Tippani; Sadanandam, Abbagani

    2012-10-01

    The activation of telomerase represents an early step in carcinogenesis. Increased telomerase expression in malignant tumors suggests that telomerase inactivation may represent a potential chemotherapeutic target. In this work, existing anticancer drugs were docked against telomerase reverse transcriptase (TERT) using a Lamarckian genetic algorithm (LGA). Autodock's scoring function was applied to each of the molecules in order to identify the inhibitor with the strongest pharmacological action. The structural insights provided by this study regarding binding poses and possible interactions, free energies of binding, and drug scores aided in the identification of potential inhibitory compounds. The ranks of the various ligands investigated were based on the final docked energy values. Among nine selected compounds, vindesine, temsirolimus, and cyclosporine were found to be more potent TERT inhibitors than the standard inhibitor, curcumin.

  16. Targeted screen for human UDP-glucuronosyltransferases inhibitors and the evaluation of potential drug-drug interactions with zafirlukast.

    PubMed

    Oda, Shingo; Fujiwara, Ryoichi; Kutsuno, Yuki; Fukami, Tatsuki; Itoh, Tomoo; Yokoi, Tsuyoshi; Nakajima, Miki

    2015-06-01

    Inhibition of drug metabolizing enzymes is a major mechanism in drug-drug interactions (DDIs). A number of cases of DDIs via inhibition of UDP-glucuronosyltranseferases (UGTs) have been reported, although the changes in pharmacokinetics are relatively small in comparison with drugs that are metabolized by cytochrome P450s. Most of the past studies have investigated hepatic UGTs, although recent studies have revealed a significant contribution of UGTs in the small intestine to drug clearance. To evaluate potential DDIs caused by inhibition of intestinal UGTs, we assessed inhibitory effects of 578 compounds, including drugs, xenobiotics, and endobiotics, on human UGT1A8 and UGT1A10, which are major contributors to intestinal glucuronidation. We identified 29 inhibitors by monitoring raloxifene glucuronidation with recombinant UGTs. All of the inhibitors potently inhibited UGT1A1 activity, as well. We found that zafirlukast is a potent general inhibitor of UGT1As and a moderate inhibitor of UGT2Bs because it monitors 4-methylumbelliferone glucuronidation by recombinant UGTs. However, zafirlukast did not potently inhibit diclofenac glucuronidation, suggesting that the inhibitory effects might be substrate specific. Inhibitory effects of zafirlukast on some UGT substrates were further investigated in human liver and human small intestine microsomes in order to evaluate potential DDIs. The R values (the ratios of intrinsic clearance with and without an inhibitor) revealed that zafirlukast has potential to cause clinical DDIs in the small intestine. Although we could not identify specific UGT1A8 and UGT1A10 inhibitors, zafirlukast was identified as a general inhibitor for UGTs in vitro. The present study suggests that the inhibition of UGT in the small intestine would be an underlying mechanism for DDIs.

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

    PubMed Central

    Ramteke, Kuldeep Hemraj; Nath, Lilakant

    2014-01-01

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

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

    DTIC Science & Technology

    2007-11-02

    AD Award Number: DAMDl7-01-C-0039 TITLE: Drug and Vaccine Evaluation in the Human Aotus Plasmodium Falciparum Model PRINCIPAL INVESTIGATOR: Nicanor... Human Aotus DAMDI7-01-C-0039 Plasmodium Falciparum Model 6. AUTHOR(S): Nicanor Obaldia, III, D.V.M. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8...evaluation of drugs and vaccines in the human malarialAotus lemurinus lemurinus monkey model experimientally infected with Plasmodium falciparum or vivax

  19. Evaluation of Drug and Vaccine Candidates in the Human Malaria/Aotus Monkey Model

    DTIC Science & Technology

    1998-03-01

    1 ■—, AD CONTRACT NUMBER DAMD17-96-C-6051 TITLE: Evaluation of Drug and Vaccine Candidates in the Human Malaria/Aotus Monkey Model PRINCIPAL...98) 4. TITLE AND SUBTITLE Evaluation of Drug and Vaccine Candidates in the Human Malaria/Aolus Monkey Model 6. AUTHOR(S) Obaldia 111, Nicanor...Laboratory Resources, National Research Council (NIH Publication No. 86-23, Revised 1985). For the protection of human subjects, the investigator

  20. Maternal drug use: evaluation of risks to breast-fed infants.

    PubMed

    Kirksey, A; Groziak, S M

    1984-01-01

    This paper, based on a review of the literature, evaluates the risks to infants of maternal drug use during lactation. The potential harm of a particular drug to the breastfed infant is related both to the complex mechanism of milk synthesis and secretion and the mode of passage of the drug from plasma into milk. The 1st part of the paper discusses mammary cell and milk synthesis, milk secretion and composition, the mode of passage of drugs into milk, and factors influencing drug concentrations in milk. Drug concentrations in milk are dependent on 6 major factors: drug dosage, proportion bound in plasma, molecular weight, lipid solubility, degree of ionization, and pH difference between plasma and milk. Drugs that are weak acids are ionized to a greater extent and are more protein-bound than weak alkaline drugs. The 2nd part of the paper evaluates the risks to breastfed infants of selected pharmacons. Some categories of drugs that contain pharmacons that should be limited or avoided by nursing mothers are alkylating agents, analgesics and anti-inflammatory agents, anticoagulants, anticonvulsants, anti-infective agents, central nervous system stimulants, hormones, laxatives, minerals, provitamins, psychotherapeutic agents, thyroid affecting agents, and vitamins. The following precautions are suggested to minimize the risks of potentially harmful pharmacons: 1) all unnecessary medications should be avoided by nrusing mothers; 2) if medication is necessary during lactation, drug dosage should be controlled and the infant should be monitored for adverse symptoms; 3) drugs should be administered shortly after breastfeeding and the interval prolonged before the next feeding; and 4) if the infant must be fed soon after a potentially harmful drug has been taken by the mother, bottle feeding is recommended.

  1. Glycosides as possible lead antimalarial in new drug discovery: future perspectives.

    PubMed

    Marya; Khan, Haroon; Ahmad, Izhar

    2017-01-15

    Malaria remains one of the major public health problems worldwide and is responsible for a large number of morbidity and mortality. Especially, in the third world countries, it is still alarming. The development of drug-resistant to Plasmodium falciparum strains has further degraded the overall situation. However, a limited number of effective drugs available emphasizes how essential it is to establish new anti-malarial compounds. New antimalarial agents with distinctive structures and mechanism of action from the natural origin are thus immediately required to treat sensitive and drug-resistant strains of malaria. over the years, phytopharmaceuticals have provided numerous lead compounds. Similarly, the success rate of botanicals in terms of clinical significance is also very high. Of them, glycosides is one of the most widely distributed and emerging class of plant secondary metabolites. This review provides an outlook to recently isolated glycosides from plants with marked antimalarial effects in an in-vitro and in-vivo protocols and thus ideal candidates for clinical trials to ascertain their clinical utility and or led compounds.

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

    SciTech Connect

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

    2012-07-27

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

  3. Performance Evaluation of Malaria Microscopists at Defense Health Facilities in Addis Ababa and Its Surrounding Areas, Ethiopia

    PubMed Central

    Nega, Desalegn; Tasew, Geremew; Taye, Bineyam; Desta, Kassu

    2016-01-01

    Background Blood film microscopy is the gold standard approach for malaria diagnosis, and preferred method for routine patient diagnosis in health facilities. However, the inability of laboratory professionals to correctly detect and identify malaria parasites microscopically leads to an inappropriate administration of anti-malarial drugs to the patients and incorrect findings in research areas. This study was carried out to evaluate the performance of laboratory professionals in malaria diagnosis in health facilities under the Defense Health Main Department in Addis Ababa and its surroundings, Ethiopia. Method A cross sectional study was conducted from June to July 2015. Totally, 60 laboratory professionals out of the selected 16 health facilities were included in the study. Data were collected by distributing standardized pre-validated malaria slide-panels and self-administered questionnaires among professionals, onsite in each study facility. Sensitivity, specificity, and strength of agreement (with kappa score) in performance among the study participants against WHO-certified expert malaria microscopists were calculated. Result Of the 60 study participants, 8.3% (5/60) correctly read all the distributed slides in terms of parasite detection, species identification and parasite counting; whereas, each of the remaining 55(91.7%) interpreted at least two slides incorrectly. The overall sensitivity and specificity of participants’ performance in detection of malaria parasites were 65.7% and 100%, respectively. Overall, fair agreement (71.4%; Kappa: 0.4) in detection of malaria parasite was observed between the study subjects and expert readers. The overall sensitivity and specificity of participants in species identification of malaria parasites were respectively 41.3% and 100%. Overall, slight agreement (51.1%; kappa: 0.04) in identification of malaria species was observed. Generally, agreement was lower in parasite detection and species identification at low

  4. Evaluation of Fluoromycobacteriophages for Detecting Drug Resistance in Mycobacterium tuberculosis▿

    PubMed Central

    Rondón, Liliana; Piuri, Mariana; Jacobs, William R.; de Waard, Jacobus; Hatfull, Graham F.; Takiff, Howard E.

    2011-01-01

    We tested a new method for detecting drug-resistant strains of Mycobacterium tuberculosis that uses a TM4 mycobacteriophage phAE87::hsp60-EGFP (EGFP-phage) engineered to contain the gene encoding enhanced green fluorescent protein (EGFP). After promising results in preliminary studies, the EGFP-phage was used to detect isoniazid (INH), rifampin (RIF), and streptomycin (STR) resistance in 155 strains of M. tuberculosis, and the results were compared to the resazurin microplate technique, with the proportion method serving as the reference standard. The resazurin technique yielded sensitivities of 94% for INH and RIF and 98% for STR and specificities of 97% for INH, 95% for RIF, and 98% for STR. The sensitivity of EGFP-phage was 94% for all three antibiotics, with specificities of 90% for INH, 93% for RIF, and 95% for STR. The EGFP-phage results were available in 2 days for RIF and STR and in 3 days for INH, with an estimated cost of ∼2$ to test the three antibiotics. Using a more stringent criterion for resistance improved the specificity of the EGFP-phage for INH and RIF without affecting the sensitivity. In preliminary studies, the EGFP-phage could also effectively detect resistance to the fluoroquinolones. The EGFP-phage method has the potential to be a valuable rapid and economic screen for detecting drug-resistant tuberculosis if the procedure can be simplified, if it can be adapted to clinical material, and if its sensitivity can be improved. PMID:21346042

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

    PubMed

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

    2013-02-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2005-06-01

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

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

    ERIC Educational Resources Information Center

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

    2012-01-01

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

  8. Drug Evaluation in the Plasmodium Falciparum-Aotus Model

    DTIC Science & Technology

    1990-06-14

    of WR 26763AC (BN:BM 01916), ketotifen WR 035917AB (BN:BL 08170), cyproheptadine WR 1544BM (BN:AR 20613), chloroquine 42 H. Conclusions 43 hL _ _ -5...WR 6379, prochlorperazine plus WR 1544, chloroquine 52 19. Toxicity evaluation of WR 267634, ketotifen, and WR 035917, cyproheptadine , both in...days. Am - 42 - G. Limited toxicity evaluation of WR 267634AC(BN:BM 01916), ketotifen, and WR 035917AB(BN:BL 08170), cyproheptadine , both in combination

  9. Evaluation of Potential Drug-Drug Interactions with Antidepressants in Two Tertiary Care Hospitals

    PubMed Central

    Rafi, Muhammad Salman; Naqvi, Syed Baqir Shyum; Khan, Muhammad Umair; Fayyaz, Muhammad; Ashraf, Nida; Khan, Maqsood Ahmed; Ahmad, Akram

    2015-01-01

    Background Limited resources of healthcare system and high use of antidepressants have raised some serious concerns regarding proper surveillance system of prescribed medicines. Not much literature is available from Pakistan regarding the potential drug-drug interactions (pDDIs) associated with antidepressants. Objective The objective of this study was to assess the frequency of pDDIs associated with antidepressants, their severity, significance and their association with patient characteristics. Materials and Methods A prospective, observational study was conducted in two major hospitals of Karachi for the period of three months. Patient profiles, medication charts, and physician notes were thoroughly reviewed to gather all the relevant information. Inclusion and exclusion criteria were set prior to data collection. The collected data was then analysed using Micromedex Drug-REAX System. Descriptive and binomial logistic regression analysis was used to express results. Results Of 245 prescriptions reviewed, 141 prescriptions had at least one pDDI (57.5%). A total of 181 pDDIs were identified in prescription containing antidepressant. The ratio of pDDI per prescriptions was 0.78. 42.5% interactions were moderate in severity, 30% of interactions were rapid in onset, and 43% were considered as significant interactions. Polypharmacy (OR=3.41, p< 0.001) and presence of chronic problems (OR=2.14, p=0.002) were significantly associated with the occurrence of pDDIs. Citalopram and diclofenac (11.6%) was commonly prescribed interacting pair in this study. Conclusion The findings of this study recorded high frequency of antidepressants associated pDDIs. Our results confirm the significant association of polypharmacy with the occurrence of pDDIs with antidepressants. Future studies are warranted to establish these results by including hospitals in different parts of the country. PMID:26393139

  10. When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

    PubMed

    Stern, Stephan T; Martinez, Marilyn N; Stevens, David M

    2016-12-01

    Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation.

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

    PubMed

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

    2016-02-01

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

  12. An interdisciplinary computational/experimental approach to evaluate drug-loaded gold nanoparticle tumor cytotoxicity

    PubMed Central

    Curtis, Louis T; England, Christopher G; Wu, Min; Lowengrub, John; Frieboes, Hermann B

    2016-01-01

    Aim: Clinical translation of cancer nanotherapy has largely failed due to the infeasibility of optimizing the complex interaction of nano/drug/tumor/patient parameters. We develop an interdisciplinary approach modeling diffusive transport of drug-loaded gold nanoparticles in heterogeneously-vascularized tumors. Materials & methods: Evaluated lung cancer cytotoxicity to paclitaxel/cisplatin using novel two-layer (hexadecanethiol/phosphatidylcholine) and three-layer (with high-density-lipoprotein) nanoparticles. Computer simulations calibrated to in-vitro data simulated nanotherapy of heterogeneously-vascularized tumors. Results: Evaluation of free-drug cytotoxicity between monolayer/spheroid cultures demonstrates a substantial differential, with increased resistance conferred by diffusive transport. Nanoparticles had significantly higher efficacy than free-drug. Simulations of nanotherapy demonstrate 9.5% (cisplatin) and 41.3% (paclitaxel) tumor radius decrease. Conclusion: Interdisciplinary approach evaluating gold nanoparticle cytotoxicity and diffusive transport may provide insight into cancer nanotherapy. PMID:26829163

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

    PubMed

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

    2005-07-01

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

  14. [Benzodiazepine drug ingestion and evaluation of after care].

    PubMed

    Dandelot, D; Bertholon, F; Pascalis, J G

    1994-01-01

    Voluntary drug ingestion with benzodiazepine represent today the most frequent method of attempt of autolysis. One must note the difficulties the doctor may find in front such problems to judge the reliability of interviews made in such difficult conditions. Residual disturbances of superior functions, more precisely of vigilance during the period with follow the suicidal action must not be overlooked. Thanks to a clinical scale easily used the residual disturbances have been put in evidence on a sample of 20 subjects who had been admitted with this aim in view in a university ward specialized in psychiatric emergencies. The possibility of continuity within middle range care must allow an improvement of minimum care of such pathologies.

  15. Evaluation of antimotion sickness drug side effects on performance

    NASA Technical Reports Server (NTRS)

    Wood, C. D.; Manno, J. E.; Manno, B. R.; Redetzki, H. M.; Wood, M. J.

    1985-01-01

    The effects of antimotion-sickness drugs on the performance in computerized-pursuit-meter tests of groups of ten 18-30-yr-old male and female subjects are investigated experimentally using double-blind placebo techniques. The results are presented in tables and graphs and discussed in detail. The proficiency scores are as good as or better than placebo values for subjects given d-amphetamine (DA) 5 or 10 mg, promethazine (P) 25 mg + scopolamine (S) 400 ng + DA 10 mg, S 1 mg + DA 10 mg, S 250-600 ng, marezine 50 mg, meclizine 50 mg, dimenhydrinate 50 mg, S 1 mg + DA 5 mg, or P 25 mg + DA 10 mg. Significantly lower scores are seen in subjects given S 800 ng or 1 mg, P 25 mg (oral or IM), P 25 mg + S 400 ng, and P 25 mg oral + P 25 mg IM + DA 10 mg.

  16. An evaluation of 'Inpharma', a drug literature abstracting service.

    PubMed

    Milne, A

    1981-09-01

    This study aimed to provide data on the characteristics of the drug literature abstracting service 'Inpharma'. Journal coverage, article yield and timeliness for a 3-year period were examined; the reliability and information content of 100 abstracts were also assessed. It was found that although 'Inpharma' is claimed to monitor a very large number of journals, over 98% of the abstracts were from 'core' journals of which there are approximately 350. Over 80% of the abstracts appeared within 4 months of publications of the original and abstracts from some of the American journals were available in the United Kingdom before the relevant primary journal. Sixteen errors were detected in 100 abstracts; five of these were typographical errors and nine deviations in accuracy. The publication is a good 'current awareness tool' but it should not be used where a comprehensive coverage of the literature is required. It is also important that the primary journal is consulted when detailed information is required.

  17. Drug-Induced Taste Disorders In Clinical Practice And Preclinical Safety Evaluation.

    PubMed

    Wang, Tao; Glendinning, John; Grushka, Miriam; Hummel, Thomas; Mansfield, Keith

    2017-01-23

    More than 200 medications can induce taste disorders in patients. They not only reduce quality of life for those affected, but can lead to malnutrition, severe dehydration and difficulty in maintaining a therapeutic regimen. Nevertheless, the impact of drug candidates on taste is rarely evaluated in preclinical toxicology studies during the early stage of drug development. Moreover, knowledge about how to investigate these adverse effect is scarce in the toxicology field. Here, we discuss the clinical status of drug-induced taste disorders in patients, with the goal of providing toxicologists with a broad understanding its prevalence, and how stressful and even dangerous it can be to affected patients. Because taste, smell and oral trigeminal sensation are highly interdependent, we also address drug-induced changes in olfactory and oral somatosensory perceptions. We then review the biology of the gustatory system (including anatomy and histology), and the latest developments about how taste contributes to flavor perception. Finally, we feature recently optimized preclinical approaches to investigate drug-induced taste change in animal models, including the development of biomarkers, morphological evaluation of taste buds and taste cells, gustatory nerve recording, and behavioral testing. Our goals are to raise awareness of drug-induced taste disorders among toxicologists, share an overview of new approaches and key studies that can be used to identify drug-induced gustatory system toxicity early in the drug development process, and to stimulate further research at this emerging interface of chemosensory disorders with toxicology.

  18. Three Years Evaluation of Drug Shortages from Educational Pharmacies in Tehran

    PubMed Central

    Gholami, Kheirollah; Kamalinia, Golnaz; Ahmadian Attari, Mohammad Mahdi; Salamzadeh, Jamshid

    2012-01-01

    The effectiveness of any drug supply systems in providing a trustworthy supply of essential drugs is a critical issue. To evaluate this effectiveness, it is necessary to watch over the status of the essential medicines in any country impartially and continuously. Some countries and also the World Health Organization (WHO) have codified a list of minimum medicines needed for a basic health care system and published them in assortments as a list of essential medicines. The aim of this study was to give an evaluation of the shortages status in Iran and identify the strengths and weaknesses of policies made in Ministry of Health during the years 2005 to 2008 in providing the essential drugs based on the WHO list of essential medicines. The reports used in this retrospective study were collected from the central purchasing unit of one of the main chain drugstores in the country (13-Aban Pharmacy) every 2 to 3 weeks. In these reports, a drug is added to the list of shortages when the requested drug is not delivered. The reports were studied and the results were analyzed based on the WHO list of essential medicines and the national drug list of Iran. The shortages always included 20 to 40 medicines from the list of essential drugs compiled by WHO. Based on this finding, the Ministry of Health and particularly Food and Drug Organization can compile a National List of Essential Medicines and try to always supply them and prevent their shortage. PMID:24250480

  19. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  20. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods

    PubMed Central

    Chinna Reddy, P; Chaitanya, K.S.C.; Madhusudan Rao, Y.

    2011-01-01

    Owing to the ease of the administration, the oral cavity is an attractive site for the delivery of drugs. Through this route it is possible to realize mucosal (local effect) and transmucosal (systemic effect) drug administration. In the first case, the aim is to achieve a site-specific release of the drug on the mucosa, whereas the second case involves drug absorption through the mucosal barrier to reach the systemic circulation. The main obstacles that drugs meet when administered via the buccal route derive from the limited absorption area and the barrier properties of the mucosa. The effective physiological removal mechanisms of the oral cavity that take the formulation away from the absorption site are the other obstacles that have to be considered. The strategies studied to overcome such obstacles include the employment of new materials that, possibly, combine mucoadhesive, enzyme inhibitory and penetration enhancer properties and the design of innovative drug delivery systems which, besides improving patient compliance, favor a more intimate contact of the drug with the absorption mucosa. This presents a brief description of advantages and limitations of buccal drug delivery and the anatomical structure of oral mucosa, mechanisms of drug permeation followed by current formulation design in line with developments in buccal delivery systems and methodology in evaluating buccal formulations. PMID:23008684

  1. CFU-GM assay for evaluation of drug myelotoxic activity.

    PubMed

    Pessina, Augusto; Bonomi, Arianna

    2007-11-01

    To study hematotoxicity of compounds on the myeloid cell compartment, the authors describe a standard procedure developed as a workable good laboratory practices-compliant protocol to determine the in vitro myelotoxic effect of drugs and chemicals. Specific protocols are presented to prepare human and murine myeloid progenitors (CFU-GM) for testing in a validated CFU-GM assay. Details are given for performing a screening test when toxicity data are not available and for passing on to an accurate inhibitory concentration-determination phase. To quantify the potential hematotoxicity of xenobiotics from their direct adverse effects on CFU-GM, the unit describes how to manage the results by means of an algorithm able to predict the acute xenobiotic exposure levels that cause maximum tolerated decreases (MTD) in absolute neutrophil count (ANC). A protocol describes a miniaturized application of the procedure in 96-well plates for high-throughput screening of compounds or for testing compounds that are available in very small quantities.

  2. Evaluation of relative MS response factors of drug metabolites for semi-quantitative assessment of chemical liabilities in drug discovery.

    PubMed

    Blanz, Joachim; Williams, Gareth; Dayer, Jerôme; Délémonté, Thierry; Gertsch, Werner; Ramstein, Philippe; Aichholz, Reiner; Trunzer, Markus; Pearson, David

    2017-02-02

    Drug metabolism studies are performed in drug discovery to identify metabolic soft spots, detect potentially toxic or reactive metabolites and provide an early insight into potential species differences. The relative peak area approach is often used to semi-quantitatively estimate the abundance of metabolites. Differences in the LC/MS responses result in an under- or overestimation of the metabolite and misinterpretation of results. The relative MS response factors of 132 structurally diverse drug candidates and their 233 corresponding metabolites were evaluated using a capillary-LC/HRMS system. All of the synthesized metabolites discussed here were previously identified as key biotransformation products in discovery investigations or predicted to be formed. The most commonly occurring biotransformation mechanisms such as oxygenation, dealkylation and amide cleavage are represented within this dataset. However, relatively few phase II metabolites were evaluated due to the limited availability of authentic standards. 85 % of these metabolites had a relative response factor (RF) in the range between 0.2 (5 fold under-prediction) and 2.0 (2 fold over-prediction) and the median MS RF was 0.6. Exceptions to this included very small metabolites that were hardly detectable. Additional experiments performed to understand the impact of the MS platform, flow rate and concentration suggested that these parameters do not have a significant impact on the RF of the compounds tested. This indicates that the use of relative peak areas to semi-quantitatively estimate the abundance of metabolites is justified in the drug discovery setting in order to guide medicinal chemistry efforts.

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

    PubMed

    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

  4. Methodology for Evaluating an Adaptation of Evidence-Based Drug Abuse Prevention in Alternative Schools

    PubMed Central

    Hopson, Laura M.; Holleran Steiker, Lori K.

    2010-01-01

    The purpose of this article is to set forth an innovative methodological protocol for culturally grounding interventions with high risk youth in alternative schools. This study utilized mixed methods to evaluate original and adapted versions of a culturally grounded substance abuse prevention program. The qualitative and quantitative methods concurrently explore behaviors around drugs and alcohol, contextual variables for youth substance abuse and related factors, cultural perspectives regarding drug-related attitudes and behaviors, and the complex reasons behind students’ substance use choices. While questionnaires are utilized to note demographics, cultural and acculturative variables, drug use, drug and alcohol attitudes and expectancies, and school culture variables, focus groups capture the voices of the students and staff and trends that cannot be fully understood via questionnaires. In this study, focus groups aid in the understanding of student drug and alcohol choices, attitudes and behaviors and help the researchers hone in on questions and necessary changes to future research procedures. PMID:20634972

  5. CDER risk assessment exercise to evaluate potential risks from the use of nanomaterials in drug products.

    PubMed

    Cruz, Celia N; Tyner, Katherine M; Velazquez, Lydia; Hyams, Kenneth C; Jacobs, Abigail; Shaw, Arthur B; Jiang, Wenlei; Lionberger, Robert; Hinderling, Peter; Kong, Yoon; Brown, Paul C; Ghosh, Tapash; Strasinger, Caroline; Suarez-Sharp, Sandra; Henry, Don; Van Uitert, Maat; Sadrieh, Nakissa; Morefield, Elaine

    2013-07-01

    The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.

  6. A Cell-Based Pharmacokinetics Assay for Evaluating Tubulin-Binding Drugs

    PubMed Central

    Wang, Yuwei; Liu, Jihua; Zhang, Jun; Wang, Liping; Chan, Jonathon; Wang, Hai; Jin, Yi; Yu, Lei; Grainger, David W.; Ying, Wenbin

    2014-01-01

    Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels. PMID:24688312

  7. Staff Working Papers of the Drug Law Evaluation Project. A Companion Volume to the Final Report of the Joint Committee of New York Drug Law Evaluation.

    ERIC Educational Resources Information Center

    1978

    The papers in this volume were prepared as part of an evaluation of the effects of the strict 1973 New York State drug laws. The first paper explores the effects of the laws on heroin use. It analyzes the trends of various indicators of heroin use in New York State over a period of several years. In order to isolate movements unique to New York,…

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

    PubMed

    Torres, Sandra Regina; Pedrazas, Carlos Henrique Silva; Correia, Marcos Paulo Veloso; Azevedo, Mario Newton Leitão de; Zamprogno, Thaís; Silva, Arley; Gonçalves, Lucio Souza; Papi, José Angelo de Souza

    2016-10-10

    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.

  9. Development and Evaluation of Cefadroxil Drug Loaded Biopolymeric Films Based on Chitosan-Furfural Schiff Base

    PubMed Central

    Dixit, Ritu B.; Uplana, Rahul A.; Patel, Vishnu A.; Dixit, Bharat C.; Patel, Tarosh S.

    2010-01-01

    Cefadroxil drug loaded biopolymeric films of chitosan-furfural schiff base were prepared by reacting chitosan with furfural in presence of acetic acid and perchloric acid respectively for the external use. Prepared films were evaluated for their strength, swelling index, thickness, drug content, uniformity, tensile strength, percent elongation, FTIR spectral analysis and SEM. The results of in vitro diffusion studies revealed that the films exhibited enhanced drug diffusion as compared to the films prepared using untreated chitosan. The films also demonstrated good to moderate antibacterial activities against selective gram positive and gram negative bacteria. PMID:21179325

  10. Evaluation of a new antinauseant drug for the prevention of motion sickness

    NASA Technical Reports Server (NTRS)

    Graybiel, A.; Knepton, J.

    1977-01-01

    The new drug, AHR 5645B, together with other drugs was evaluated in tests, conducted with eight male subjects, concerning its ability to prevent motion sickness. It was found that AHR 5645B, used in doses of 20, 50, and 100 mg, was not efficacious in preventing experimental motion sickness. A combination of 50 mg meclizine and 25 mg ephedrine sulfate produced the best results. Favorable results were also obtained with a combination of 12.5 mg promethazine hydrochloride and 12.5 mg ephedrine sulfate. The findings in the reported experiment point to the difficulty of identifying a highly efficacious antimotion sickness drug for everyone.

  11. Systematic Evaluation of Drug-Loaded Hydrogels for Application in Osteosarcoma Treatment.

    PubMed

    Ali Gumustas, Seyit; Isyar, Mehmet; Topuk, Savas; Yilmaz, Ibrahim; Oznam, Kadir; Onay, Tolga; Ofluoglu, Onder; Mahirogullari, Mahir

    This is a literature review of studies focusing on the preparation of hydrogels for use as oncological drug delivery systems in the treatment of osteosarcoma (OS). The databases of the US National Library of Medicine National Institutes of Health, Embase, OVID, and Cochrane Library, and the references of retrieved studies, were traced from 1843 to December 21, 2015, without language restrictions. The obtained data were evaluated by complementary statistical methods. Potentially relevant studies were found and included in the analysis. OS-specific chemotherapeutic agents can be successfully embedded within the hydrogels and these drug-loaded hydrogels can be applied locally, rather than systemically, without organ tissue toxicity. Further, OS-specific drug-loaded hydrogels significantly increased tumor inhibition and decreased osteolysis and lung metastases. Drug-loaded hydrogels could be useful in the treatment of OS, although their development remains at the experimental phase. Following evaluation of their application in surgery and the completion of drug release kinetics studies, drug-loaded hydrogels could be tested on living mammals in large samples with the aim of applying these in clinical settings. In the future, development of such drug delivery systems and application of targeted approaches against osteosarcoma and other malignancies may render surgery, radiotherapy and chemotherapy unnecessary.

  12. A Weighty Matter: Heaviness Influences the Evaluation of Disease Severity, Drug Effectiveness, and Side Effects

    PubMed Central

    Kaspar, Kai

    2013-01-01

    Peoples' perception of diseases and pharmaceutical drugs is a critical issue in health research. Beliefs about disease severity influence the compliance with recommendations for convalescence and the motivation to perform proper health-behavior. The estimated effectiveness of drugs and severity of side effects influence medication adherence and contribute to placebo effects. The present paper closes the gap between these effects and the concept of embodied cognition from a metaphor-enriched perspective. In five studies, we demonstrate that the bodily sensation of weight influences our evaluations of diseases and drugs. The experience of heaviness enhanced the estimated seriousness of diseases and the estimated effectiveness of drugs. The perceived seriousness of drug side effects was also affected by weight but only when drug effectiveness was not attended to. Moreover, the incidental sensation of weight shows a novel effect when evaluating weight-related drugs. The results are in line with the idea of embodied metaphors and reveal important boundary conditions which contribute to a better understanding of the underlying mechanisms. PMID:24244302

  13. Development, use and evaluation of drugs: the dominating technology in the health care system.

    PubMed

    Hansen, E H; Launsø, L

    1987-01-01

    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. Drugs fit perfectly the technical perception of disease, a perception which prevails in the pharmaceutical industry, medical science and in the treatment of disease. This perception believes that a disease is due to an attack or dysfunction in the biological-mechanical conditions of the individual. 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 to special Danish circumstances but are valid for other countries as well [1, 2]. (Norris R. Pills, Pesticides & Profits. North River Press, 1982; Braithwaite J. Corporate Crime in the Pharmaceutical Industry. Routledge & Kegan Paul, London, 1984) The empirical data in this article derive from Denmark, however.

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

    PubMed

    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.

  15. Injections, Cocktails and Diviners: Therapeutic Flexibility in the Context of Malaria Elimination and Drug Resistance in Northeast Cambodia

    PubMed Central

    Gryseels, Charlotte; Uk, Sambunny; Erhart, Annette; Gerrets, René; Sluydts, Vincent; Durnez, Lies; Muela Ribera, Joan; Hausmann Muela, Susanna; Menard, Didier; Heng, Somony; Sochantha, Tho; D’Alessandro, Umberto; Coosemans, Marc; Peeters Grietens, Koen

    2013-01-01

    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. PMID:24244678

  16. Model for the evaluation of drug-dispensing services in primary health care

    PubMed Central

    Sartor, Vanessa de Bona; de Freitas, Sergio Fernando Torres

    2014-01-01

    OBJECTIVE To develop a model for evaluating the efficacy of drug-dispensing service in primary health care. METHODS An efficacy criterion was adopted to determine the level of achievement of the service objectives. The evaluation model was developed on the basis of a literature search and discussions with experts. The applicability test of the model was conducted in 15 primary health care units in the city of Florianópolis, state of Santa Catarina, in 2010, and data were recorded in structured and pretested questionnaires. RESULTS The model developed was evaluated using five dimensions of analysis for analysis. The model was suitable for evaluating service efficacy and helped to identify the critical points of each service dimension. CONCLUSIONS Adaptations to the data collection technique may be required to adjust for the reality and needs of each situation. The evaluation of the drug-dispensing service should promote adequate access to medications supplied through the public health system. PMID:25372174

  17. In vivo evaluation of drug-drug interaction via mechanism-based inhibition by macrolide antibiotics in cynomolgus monkeys.

    PubMed

    Ogasawara, Akihito; Negishi, Isao; Kozakai, Kazumasa; Kume, Toshiyuki

    2009-11-01

    Irreversible inhibition, characterized as mechanism-based inhibition (MBI), of cytochrome P450 in drugs has to be avoided for their safe use. A comprehensive assessment of drug-drug interaction (DDI) potential is important during the drug discovery process. In the present study, we evaluated the effects of macrolide antibiotics, erythromycin (ERM), clarithromycin (CAM), and azithromycin (AZM), which are mechanism-based inhibitors of CYP3A, on biotransformation of midazolam (MDZ) in monkeys. These macrolides inhibited the formation of 1'-hydroxymidazolam in monkey microsomes as functions of incubation time and macrolide concentration. Furthermore, the inactivation potentials of macrolides (k(inact)/K(I): CAM congruent with ERM > AZM) were as effective as that observed in human samples. In in vivo studies, MDZ was administered orally (1 mg/kg) without or with multiple oral dosing of macrolides (15 mg/kg, twice a day on days 1-3). On day 3, the area under the plasma concentration-time curve (AUC) of MDZ increased 7.0-, 9.9-, and 2.0-fold with ERM, CAM, and AZM, respectively, compared with MDZ alone. Furthermore, the effects of ERM and CAM on the pharmacokinetics of MDZ were also observed on the day (day 4) after completion of macrolide treatments (AUC changes: 7.3- and 7.3-fold, respectively). Because the plasma concentrations of macrolides immediately before MDZ administration on day 4 were much lower than the IC(50) values for reversible CYP3A inhibition, the persistent effects may be predominantly caused by CYP3A inactivation. These results suggest that the monkey might be a suitable animal model to predict DDIs caused by MBI of CYP3A.

  18. Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation.

    PubMed

    Ha, Michael A; Sieg, Adam C

    2017-02-01

    Extracorporeal membrane oxygenation (ECMO) is a life-support modality used in patients with refractory cardiac and/or respiratory failure. A significant resurgence in the use ECMO has been seen in recent years as a result of substantial improvements in technology and survival benefit. With expanding ECMO use, a better understanding of how ECMO affects drug pharmacokinetics (PK) is necessary. The vast majority of PK studies in patients receiving ECMO have been conducted within neonatal or pediatric populations or within a controlled environment (e.g., in vitro or ex vivo). Because of significant differences in absorption, distribution, metabolism, and excretion, it may be inappropriate to extrapolate these PK data to adults. Thus, the aims of this review are to evaluate the changes in drug PK during ECMO and to summarize the available PK data for common drugs used in the adult critically ill patients during ECMO support. A search of the PubMed (1965-July 2016), EMBASE (1965-July 2016), and Cochrane Controlled Trial Register databases was performed. All relevant studies describing PK alterations during ECMO in ex vivo experiments and in adults were included. Evaluation of the data indicated that drug PK in adults receiving ECMO support may be significantly altered. Factors influencing these alterations are numerous and have intricate relationships with each other but can generally be classified as ECMO circuit factors, drug factors, and patient factors. Commonly used drugs in these patients include antimicrobials, sedatives, and analgesics. PK data for most of these drugs are generally lacking; however, recent research efforts in this patient population have provided some limited guidance in drug dosing. With an improved understanding of altered drug PK secondary to ECMO therapy, optimization of pharmacotherapy within this critically ill population continues to move forward.

  19. 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.

    PubMed

    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, p<0.05, Spearman's correlation test). Our findings suggest that the taste-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.

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

    PubMed Central

    Prabhu, P; Nitish, Kumar R; Koland, M; Harish, NM; Vijayanarayan, K; Dhondge, G; Charyulu, RN

    2010-01-01

    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. PMID:21264093

  1. Molecular approaches to target discovery:--evaluating targets for anti-tuberculosis drug discovery programmes.

    PubMed

    Balganesh, T S; Furr, B J A

    2007-06-01

    Selection of appropriate targets for launching antituberculosis drug discovery programmes is challenging. This challenge is magnified by the limited repertoire of 'validated targets' and the paucity of clinically successful drugs. However, continued understanding of the biology of the microbe and its interaction with the host has enabled detailed evaluation of several interesting pathways and novel targets. The value of a target that is suitable for antituberculosis drug discovery needs to be defined not only in the context of its 'essentiality' for survival in vitro but also against a variety of properties relevant to activities in the drug discovery process, e.g.; selectivity, vulnerability, suitability for structural studies, ability to monitor inhibition in whole cells etc. It is also rarely feasible to obtain all the relevant information on the target prior to the launch of a discovery programme. Thus, there is a continuous confidence-building exercise on the validity of a target. Several novel approaches have enabled exploitation of the mycobacterial genome and prioritisation of putative targets; the concept of 'sterilisation' is now being evaluated not only through the availability of structurally diverse probe compounds but also by the ability to characterise metabolic pathways in vivo. The impact of the current knowledge base on the different facets of 'target validation' relevant to antituberculosis drug discovery is discussed in this article with emphasis on developing appropriate matrix systems to prioritise them. The article also discusses the influence of lead generation approaches with specific reference to antibacterial drug discovery.

  2. Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches

    PubMed Central

    Kim, Marlene; Sedykh, Alexander; Chakravarti, Suman K.; Saiakhov, Roustem D.; Zhu, Hao

    2014-01-01

    Purpose Oral bioavailability (%F) is a key factor that determines the fate of a new drug in clinical trials. Traditionally, %F is measured using costly and time -consuming experimental tests. Developing computational models to evaluate the %F of new drugs before they are synthesized would be beneficial in the drug discovery process. Methods We employed Combinatorial Quantitative Structure-Activity Relationship approach to develop several computational %F models. We compiled a %F dataset of 995 drugs from public sources. After generating chemical descriptors for each compound, we used random forest, support vector machine, k nearest neighbor, and CASE Ultra to develop the relevant QSAR models. The resulting models were validated using five-fold cross-validation. Results The external predictivity of %F values was poor (R2=0.28, n=995, MAE=24), but was improved (R2=0.40, n=362, MAE=21) by filtering unreliable predictions that had a high probability of interacting with MDR1 and MRP2 transporters. Furthermore, classifying the compounds according to the %F values (%F<50% as “low”, %F≥50% as ‘high”) and developing category QSAR models resulted in an external accuracy of 76%. Conclusions In this study, we developed predictive %F QSAR models that could be used to evaluate new drug compounds, and integrating drug-transporter interactions data greatly benefits the resulting models. PMID:24306326

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

    PubMed

    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.

  4. Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union.

    PubMed

    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.

  5. Preparation and evaluation of cyclodextrin polypseudorotaxane with PEGylated liposome as a sustained release drug carrier

    PubMed Central

    Hayashida, Kayoko; Higashi, Taishi; Kono, Daichi; Motoyama, Keiichi; Wada, Koki

    2014-01-01

    Summary Cyclodextrins (CDs) can form polypseudorotaxanes (PPRXs) with drugs or drug carriers possessing linear polymers such as polyethylene glycol (PEG). On the other hand, PEGylated liposomes have been utilized as a representative anticancer drug carrier. However, little is known about the formation of CD PPRX with PEGylated liposome. In the present study, we first report the formation of CD PPRX with PEGylated liposome and evaluate it as a sustained release drug carrier. PEGylated liposome encapsulating doxorubicin was disrupted by the addition of α-CD. Meanwhile, γ-CD included two PEG chains and/or one bending PEG chain of PEGylated liposome and formed PPRX without the disruption of the membrane integrity of the PEGylated liposome. Moreover, the release of doxorubicin and/or PEGylated liposome encapsulating doxorubicin from the PPRX was prolonged in accordance with the matrix type release mechanism. These findings suggest the potential of γ-CD PPRX as sustained release carriers for PEGylated liposome products. PMID:25550741

  6. Preparation and evaluation of cyclodextrin polypseudorotaxane with PEGylated liposome as a sustained release drug carrier.

    PubMed

    Hayashida, Kayoko; Higashi, Taishi; Kono, Daichi; Motoyama, Keiichi; Wada, Koki; Arima, Hidetoshi

    2014-01-01

    Cyclodextrins (CDs) can form polypseudorotaxanes (PPRXs) with drugs or drug carriers possessing linear polymers such as polyethylene glycol (PEG). On the other hand, PEGylated liposomes have been utilized as a representative anticancer drug carrier. However, little is known about the formation of CD PPRX with PEGylated liposome. In the present study, we first report the formation of CD PPRX with PEGylated liposome and evaluate it as a sustained release drug carrier. PEGylated liposome encapsulating doxorubicin was disrupted by the addition of α-CD. Meanwhile, γ-CD included two PEG chains and/or one bending PEG chain of PEGylated liposome and formed PPRX without the disruption of the membrane integrity of the PEGylated liposome. Moreover, the release of doxorubicin and/or PEGylated liposome encapsulating doxorubicin from the PPRX was prolonged in accordance with the matrix type release mechanism. These findings suggest the potential of γ-CD PPRX as sustained release carriers for PEGylated liposome products.

  7. Evaluation of enantioselective binding of basic drugs to plasma by ACE.

    PubMed

    Martínez-Gómez, María Amparo; Villanueva-Camañas, Rosa María; Sagrado, Salvador; Medina-Hernández, Maria José

    2007-08-01

    The present paper deals with the evaluation of the stereoselective binding of antihistamines (brompheniramine, chlorpheniramine, hydroxyzine, orphenadrine and phenindamine), phenothiazines (promethazine and trimeprazine) and a local anesthetic (bupivacaine) to human plasma proteins. Since all of them are drugs highly bound to proteins, a methodology to determine the bound fraction of each drug enantiomer was proposed. This methodology includes the incubation of samples containing plasma and racemic drug, ultrafiltration of the mixture and the chiral separation of enantiomers in the bound drug fraction using affinity EKC (AEKC)-partial filling technique and HSA as chiral selector. The results shown in this paper represent the first evidence of the enantioselective binding of some antihistamines such as brompheniramine, hydroxyzine, orphenadrine and phenindamine and the phenothiazines, promethazine and trimeprazine, to human plasma proteins. The binding of phenindamine to plasma presented the highest enantioselectivity (ES) (ES = 2.5) followed by trimeprazine (ES = 1.5) and promethazine (ES = 1.4).

  8. Drug Recognition Evaluation and Chemical Confirmation of a 25C-NBOMe-Impaired Driver.

    PubMed

    Rajotte, James W; Palmentier, Jean-Paul F P; Wallage, Helena Rachelle

    2017-03-06

    This case report details an individual arrested for drug-impaired driving after leaving the scene of multiple motor vehicle collisions and evading police. The driver was examined by a drug recognition expert and failed the drug recognition evaluation. The driver admitted to using cocaine, marijuana, an antidepressant medication and "N-bomb," a novel psychoactive substance that possesses hallucinogenic properties. Toxicological analyses at the Centre of Forensic Sciences' Toronto laboratory revealed only the substance 2-[4-chloro-2,5-dimethoxyphenyl]-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) in the accused's urine. This is the first report in which 25C-NBOMe was identified through DRE and toxicological analyses in a drug-impaired driver.

  9. Drug Safety

    MedlinePlus

    ... 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 ...

  10. [Guidance of FDA risk evaluation and mitigation strategy and enlightenment to drug risk management of post-marketing Chinese medicine].

    PubMed

    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.

  11. Using Elite Athletes to Promote Drug Abstinence: Evaluation of a Single-Session School-Based Drug Use Prevention Program Delivered by Junior Hockey Players

    ERIC Educational Resources Information Center

    Wong, Jennifer

    2016-01-01

    School-based substance use prevention programs are a common method to approaching drug use in youths. Project SOS is a single-session drug prevention program developed by police officers and delivered by elite junior hockey players to students in grades 6 and 7. The current study evaluates the effects of Project SOS at achieving its objectives of…

  12. An Evaluation of the Fidelity of Implementation of a School-Based Drug Abuse Prevention Program: Project Toward No Drug Abuse (TND)

    ERIC Educational Resources Information Center

    Skara, Silvana; Rohrbach, Louise Ann; Sun, Ping; Sussman, Steve

    2005-01-01

    This article provides an implementation fidelity evaluation of the fourth experimental trial of Project Towards No Drug Abuse (TND). Two theoretical content components of the curriculum were examined to increase our understanding of the active ingredients of successful drug abuse prevention programs. A total of 18 senior high schools were randomly…

  13. An Initial Evaluation of the North Carolina Alcohol and Drug Education Traffic Schools. Volume II: Appendices.

    ERIC Educational Resources Information Center

    Popkin, Carol L.; And Others

    This volume is the second part of a report evaluating the North Carolina Alcohol Drug Education Traffic Schools (ADETS), established for the primary purpose of treating first offenders convicted of driving under the influence (DUI). These appendices include copies of legislation pertaining to the schools; a copy of the DMH 2604 referral form; an…

  14. Drug Information to Patient Care Areas via Television: Preliminary Evaluation of Two Years' Experience

    ERIC Educational Resources Information Center

    Springer, Sandra J.; And Others

    1978-01-01

    The research project described was undertaken to study the impact of the use of a closed circuit television system to deliver information about drugs, chemicals, and poisons from a central resource location to health professionals in patient care areas. Evaluation techniques included questionnaires, interviews with users, and extramural…

  15. SPICED: Evaluation of a Drug Education Project in Kirklees Primary Schools

    ERIC Educational Resources Information Center

    Crosswaite, C.; Tooby, J.; Cyster, R.

    2004-01-01

    Objective: To investigate the process, implementation, and short-term outcomes of a drug education programme (SPICED) introduced in Kirklees schools, West Yorkshire. Design: A retrospective evaluation using mixed methods. Setting: Ten primary schools in West Yorkshire. Methods: Interviews with professionals, survey of parents, focus groups with…

  16. Reliability and Validity of Self-Report Measures to Evaluate Drug and Violence Prevention Programs

    ERIC Educational Resources Information Center

    Komro, Kelli; Perry, Cheryl L.; Munson, Karen A.; Stigler, Melissa H.; Farbakhsh, Kian

    2004-01-01

    The purpose of this paper is to outline the evaluation plan for the Minnesota D.A.R.E. Plus Project, a drug and violence prevention program for young adolescents, and to present the results of psychometric analyses on the measures that will be used in the assessment of the intervention program. The survey instrument was tested using different…

  17. Staff and Client Perspectives on the Journey Mapping Online Evaluation Tool in a Drug Court Program

    ERIC Educational Resources Information Center

    Crunkilton, Dhira D.

    2009-01-01

    The purpose of this study was to assess staff and client perspectives on the Internet-based Journey Mapping program evaluation tool. A drug court program was chosen for a case study research design. Six staff and 10 clients participated in interviews and observations, and also responded to a questionnaire. A staff survey provided additional data.…

  18. A Census of Prison-Based Drug Treatment Programs: Implications for Programming, Policy, and Evaluation

    ERIC Educational Resources Information Center

    Welsh, Wayne N.; Zajac, Gary

    2004-01-01

    Despite a growing realization that unmeasured programmatic differences influence prison-based drug treatment effectiveness, few attempts to systematically measure such differences have been made. To improve program planning and evaluation in this area, we developed a census instrument to collect descriptive information about 118 prison-based drug…

  19. 78 FR 26374 - An Evaluation of the Prescription Drug User Fee Act Workload Adjuster; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-06

    ... HUMAN SERVICES Food and Drug Administration An Evaluation of the Prescription Drug User Fee Act Workload... on an assessment of the Prescription Drug User Fee Act (PDUFA) Workload Adjuster conducted by an... identified with the docket number found in brackets in the heading of this document. FOR FURTHER...

  20. 75 FR 14602 - Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation; Opening of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-26

    ... HUMAN SERVICES Food and Drug Administration (formerly Docket No. FDA-2008-D-0128) Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation; Opening of Comment Period for Future Revision of Guidance Dated July 2009; Public Conference AGENCY: Food and Drug Administration, HHS....

  1. Implementation evaluation of the Blueprint multi-component drug prevention programme: fidelity of school component delivery.

    PubMed

    Stead, Martine; Stradling, Robert; MacNeil, Morag; MacKintosh, Anne Marie; Minty, Sarah

    2007-11-01

    In order to achieve their desired aims, evidence-based, theory-driven drug education programmes need to be implemented as intended. Measurement of 'fidelity of implementation' is now included increasingly as part of programme evaluation, although measures and methods are sometimes limited. A more sophisticated approach to assessing implementation fidelity, based on Dane & Schneider's (1998) five dimensions, was used to examine the classroom curriculum element of the Blueprint programme. Blueprint was the largest and most rigorous evaluation of a multi-component drug prevention programme to date in the United Kingdom. Lessons were, overall, delivered with reasonable fidelity, although teachers did not always understand the thinking behind particular activities, suggesting that training needs to focus not only on content and methods but why particular approaches are important. Different dimensions of fidelity could conflict with one another: under pressure of time, generic elements and processes designed to reflect on learning were sometimes sacrificed in order that core drug education activities could be completed. Future drug education curricula need to build in more flexibility for discussion without compromising core evidence-based elements. Even with substantial training and support, individual variations in delivery were found, although few differences were found between teachers with prior expertise and teachers new to drug education. The methods and measures applied in the Blueprint study all represent attempts to improve on previous measures in terms of both reliability and sensitivity. In this respect the Blueprint study represents a valuable contribution to the science of implementation fidelity.

  2. Evaluation of the physicochemical properties of liposomes as potential carriers of anticancer drugs: spectroscopic study

    NASA Astrophysics Data System (ADS)

    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).

  3. Evaluation of drug-targetable genes by defining modes of abnormality in gene expression.

    PubMed

    Park, Junseong; Lee, Jungsul; Choi, Chulhee

    2015-09-04

    In the post-genomic era, many researchers have taken a systematic approach to identifying abnormal genes associated with various diseases. However, the gold standard has not been established, and most of these abnormalities are difficult to be rehabilitated in real clinical settings. In addition to identifying abnormal genes, for a practical purpose, it is necessary to investigate abnormality diversity. In this context, this study is aimed to demonstrate simply restorable genes as useful drug targets. We devised the concept of "drug targetability" to evaluate several different modes of abnormal genes by predicting events after drug treatment. As a representative example, we applied our method to breast cancer. Computationally, PTPRF, PRKAR2B, MAP4K3, and RICTOR were calculated as highly drug-targetable genes for breast cancer. After knockdown of these top-ranked genes (i.e., high drug targetability) using siRNA, our predictions were validated by cell death and migration assays. Moreover, inhibition of RICTOR or PTPRF was expected to prolong lifespan of breast cancer patients according to patient information annotated in microarray data. We anticipate that our method can be widely applied to elaborate selection of novel drug targets, and, ultimately, to improve the efficacy of disease treatment.

  4. Analytical evaluation of four on-site oral fluid drug testing devices.

    PubMed

    Vanstechelman, Sylvie; Isalberti, Cristina; Van der Linden, Trudy; Pil, Kristof; Legrand, Sara-Ann; Verstraete, Alain G

    2012-03-01

    The use of oral fluid (OF) as an alternative matrix for the detection of drugs of abuse has increased over the last decade, leading to the need for a rapid, simple, and reliable on-site OF testing device. Four on-site OF drug testing devices (Dräger DrugTest 5000, Cozart DDS, Mavand Rapid STAT, and Innovacon OrAlert) were evaluated on 408 volunteers at drug treatment centers. UPLC-MS-MS results were used as reference to determine sensitivity, specificity and accuracy for each device, applying Belgian legal confirmation cutoffs for benzoylecgonine, cocaine, and THC (10 ng/mL); morphine and 6-acetylmorphine (5 ng/mL); and amphetamine and 3,4-methylenedioxymethylamphetamine (25 ng/mL). Sensitivity for cocaine was 50%, 50%, 27%, and 11% for DrugTest, OrAlert, Rapid STAT, and DDS 806, respectively. For opiates, sensitivities were 84%, 73%, 77%, and 65%, respectively. For THC, the sensitivities were 81%, 23%, 43%, and 28%, respectively. For amphetamines, the sensitivities were 75%, 33%, 17%, and 67%, respectively. Specificity was >88% for opiates and THC, > 90% for amphetamines, and > 97% for cocaine. All tests showed good specificity. DrugTest had the highest sensitivity, although it was still low for some analytes.

  5. Evaluation of drug load and polymer by using a 96-well plate vacuum dry system for amorphous solid dispersion drug delivery.

    PubMed

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

    2012-06-01

    It is well recognized that poor dissolution rate and solubility of drug candidates are key limiting factors for oral bioavailability. While numerous technologies have been developed to enhance solubility of the drug candidates, poor water solubility continuously remains a challenge for drug delivery. Among those technologies, amorphous solid dispersions (SD) have been successfully employed to enhance both dissolution rate and solubility of poorly water-soluble drugs. This research reports a high-throughput screening technology developed by utilizing a 96-well plate system to identify optimal drug load and polymer using a solvent casting approach. 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. Validation of this method was demonstrated with three marketed drugs as well as with one internal compound. Scale up of the internal compound SD by spray drying further confirmed the validity of this method, and its quality was comparable to a larger scale process. Here, we demonstrate that our system is highly efficient, cost-effective, and robust to evaluate the feasibility of spray drying technology to produce amorphous solid dispersions.

  6. Current opinion: safety evaluation of drug metabolites in development of pharmaceuticals.

    PubMed

    Naito, Shinsaku; Furuta, Shigeru; Yoshida, Takemi; Kitada, Mitsukazu; Fueki, Osamu; Unno, Takashi; Ohno, Yasuo; Onodera, Hiroshi; Kawamura, Nobuyuki; Kurokawa, Misao; Sagami, Fumio; Shinoda, Kazutoshi; Nakazawa, Takahiro; Yamazaki, Tsuneyoshi

    2007-10-01

    Safety assessment of drug metabolites in the development of pharmaceuticals was discussed in January 2007 at the kick-off meeting of a "Drug Evaluation Forum", with reference to the views of clinicians and other academic representatives. Safety evaluation of metabolites cannot readily be based on a single theoretical framework, and basically a case-by-case approach is called for. These evaluations should be performed precisely and an accurate profile secured taking into account adverse reactions that are unpredictable from the parent compound administered in clinical studies and any signs or symptoms that may be associated with the metabolites. In addition, elimination of scientifically meaningless metabolite safety assessment studies is essential for prompt supply of high-quality drugs to the medical frontline. Preparation of an outline concept paper would be useful for achievement of shared understanding of issues of this type. Collective viewpoints obtained in this fashion are also relevant to the discussion on the need for guidance, and given a degree of flexibility may also be helpful for drug development and, in turn, society at large.

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

    NASA Astrophysics Data System (ADS)

    Ghosh, Goutam

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

  8. Evaluating the roles of autophagy and lysosomal trafficking defects in intracellular distribution-based drug-drug interactions involving lysosomes.

    PubMed

    Logan, Randall; Kong, Alex; Krise, Jeffrey P

    2013-11-01

    Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs.

  9. Automated sleep EEG analysis applied to the evaluation of drugs: illustration by study of clorazepate dipotassium.

    PubMed

    Smith, J R; Karacan, I; Keane, B P; Yang, M

    1976-12-01

    An automated sleep EEG analysis system was used to evaluate the effects of clorazepate dipotassium in normal subjects. Ten young-adult men slept 18 consecutive nights in the laboratory. On days 8-15 clorazepate (7.5 mg) was administered three times daily; on days 5-7 and 16-18 a placebo was administered in a similar fashion. The drug reduced amounts of alpha and delta activity and increased the amount of beta activity and the number of spindles. These effects generally persisted through the 3 day placebo recovery period. Our results suggest that sleep EEG waveform descriptors are sensitive indicators of drug activity and that beta activity in particular may be useful in the detailed description of various drug effects.

  10. [DNA microarrays--perspective of application for drug effectivity and safety evaluation].

    PubMed

    Roman, Iza

    2008-01-01

    Microarray technology provides a unique tool for the determination of gene expression at the level of messenger RNA (mRNA). Microarray has been successfully applied to the high throughput simultaneous expression of many thousands of genes in a single experiment. One important application of DNA microarray technology, within the context of drugs effectiveness and safety evaluation studies, is its use as a screening tool for the identification of biochemical pathways, potential targets for novel molecular therapeutics, for the identification of molecular mechanisms of toxicity and to understand and predict individual drug sensitivity and resistance. The purpose of this review is presentation of the utility of DNA microarray technology in all phases of the drug discovery process.

  11. Self-microemulsifying drug-delivery system for improved oral bioavailability of probucol: preparation and evaluation

    PubMed Central

    Sha, Xianyi; Wu, Juan; Chen, Yanzuo; Fang, Xiaoling

    2012-01-01

    The objective of our investigation was to design a self-microemulsifying drug-delivery system (SMEDDS) to improve the bioavailability of probucol. SMEDDS was composed of probucol, olive oil, Lauroglycol FCC, Cremophor EL, Tween-80, and PEG-400. Droplet sizes were determined. In vitro release was investigated. Pharmacokinetics and bioavailability of probucol suspension, oil solution, and SMEDDS were evaluated and compared in rats. Plasma drug concentration was determined by high-performance liquid chromatography. After administration of probucol suspension, plasma drug concentration was very low. Relative bioavailability of SMEDDS was dramatically enhanced in an average of 2.15- and 10.22-fold that of oil solution and suspension, respectively. It was concluded that bioavailability of probucol was enhanced greatly by SMEDDS. Improved solubility and lymphatic transport may contribute to the enhancement of bioavailability. PMID:22359449

  12. Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.

    PubMed

    Ishiguro, Naoki; Shimizu, Hidetada; Kishimoto, Wataru; Ebner, Thomas; Schaefer, Olaf

    2013-01-01

    Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.

  13. Formulation and Evaluation of a Self-microemulsifying Drug Delivery System Containing Bortezomib.

    PubMed

    Hong, Eon-Pyo; Kim, Ju-Young; Kim, Su-Hyeon; Hwang, Kyu-Mok; Park, Chun-Woong; Lee, Hyo-Jung; Kim, Dong-Wook; Weon, Kwon-Yeon; Jeong, Seo Young; Park, Eun-Seok

    2016-01-01

    The purposes of the present study were to develop a self-microemulsifying drug delivery system (SMEDDS) containing bortezomib, a proteasome inhibitor. The solubility of the drug was evaluated in 15 pharmaceutical excipients. Combinations of oils, surfactants and cosurfactants were screened by drawing pseudo-ternary phase diagrams. The system exhibiting the largest region of microemulsion was considered optimal. Bortezomib SMEDDS spontaneously formed a microemulsion when diluted with an aqueous medium with a median droplet size of approximately 20-30 nm. In vitro release studies showed that the SMEDDS had higher initial release rates for the drug when compared with the raw drug material alone. Measurement of the viscosity, size, and ion conductivity indicated that a phase inversion from water in an oil system to oil in a water system occurred when the weight ratio of the water exceeded 30% of the entire microemulsion system. In a pharmacokinetics study using rats, the bortezomib microemulsion failed to improve the bioavailability of the drug. The reason was assumed to be degradation of the drug in the microemulsion in the gastrointestinal tract. However, bortezomib in Labrasol(®) solution (an aqueous solution containing 0.025% Labrasol(®)) showed significantly increased area under the curve from 0-24 h (AUC0-24 h) and maximum plasma concentration (Cmax) values compared to the drug suspension. The findings of this study imply that oral delivery of a bortezomib and colloidal system containing Labrasol(®) could be an effective strategy for the delivery of bortezomib.

  14. [Evaluation of the medical value of a drug. A necessity for the Transparency Commission].

    PubMed

    Avouac, B

    1992-01-01

    The marketing approval (AMM) is based on criteria of pharmaceutical quality, efficacy and safety of use. Before marketing, the data are collected by means of double-blind, randomized, prospective clinical trials that compare the study product to a reference product. A post-AMM assessment is needed to define the increase of the medical benefit (ASMR) and the therapeutic value of the new drugs. The quantification of the ASMR is essential for registration on the list of drugs reimbursable for those who benefit from Social Security. The evaluation of the therapeutic value and the nature of the affection treated are the criteria upon which the reimbursement ratio is chosen. After marketing, the reevaluation of the medical benefit and the drugs' usefulness may be compared to the treatment's net medical cost (direct + indirect cost--avoided cost) in cost/utility or cost/benefit studies. The Transparency Commission has worked out a scale of assessment of the ASMR which will orient recommendation, or non-recommendation, of registration on the list of reimbursable drugs as well as price fixing proposals. In the future, the Transparency Commission is to strengthen its position regarding the good use of the drug through a better prescriber information system. Thanks to the pharmaco-epidemiology and the pharmaco-vigilance data, the Transparency Commission will be able to guarantee the post-marketing follow-up of the drugs. The examination of the products' conditions of use, the reevaluation of the treatment's advantages based on the utility studies and the epidemiological surveys, and the cost-benefit studies will contribute to a medical control of health spending linked to drug consumption.

  15. Evaluation of trypanocidal activity of combinations of anti-sleeping sickness drugs with cysteine protease inhibitors.

    PubMed

    Steverding, Dietmar

    2015-01-01

    Chemotherapy of human African trypanosomiasis (HAT) is unsatisfactory because only a few drugs, with serious side effects and poor efficacy, are available. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, here the trypanocidal activity of the cysteine protease inhibitor K11777 in combination with current anti-HAT drugs using bloodstream forms of Trypanosoma brucei was investigated. Isobolographic analysis was used to determine the interaction between cysteine protease inhibitors (K11777, CA-074Me and CAA0225) and anti-HAT drugs (suramin, pentamidine, melarsoprol and eflornithine). Bloodstream forms of T. brucei were incubated in culture medium containing cysteine protease inhibitors or anti-HAT drugs alone or in combination at a 1:1 fixed-dose ratio. After 48 h incubation, live cells were counted, the 50% growth inhibition values determined and combination indices calculated. The general cytotoxicity of drug combinations was evaluated with human leukaemia HL-60 cells. Combinations of K11777 with suramin, pentamidine and melarsoprol showed antagonistic effects while with eflornithine a synergistic effect was observed. Whereas eflornithine antagonises with CA-074Me, an inhibitor inactivating the targeted TbCATL only under reducing conditions, it synergises with CAA0255, an inhibitor structurally related to CA-074Me which inactivates TbCATL independently of thiols. These findings indicate an essential role of thiols for the synergistic interaction between K11777 and eflornithine. Encouragingly, the K11777/eflornithine combination displayed higher trypanocidal than cytotoxic activity. The results of this study suggest that the combination of the cysteine protease inhibitor K11777 and eflornithine display promising synergistic trypanocidal activity that warrants further investigation of the drug combination as possible alternative treatment of HAT.

  16. A critical evaluation of Amicon Ultra centrifugal filters for separating proteins, drugs and nanoparticles in biosamples.

    PubMed

    Johnsen, Elin; Brandtzaeg, Ole Kristian; Vehus, Tore; Roberg-Larsen, Hanne; Bogoeva, Vanya; Ademi, Ornela; Hildahl, Jon; Lundanes, Elsa; Wilson, Steven Ray

    2016-02-20

    Amicon(®) Ultra centrifugal filters were critically evaluated for various sample preparations, namely (a) proteome fractionation, (b) sample cleanup prior to liquid chromatography mass spectrometry (LC-MS) measurement of small molecules in cell lysate, and (c) separating drug-loaded nanoparticles and released drugs for accurate release profiling in biological samples. (a) Filters of supposedly differing molar mass (MM) selectivity (10, 30, 50 and 100K) were combined to attempt fractionation of samples of various complexity and concentration. However, the products had surprisingly similar MM retentate/filtrate profiles, and the filters were unsuited for proteome fractionation. (b) Centrifugal filtration was the only clean-up procedure in a FDA-guideline validated LC-MS method for determining anti-tuberculosis agents rifampicin and thioridazine in macrophage cell lysate. An additional organic solvent washing step (drug/protein-binding disruption) was required for satisfactory recovery. (c) The centrifugation filters are well suited for separating drugs and nanoparticles in simple aqueous solutions, but significantly less so for biological samples, as common drug-protein binding disruptors can dissolve NPs or be incompatible with LC-MS instrumentation.

  17. Benefits attained from space flight in pre-clinical evaluation of candidate drugs

    NASA Astrophysics Data System (ADS)

    Stodieck, Louis S.; Bateman, Ted; Ayers, Reed; Ferguson, Virginia; Simske, Steve

    1998-01-01

    Modern medicine has made great strides in recent decades. The promises of biotechnology and advances in gene identification and manipulation offer tremendous potential for treatment of disease. However, developing new drug therapies by biotechnology and pharmaceutical companies is still a very costly and time consuming process. One of the important milestones in drug development is the successful completion of preclinical evaluation. During this phase, drug candidates must be shown to be safe, yet effective as a treatment of the target disease or disorder. Critical for preclinical testing is the availability of biomedical test models that adequately mimic the target disease. A good model will 1) allow confident prediction of a drug's effects before expensive clinical trials are begun, 2) provide convincing data for use in an FDA new drug application and 3) minimize the time required for testing. Space flight may offer a completely unique and new set of biomedical models for use in pharmaceutical testing. This paper highlights some examples of recent experiments done in space to test new compounds for Chiron, (Emmeryville, CA) and discusses the importance of the International Space Station to greatly expand such commercial opportunities.

  18. Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

    PubMed

    Boche, Mithila; Pokharkar, Varsha

    2016-05-20

    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.

  19. Genotoxic evaluation of the antimalarial drug, fansidar, in cultured human lymphocytes.

    PubMed

    Abou-Eisha, A; Afifi, M

    2004-09-01

    Fansidar (pyrimethamine-sulfadoxine) has been used extensively worldwide for the treatment of chloroquine resistant Plasmodium falciparum malaria, toxoplasmosis and Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Because of the wide usage of pyrimethamine-sulfadoxine in developing countries and the lake of information from open literature and reports from manufacturers about the genotoxicity of such antimalarial drug, the present work was suggested. The possible genetic toxicity of fansidar has been evaluated in human peripheral blood lymphocyte cultures. The frequencies of sister-chromatid exchanges (SCE) and micronuclei (MN) were scored as genetic endpoints. Both tests covering a wide range of induced genetic damage as primary DNA damage, clastogenicity and aneugenicity. Cultures were set up by using blood samples from two healthy donors and the treatment was done using different fansidar concentrations ranging from 1:20 to 10:200 microg/ml. From our results, it appears that this drug is able to induce moderate genotoxic effects, as revealed by the increases found in SCE and MN frequencies in cultures from the two donors at the two highest concentrations tested (5:100 and 10:200 microg/ml). In addition, cyotoxic/cytostatic effects of fansidar were revealed by a decrease in the proliferative rate index (PRI) and in the cytokinesis block proliferation index (CBPI). Our findings suggest that the use of this drug should be restricted to situations where other antimalarial drugs cannot be used. The drug should never be given to pregnant women.

  20. Cell based approaches for evaluation of drug-induced liver injury.

    PubMed

    Greer, Mhairi L; Barber, Jane; Eakins, Julie; Kenna, J Gerry

    2010-02-09

    An improved understanding of mechanisms that underlie drug-induced liver injury (DILI) is required to enable design of drugs that have minimal potential to cause this adverse reaction in man. Available evidence suggests DILI arises in susceptible patients because of an imbalance between chemical insults (which are an inherent property of certain drugs and/or their metabolites) and the ability of the liver to mount compensatory/adaptive responses. In vivo safety testing in pre-clinical species ensures that drugs which enter clinical trials do not cause reproducible and dose-dependent liver injury in man, but is of limited value for exploration of underlying mechanisms and does not assess potential to cause rare idiosyncratic DILI. This review highlights the value that can be gained from in vitro studies using cultured hepatocytes and also hepatocyte-derived cell lines transfected with individual human cytochrome P450 (CYP450) isoforms. We have evaluated a range of mechanisms and endpoints (cell necrosis, mitochondrial injury, inhibition of biliary transporters and metabolite-mediated toxicity) using these model systems. Our data indicate that multiple mechanisms are likely to be involved in development of idiosyncratic DILI in man caused by numerous drugs, e.g. the anticonvulsant chlorpromazine.

  1. Evaluation of physico-mechanical properties of drug-excipients agglomerates obtained by crystallization.

    PubMed

    Maghsoodi, M; Tajalli Bakhsh, A S

    2011-06-01

    Spherical crystallization (SC) of carbamazepine (CBZ) was carried out for preparation of the agglomerates using the solvent change method. The potential of the intraagglomerate addition of sodium starch glycolate (SSG) as a disintegrant agent and povidone (PVP) as a hydrophilic polymer was also evaluated. The process of SC involved recrystallization of CBZ and its simultaneous agglomeration with additives. An ethanol:isopropyl acetate:water system was used where isopropyl acetate acted as a bridging liquid and ethanol and water as good and bad solvents, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and Scanning electron microscopy and were evaluated for yield, flowability, disintegration time and drug release. CBZ agglomerates exhibited significantly improved micromeritic properties as well as dissolution behavior in comparison to conventional drug crystals. The dissolution rate of drug from agglomerates was enhanced by inclusion of SSG, while addition of PVP to CBZ/SSG agglomerates led to reduction in the release rate of CBZ even below that of the conventional drug crystals. SC process can be considered as a suitable alternative to conventional granulation process to obtain agglomerates of CBZ with excipients with improved micromeritic properties and modified dissolution rate.

  2. Thermosensitive hydrogel for periodontal application: in vitro drug release, antibacterial activity and toxicity evaluation.

    PubMed

    Pakzad, Yousef; Ganji, Fariba

    2016-02-01

    Injectable thermosensitive chitosan hydrogel is an attractive temperature-induced sol-gel solution that is widely used in drug delivery and biomedical applications. In this study, an injectable antimicrobial delivery system for periodontal treatment based on chitosan/gelatin/β-glycerolphosphate solution has been developed. The result of thermal and mechanical evaluations of chitosan/gelatin/β-glycerolphosphate hydrogel showed that adding gelatin to chitosan/β-glycerolphosphate solution significantly decreased gelling time and increased gel strength at 37℃. The antimicrobial agents chosen for release studies were metronidazole with a low molecular weight and vancomycin hydrochloride with a high molecular weight. The initial burst and total in vitro drug release for metronidazole was 13% and 67%, respectively. The initial burst and total drug release for vancomycin hydrochloride was relatively low at 3% and 23%, respectively. The momentary and total percentage of metronidazole accumulated in the phosphate buffer revealed that chitosan/gelatin/β-glycerolphosphate can develop and maintain sustained release of metronidazole in concentrations that are effective for eliminating pathogenic bacteria over time. Cytotoxicity evaluations show that chitosan/gelatin/β-glycerolphosphate thermosensitive hydrogel is a drug carrier with no cytotoxic effects.

  3. Characterization of Mouse Models of Mycobacterium avium Complex Infection and Evaluation of Drug Combinations

    PubMed Central

    Almeida, Deepak V.; Tyagi, Sandeep; Converse, Paul J.; Ammerman, Nicole C.; Grosset, Jacques H.

    2015-01-01

    The Mycobacterium avium complex is the most common cause of nontuberculous mycobacterial lung disease worldwide; yet, an optimal treatment regimen for M. avium complex infection has not been established. Clarithromycin is accepted as the cornerstone drug for treatment of M. avium lung disease; however, good model systems, especially animal models, are needed to evaluate the most effective companion drugs. We performed a series of experiments to evaluate and use different mouse models (comparing BALB/c, C57BL/6, nude, and beige mice) of M. avium infection and to assess the anti-M. avium activity of single and combination drug regimens, in vitro, ex vivo, and in mice. In vitro, clarithromycin and moxifloxacin were most active against M. avium, and no antagonism was observed between these two drugs. Nude mice were more susceptible to M. avium infection than the other mouse strains tested, but the impact of treatment was most clearly seen in M. avium-infected BALB/c mice. The combination of clarithromycin-ethambutol-rifampin was more effective in all infected mice than moxifloxacin-ethambutol-rifampin; the addition of moxifloxacin to the clarithromycin-containing regimen did not increase treatment efficacy. Clarithromycin-containing regimens are the most effective for M. avium infection; substitution of moxifloxacin for clarithromycin had a negative impact on treatment efficacy. PMID:25624335

  4. Rationale to evaluate medically supervised safer smoking facilities for non-injection illicit drug users.

    PubMed

    Collins, Courtney L C; Kerr, Thomas; Tyndall, Mark W; Marsh, David C; Kretz, Patricia S; Montaner, Julio S; Wood, Evan

    2005-01-01

    Many cities are experiencing ongoing infectious disease epidemics and substantial community harm as a result of illicit drug use. In an effort to reduce these public order and public health concerns, consideration has been given to the opening in Vancouver of a safer smoking facility (SSF). The present review was conducted to examine if there is a rationale to support the evaluation of a SSF in the Canadian context. Available evidence suggests that conventional drug control strategies are insufficient to address the health and community harms of non-injection drug use, and that the public order benefits of supervised injection facilities may be relevant to SSFs. In addition, there is persuasive evidence to suggest there is potential for blood-borne disease transmission through the sharing of smoking paraphernalia, and the potential for SSFs to address this concern is a pressing public health question. Also relevant to this topic are interventions to prevent transition into injection drug use, and SSFs may also be evaluated as a potential strategy to address this concern.

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

    PubMed

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

    2016-01-01

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

  6. Driving under the influence of drugs -- evaluation of analytical data of drugs in oral fluid, serum and urine, and correlation with impairment symptoms.

    PubMed

    Toennes, Stefan W; Kauert, Gerold F; Steinmeyer, Stefan; Moeller, Manfred R

    2005-09-10

    A study was performed to acquire urine, serum and oral fluid samples in cases of suspected driving under the influence of drugs of abuse. Oral fluid was collected using a novel sampling/testing device (Dräger DrugTest System). The aim of the study was to evaluate oral fluid and urine as a predictor of blood samples positive for drugs and impairment symptoms. Analysis for cannabinoids, amphetamine and its derivatives, opiates and cocaine was performed in urine using the Mahsan Kombi/DOA4-test, in serum using immunoassay and gas chromatography-mass spectrometry (GC-MS) confirmation and in oral fluid by GC-MS. Police and medical officer observations of impairment symptoms were rated and evaluated using a threshold value for the classification of driving inability. Accuracy in correlating drug detection in oral fluid and serum were >90% for all substances and also >90% in urine and serum except for THC (71.0%). Of the cases with oral fluid positive for any drug 97.1% of corresponding serum samples were also positive for at least one drug; of drug-positive urine samples this were only 82.4%. In 119 of 146 cases, impairment symptoms above threshold were observed (81.5%). Of the cases with drugs detected in serum, 19.1% appeared not impaired which were the same with drug-positive oral fluid while more persons with drug-positive urine samples appeared uninfluenced (32.7%). The data demonstrate that oral fluid is superior to urine in correlating with serum analytical data and impairment symptoms of drivers under the influence of drugs of abuse.

  7. Development, Characterization, and Pharmacodynamic Evaluation of Hydrochlorothiazide Loaded Self-Nanoemulsifying Drug Delivery Systems

    PubMed Central

    Yadav, Pankajkumar S.; Yadav, Ekta; Verma, Amita; Amin, Saima

    2014-01-01

    The objective of the current work was to develop optimized self-nanoemulsifying drug delivery systems (SNEDDS) and evaluate their in vitro and in vivo performance. The research comprised various studies which includes solubility studies in various vehicles, pseudoternary phase diagram construction, and preparation and characterization of SNEDDS along with in vitro dissolution and in vivo pharmacodynamic profiling. Based on dissolution profile, a remarkable increase in rate of dissolution was observed in comparison with plain drug and marketed formulation. Optimized SNEDDS formulation was composed of Capmul MCM (19.17% w/w), Tween 80 (57.5% w/w), Transcutol P (12.7% w/w), and HCT (4.17% w/w). In vivo pharmacodynamic evaluation in Wistar rats showed considerable increase in pharmacological effect of HCT by SNEDDS formulation as compared with plain HCT. PMID:25580455

  8. [Evaluation point of rational drug use of traditional Chinese medicine in market].

    PubMed

    Gao, Rui; Sun, Mingyue; Xie, Yanming

    2011-10-01

    Minimizing the underlying risk and maximizing the benefits of drag users, by using drags under a safe, efficient and economical principle, is both the requirement and purpose of clinical rational drug use. This paper evaluates the clinical application of traditional Chinese medicine (TCM) in the market based on its characteristics, considering if the drugs are safely applied, if the medicine has an anticipated effect, and if the medicine is properly priced. This paper also brings the idea of establishing an evaluation system integrated with the characteristics of TCM to monitor the clinical application of TCM after going into the market and thus further optimizes the clinical instructions of applying TCM and helps to guide the appropriate usage of TCM.

  9. Is Project Towards No Drug Abuse (Project TND) an evidence-based drug and violence prevention program? A review and reappraisal of the evaluation studies.

    PubMed

    Gorman, Dennis M

    2014-08-01

    This paper critically reviews the published evidence pertaining to Project Towards No Drug Abuse (Project TND). Publications from seven evaluation studies of Project TND are reviewed, and the results from these are discussed as related to the following outcomes: main effects on the use of cigarettes, alcohol and marijuana; main effects on the use of "hard drugs," defined in the evaluations as cocaine, hallucinogens, stimulants, inhalants, ecstasy and other drugs (e.g., depressants, PCP, steroids and heroin); subgroup and interaction analyses of drug use; and violence-related behaviors. Very few main effects have been found for cigarette, alcohol and marijuana use in the Project TND evaluations. While studies do report main effects for hard drug use, these findings are subject to numerous threats to validity and may be attributable to the data analyses employed. Similarly, while isolated subgroup and interaction effects were found for alcohol use among baseline nonusers and some violence-related behaviors in the early Project TND evaluations, these findings have not been replicated in more recent studies and may result from multiple comparisons between study conditions. In conclusion, there is little evidence to support the assertion that Project TND is an effective drug or violence prevention program. The broader implications of these findings for prevention science are discussed and suggestions are made as to how the quality of research in the field might be improved.

  10. [Evaluation of the effectiveness of a prison-based drug treatment].

    PubMed

    Casares-López, María José; González-Menéndez, Ana M; Fernández-García, M Paula; Villagrá, Patricia

    2012-05-01

    The present study evaluated the effectiveness of a drug-free unit (DFU) in reducing the use of substances by incarcerated adult offenders, and to analyze changes in the addiction severity index, motivation, and personality caused by the program. This is an external evaluation, with an ex post facto design with repeated measures. Eighty-seven prisoners from the DFU were evaluated during the first year of residence in the program. Most are young men, polydrug addicts and mainly serving sentences for public health crimes and property offenses. There is need of psychiatric treatment at the baseline, with 85% comorbid personality disorders. Motivation for treatment is low, and remains stable over 12 month's duration of the study. The DFU was found to have a significant effect in reducing the use of drugs by offenders and to improve the drug and family composite scores, also reducing scores on personality scales. However, it fails to change medical and psychiatric scores, so that the need for intervention in these areas is underscored.

  11. A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity.

    PubMed

    Bale, Shyam Sundhar; Sridharan, Gautham Vivek; Golberg, Inna; Prodanov, Ljupcho; McCarty, William J; Usta, Osman Berk; Jindal, Rohit; Yarmush, Martin L

    2015-12-01

    To evaluate drug and metabolite efficacy on a target organ, it is essential to include metabolic function of hepatocytes, and to evaluate metabolite influence on both hepatocytes and the target of interest. Herein, we have developed a two-chamber microfabricated device separated by a membrane enabling communication between hepatocytes and cancer cells. The microscale environment created enables cell co-culture in a low media-to-cell ratio leading to higher metabolite formation and rapid accumulation, which is lost in traditional plate cultures or other interconnected models due to higher culture volumes. We demonstrate the efficacy of this system by metabolism of tegafur by hepatocytes resulting in cancer cell toxicity.

  12. Evaluation of the Identification Power of RPLC Analyses in the Screening for Drug Compounds

    PubMed Central

    Dumarey, Melanie; Heyden, Yvan Vander; Rutan, Sarah C.

    2010-01-01

    The identification of drugs of abuse is an important issue in forensic science. The main goal is to trace and identify as many drugs as possible in the shortest possible time preferably with a simple analysis method. One possibility is to screen samples using a Liquid Chromatography – Diode Array Detection (LC-DAD) system. However, when simultaneously performing another analysis on a chromatographic column exhibiting selectivity differences from the first one, i.e., orthogonal or dissimilar columns, a greater number of drugs can be possibly identified without investing a lot of extra time or money. The primary difficulty is then selecting the most appropriate columns. In this paper, it is demonstrated that selecting the most dissimilar columns based on measures such as correlation or Snyder’s Fs value is not optimal, because these measures do not take into account the identification power of the individual systems. This implies that a large number of drugs may not necessarily be identified on the systems selected using these criteria. Therefore, three other measures are tested to evaluate the identification power obtained by parallel screening on two columns or by comprehensive two-dimensional LC (LC×LC). The simplest approach is counting the number of compounds separable with a difference in retention time greater than a predefined critical value. However, this measure does not reflect the co-elution pattern of the unidentified drugs nor the separation degree of all compounds. The second tested measure, information, enables differentiation between systems identifying the same number of compounds, but resulting in a different co-elution pattern. Multivariate selectivity, the third tested parameter, takes into account the degree of separation of all compounds and has the advantage that it reflects the gain in identification power achieved by introducing DAD data. All three proposed measures also enable evaluation of whether the corresponding LC×LC method will

  13. Evaluation of Tissue Interactions with Mechanical Elements of a Transscleral Drug Delivery Device

    PubMed Central

    Cohen, Sarah J.; Chan, Robison V. Paul; Keegan, Mark; Andreoli, Christopher M.; Borenstein, Jeffrey T.; Miller, Joan W.; Gragoudas, Evangelos S.

    2012-01-01

    The goal of this work was to evaluate tissue-device interactions due to implantation of a mechanically operated drug delivery system onto the posterior sclera. Two test devices were designed and fabricated to model elements of the drug delivery device—one containing a free-spinning ball bearing and the other encasing two articulating gears. Openings in the base of test devices modeled ports for drug passage from device to sclera. Porous poly(tetrafluoroethylene) (PTFE) membranes were attached to half of the gear devices to minimize tissue ingrowth through these ports. Test devices were sutured onto rabbit eyes for 10 weeks. Tissue-device interactions were evaluated histologically and mechanically after removal to determine effects on device function and changes in surrounding tissue. Test devices were generally well-tolerated during residence in the animal. All devices encouraged fibrous tissue formation between the sclera and the device, fibrous tissue encapsulation and invasion around the device, and inflammation of the conjunctiva. Gear devices encouraged significantly greater inflammation in all cases and a larger rate of tissue ingrowth. PTFE membranes prevented tissue invasion through the covered drug ports, though tissue migrated in through other smaller openings. The torque required to turn the mechanical elements increased over 1000 times for gear devices, but only on the order of 100 times for membrane-covered gear devices and less than 100 times for ball bearing devices. Maintaining a lower device profile, minimizing microscale motion on the eye surface and covering drug ports with a porous membrane may minimize inflammation, decreasing the risk of damage to surrounding tissues and minimizing disruption of device operation. PMID:24300189

  14. Evaluation of tissue interactions with mechanical elements of a transscleral drug delivery device.

    PubMed

    Cohen, Sarah J; Chan, Robison V Paul; Keegan, Mark; Andreoli, Christopher M; Borenstein, Jeffrey T; Miller, Joan W; Gragoudas, Evangelos S

    2012-03-12

    The goal of this work was to evaluate tissue-device interactions due to implantation of a mechanically operated drug delivery system onto the posterior sclera. Two test devices were designed and fabricated to model elements of the drug delivery device-one containing a free-spinning ball bearing and the other encasing two articulating gears. Openings in the base of test devices modeled ports for drug passage from device to sclera. Porous poly(tetrafluoroethylene) (PTFE) membranes were attached to half of the gear devices to minimize tissue ingrowth through these ports. Test devices were sutured onto rabbit eyes for 10 weeks. Tissue-device interactions were evaluated histologically and mechanically after removal to determine effects on device function and changes in surrounding tissue. Test devices were generally well-tolerated during residence in the animal. All devices encouraged fibrous tissue formation between the sclera and the device, fibrous tissue encapsulation and invasion around the device, and inflammation of the conjunctiva. Gear devices encouraged significantly greater inflammation in all cases and a larger rate of tissue ingrowth. PTFE membranes prevented tissue invasion through the covered drug ports, though tissue migrated in through other smaller openings. The torque required to turn the mechanical elements increased over 1000 times for gear devices, but only on the order of 100 times for membrane-covered gear devices and less than 100 times for ball bearing devices. Maintaining a lower device profile, minimizing microscale motion on the eye surface and covering drug ports with a porous membrane may minimize inflammation, decreasing the risk of damage to surrounding tissues and minimizing disruption of device operation.

  15. Evaluation, use, and usefulness of prescription drug information sources among Anglo and Hispanic Americans.

    PubMed

    Delorme, Denise E; Huh, Jisu; Reid, Leonard N

    2010-01-01

    This survey was conducted to determine and compare how Anglo and Hispanic Americans evaluate and use interpersonal, advertising, and mediated sources of prescription drug information. Findings suggest the following: (1) Hispanics rely on doctors, Internet advertising sources, and direct-to-consumer advertising (DTCA), while Anglos frequently use health-related websites and health care professionals; (2) Anglos are more likely to use health-related websites such as WebMD, although Anglos and Hispanics do not appear significantly different in Internet source usefulness evaluation; (3) Hispanics rely on television (TV) and DTC TV advertising more than Anglos, and this tendency is stronger for strong than weak Hispanic identifiers; (4) Hispanics evaluate TV news stories and TV advertising as more useful than Anglos; (5) Hispanics evaluate DTCA more positively and with less skepticism than Anglos; and (6) Hispanic ethnic identification level is positively related to preferences for Spanish-language media and health care professionals.

  16. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

    PubMed

    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.

  17. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction

    PubMed Central

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S. Stevens

    2015-01-01

    Opinion Statement 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. PMID:26009706

  18. Nanomiemgel - A Novel Drug Delivery System for Topical Application - In Vitro and In Vivo Evaluation

    PubMed Central

    Somagoni, Jaganmohan; Boakye, Cedar H. A.; Godugu, Chandraiah; Patel, Apurva R.; Mendonca Faria, Henrique Antonio; Zucolotto, Valtencir; Singh, Mandip

    2014-01-01

    Aim The objective of this study was to formulate and evaluate a unique matrix mixture (nanomiemgel) of nanomicelle and nanoemulsion containing aceclofenac and capsaicin using in vitro and in vivo analyses and to compare it to a marketed formulation (Aceproxyvon). Methods Nanomicelles were prepared using Vitamin E TPGS by solvent evaporation method and nanoemulsion was prepared by high-pressure homogenization method. In vitro drug release and human skin permeation studies were performed and analyzed using HPLC. The efficiency of nanomiemgel as a delivery system was investigated using an imiquimod-induced psoriatic like plaque model developed in C57BL/6 mice. Results Atomic Force Microscopy images of the samples exhibited a globular morphology with an average diameter of 200, 250 and 220 nm for NMI, NEM and NMG, respectively. Nanomiemgel demonstrated a controlled release drug pattern and induced 2.02 and 1.97-fold more permeation of aceclofenac and capsaicin, respectively than Aceproxyvon through dermatomed human skin. Nanomiemgel also showed 2.94 and 2.09-fold greater Cmax of aceclofenac and capsaicin, respectively than Aceproxyvon in skin microdialysis study in rats. The PASI score, ear thickness and spleen weight of the imiquimod-induced psoriatic-like plaque model were significantly (p<0.05) reduced in NMG treated mice compared to free drug, NEM, NMI & Aceproxyvon. Conclusion Using a new combination of two different drug delivery systems (NEM+NMI), the absorption of the combined system (NMG) was found to be better than either of the individual drug delivery systems due to the utilization of the maximum possible paths of absorption available for that particular drug. PMID:25546392

  19. Comprehensive evaluation of carboxylated nanodiamond as a topical drug delivery system

    PubMed Central

    Lim, Dae Gon; Kim, Ki Hyun; Kang, Eunah; Lim, Sun Hee; Ricci, Jeremy; Sung, Si Kwon; Kwon, Myoung Taek; Jeong, Seong Hoon

    2016-01-01

    The best strategy in the development of topical drug delivery systems may be to facilitate the permeation of drugs without any harmful effects, while staying on the skin surface and maintaining stability of the system. Nanodiamonds (NDs) play a key role with their excellent physicochemical properties, including high biocompatibility, physical adsorption, reactive oxygen species (ROS) scavenging capability, and photostabilizing activity. Z-average sizes of carboxylated ND (ND–COOH) agglutinate decreased significantly as the pH increased. Fluorescein-conjugated ND was observed only on the stratum corneum, and no sample diffused into the dermal layer even after 48 hours. Moreover, ND–COOH and ND–COOH/eugenol complex did not show significant toxic effects on murine macrophage cells. ND improved in vitro skin permeation >50% acting as a “drug reservoir” to maintain a high drug concentration in the donor chamber, which was supported by quartz crystal microbalance results. Moreover, ND–COOH could adsorb a drug amount equivalent to 80% of its own weight. A photostability study showed that ND–COOH increased the photostability ~47% with regard to rate constant of the eugenol itself. A significant decrease in ROS was observed in the ND–COOH and ND–COOH/eugenol complex compared with the negative control during intracellular ROS assay. Moreover, ROS and cupric reducing antioxidant capacity evaluation showed that ND–COOH had synergistic effects of antioxidation with eugenol. Therefore, ND–COOH could be used as an excellent topical drug delivery system with improved permeability, higher stability, and minimized safety issue. PMID:27307736

  20. Formulation and Evaluation of Chondroitin Sulphate Tablets of Aceclofenac for Colon Targeted Drug Delivery

    PubMed Central

    Ramasamy, Thiruganesh; Subbaih Khandasamy, Umadevi; Shanmugam, Suresh; Ruttala, Himabindhu

    2012-01-01

    The aim of the present study was to develop a single unit, site-specific matrix tablets of aceclofenac allowing targeted drug release in the colon with a microbially degradable polymeric carrier, chondroitin suphate (CS) and to coat the optimized batches with a pH dependent polymeric. The tablets were prepared by wet granulation method using starch mucilage as a binding agent and HPMC K-100 as a swellable polymer. Chondroitin Sulphate and drug and physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The tablets were tested for their in-vitro dissolution characteristics in various simulated gastric fluids for their suitability as a colon-specific drug delivery system and also the tablets were evaluated for physicochemical properties, drug content, water percentage swelling and erosion characteristics. The dissolution data demonstrates that the 10% w/w increase in coating level of the pH dependent polymer (Eudragit L-100 and Eudragit S-100 in a ratio of 1 : 4 prevented the drug release in the simulated gastric fluid (pH 1.2-SGF) and the simulated intestinal fluid (pH 7.4-SIF). The dissolution rate of the tablet is dependent upon the concentration of Chondroitin sulphate in the simulated colonic fluid (SCF). The rapid increase in release of aceclofenac in SCF was revealed as due to the degradation of the Chondroitin sulphate membrane by bacterial enzymes. The studies confirmed that, the designed system could be used potentially as a carrier for colon delivery of aceclofenac by regulating drug release in stomach and the small intestine. PMID:24250470

  1. Evaluation of the functionality of biodegradable polymeric platforms for drug delivery systems

    NASA Astrophysics Data System (ADS)

    Gioti, M.; Karagkiozaki, V.; Basgiouraki, A.; Karagiannidis, P. G.; Logothetidis, S.

    2013-09-01

    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.

  2. The Bo-RBC-SCID mouse model for evaluating the efficacy of anti-theilerial drugs.

    PubMed

    Hagiwara, K; Tsuji, M; Ishihara, C; Tajima, M; Kurosawa, T; Iwai, H; Takahashi, K

    1993-02-01

    We have previously developed a mouse model which allowed the proliferation of Theileria sergenti in severe combined immunodeficiency (SCID) mice with circulating bovine erythrocytes (Bo-RBC). In the present study, this model was utilized to test the efficacy of anti-theilerial drugs. Bo-RBC-SCID mice were created by giving periodic transfusions of T. sergenti-free Bo-RBC, and subsequently infecting with T. sergenti. Three anti-protozoal compounds, Pamaquine (Yamanouchi Pharmaceutical Co. Ltd), Ganaseg (Japan CIBA-GEIGY Ltd) and Buparvaquone (Coopers Animal Health Ltd), were subcutaneously administered into the mice at doses recommended for cattle therapy. Blood examinations demonstrated that all three drugs significantly reduced the level of parasitemia although Ganaseg was effective only at a dose five times higher than that recommended for cattle therapy. Administration of the drugs neither caused any sign of acute toxicity nor changed the rate of Bo-RBC in the SCID mice's circulating blood cells. The results indicate that the Bo-RBC-SCID mouse model may offer a useful in vivo system for evaluating the efficacy of anti-protozoal drugs against T. sergenti.

  3. Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds.

    PubMed

    Martin, Baptiste; Brouillet, Fabien; Franceschi, Sophie; Perez, Emile

    2016-08-01

    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.

  4. Evaluation of drug-induced changes in myocardial repolarisation using the paced evoked response.

    PubMed Central

    Donaldson, R M; Rickards, A F

    1982-01-01

    The use of the pace evoked response system in the assessment of drug-induced changes in myocardial repolarisation is reported. Using a conventional pacing electrode lead for both pacing and sensing, this system records the dominantly local repolarisation which follows a controlled (paced) depolarisation from the same site. Measurements of the latency of the ventricular evoked response at matched heart rates before and after drug administration permit the accurate direct comparison of the effects of drugs with class 3 mode of action on cardiac muscle repolarisation. Using this method we have evaluated the effect on the timing of the evoked T wave of two drugs which are known to prolong phase 2 of the action potential. Intravenous amiodarone (5 mg/kg) prolonged the stimulus-peak evoked T wave interval by an average of 39-4 ms (15% of control values); three hours after oral bethanidine (2 mg/kg) this interval increased by an average of 25.8 ms (10% of control values). The effect of therapeutic interventions on the latency of the local paced evoked response provides a simple, accurate assessment of their effect on the cellular action potential duration and constitutes a new tool in electrophysiological investigations. PMID:7126390

  5. Electrochemical evaluation of the interaction between ascorbic acid and the cardiotonic drug RS-82856.

    PubMed

    Visor, G C; Lin, L H; Kenley, R A; Venuti, M C; Alvarez, R

    1987-12-01

    The solution phase interaction between ascorbic acid and the cardiotonic drug N-cyclohexyl-N-methyl-4(7-oxy 1,2,3,5-tetrahydroimidazol[2,1-b] quinazolin-2-one butyramide (RS-82856) was evaluated using a differential pulse voltammetric technique. Shifts in the peak potential of ascorbic acid to higher energy as well as decreases in peak current values were monitored as a function of RS-82856 concentration. The electrochemical data were obtained under conditions where both the drug and the ascorbic acid concentrations exhibited linear relationships with peak current values. The methodology was extended to the study of two other structurally related phosphodiesterase inhibitors cilostamide and anagrelide. The complexation of these drugs with ascorbic acid were also characterized by decreases in the diffusion currents of ascorbic acid as well as by anodic shifts in the peak potential. The significance of these observations may be related to the inhibition of cyclic nucleotide phosphodiesterase activity by both the drugs tested and the ascorbic acid.

  6. Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug.

    PubMed

    Comoglu, Tansel; Unal, Burcu

    2015-01-01

    Orally fast disintegrating tablets (FDTs or ODTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Although the FDT area has passed its infancy, as shown by a large number of commercial products on the market, there are still many aspects to improve in the FDT formulations. Despite advances in the FDT technologies, formulation of hydrophobic drugs is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model hydrophobic drug; meloxicam, without affecting the fast disintegrating properties of the formulation. In order to enhance the solubilization of meloxicam in FDT formulations, β cyclodextrin inclusion complex of the drug is prepared and FDTs containing meloxicam--β cyclodextrin inclusion complex (F1 A and F2 A) were compared and evaluated with the FDTs containing pure meloxicam (F1 and F2) by means of in vitro quality control tests.

  7. Formulation and evaluation of nano based drug delivery system for the buccal delivery of acyclovir.

    PubMed

    Al-Dhubiab, Bandar E; Nair, Anroop B; Kumria, Rachna; Attimarad, Mahesh; Harsha, Sree

    2015-12-01

    Oral bioavailability of acyclovir is limited, primarily because of low permeability across the gastrointestinal membrane. The purpose of this study is the prospective evaluation of buccal films impregnated with acyclovir loaded nanospheres as a drug delivery system to improve systemic bioavailability. Acyclovir polymeric nanospheres were prepared by double emulsion solvent evaporation technique. Nanospheres were embedded into buccoadhesive films (A1-A4) comprising of different concentrations of polymers (Eudragit RL 100, HPMC K15 and carbopol 974P). Films were characterized for physico-mechanical properties, mucoadhesive strength, hydration, drug release and ex vivo permeation. In vivo studies were carried out on rabbits to assess the pharmacokinetic profile of buccal film (A3) as compared to oral therapy. The prepared films demonstrated excellent physical properties, adequate hydration and buccoadhesive strength. In vitro drug release data inferred that the drug release was dependent on the composition of film. Ex vivo permeation studies indicated greater flux in film A3. In vivo studies revealed a significant enhancement in absorption of acyclovir (P<0.0001) with Cmax (~3 folds) and AUC0-α (~8 folds, P<0.0001) when compared to oral dosing. Moreover, the extended Tmax value (6h) signifies the potential of the prepared film to prolong acyclovir delivery. Given the promising results, the study concludes that the developed buccal film (A3) impregnated with acyclovir loaded nanospheres could be a promising approach for effective delivery of acyclovir.

  8. Preparation and evaluation of sustained drug release from pluronic polyol rectal suppositories.

    PubMed

    Anderson, D; Amomo, M M

    2001-01-01

    Suppository dosage forms offer several advantages in drug delivery and can be compounded in a pharmacy setting for the needs of the individual patient. In this study, we have examined the use of Pluronic polyols in the development of sustained-release rectal suppository formulations. Solid and liquid Pluronic poyols (Pluronic L61, F68, L101, and F108) were combined in a weight ratio ranging from 80:20 (solid to liquid) to 70:30 to prepare the bases. The release behavior of a model drug, riboflavin, from the suppositories wee evaluated by means of the United Stated Pharmacopeia Basket Dissolution Method. When compared with the control Polybase suppository, which released 50% of the drug (t50) in about 7.23 minutes, Pluronic F68/L61 suppositories at an 80:20 weight ratio exhibited a t50 of 86.5 minutes (1.44 hours). Riboflavin release from suppositories made with Pluronic F108/L101 was even further delayed. The t50 of riboflavin from Pluronic F108/L101 suppositories at an 80:20 weight ratio, for instance, was 274.4 minutes (4.6 hours). The results of this study show that by choosing specific combinations of Pluronic polyols and weight ratios, compounding pharmacists can prepare sustained-release suppository formulations that can deliver drugs within minutes to hours. This flexibility of compounding sustained-release suppositories is beneficial, especially for the management of chronic pain in cancer patients.

  9. Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

    PubMed Central

    Irvine, Cadi M. J.; Sena, Emily S.; Egan, Kieren J.; Carmichael, Gary G.; Tariq, Afiyah; Pavitt, Sue; Chataway, Jeremy; Macleod, Malcolm R.; Chandran, Siddharthan

    2015-01-01

    Objective To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. Design Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. Results We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. Conclusions We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders. PMID:25856304

  10. Development, Characterization and Evaluation of Solid Lipid Nanoparticles as a potential Anticancer Drug Delivery System

    NASA Astrophysics Data System (ADS)

    Patel, Meghavi

    Solid lipid nanoparticles (SLNs) consist of spherical solid lipid particles in the nanometer size range, which are dispersed in water or in an aqueous surfactant solution. SLN technology represents a promising new approach to deliver hydrophilic as well as lipophilic drugs. The commercialization of SLN technology remains limited despite numerous efforts from researchers. The purpose of this research was to advance SLN preparation methodology by investigating the feasibility of preparing glyceryl monostearate (GMS) nanoparticles by using three preparation methods namely microemulsion technique, magnetic stirring technique and temperature modulated solidification technique of which the latter two were developed in our laboratory. An anticancer drug 5-fluorouracil was incorporated in the SLNs prepared via the temperature modulated solidification process. Optimization of the magnetic stirring process was performed to evaluate how the physicochemical properties of the SLN was influenced by systematically varying process parameters including concentration of the lipid, concentration of the surfactant, type of surfactant, time of stirring and temperature of storage. The results demonstrated 1:2 GMS to tween 80 ratio, 150 ml dispersion medium and 45 min stirring at 4000 RPM speed provided an optimum formulation via the temperature modulated solidification process. SLN dispersions were lyophilized to stabilize the solid lipid nanoparticles and the lyophilizates exhibited good redispersibility. The SLNs were characterized by particle size analysis via dynamic light scattering (DLS), zeta potential, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), drug encapsulation efficiency and in vitro drug release studies. Particle size of SLN dispersion prepared via the three preparation techniques was approximately 66 nm and that of redispersed lyophilizates was below 500 nm. TEM images showed spherical to oval particles that were less dense in the core

  11. Evaluation of the crystalline and amorphous states of drug products by nanothermal analysis and Raman imaging.

    PubMed

    Nakamoto, Keizo; Urasaki, Tetsuhiko; Hondo, Satoko; Murahashi, Naokazu; Yonemochi, Etsuo; Terada, Katuhide

    2013-03-05

    In recent years, amorphous formulations and other special dosage forms of drug products have been investigated to achieve adequate solubility and disintegration. We have evaluated the distribution of crystalline and amorphous states of a drug product using Nanothermal analysis (Nano-TA) and Raman imaging methods. Compared to conventional differential scanning calorimetry, Nano-TA can be used to more rapidly characterize the crystalline and amorphous states of model formulations, including their ingredient distributions, without any sample preparation. In the current study, imaging maps obtained for specific model formulations were evaluated on the basis of their visual appearance and the physicochemical properties of the active pharmaceutical ingredient (API). In addition, the crystalline and amorphous states of the model formulations were distinguished by Raman mapping. Nano-TA was found to be useful for the characterization of crystalline and amorphous states of APIs and the distribution of other ingredients. This technology could be used to monitor the changes in crystalline forms of drug substances and dosage forms during processing. In addition, Nano-TA can be used to characterize amorphous states.

  12. Evaluation of powder mixtures and hydrophilic gastroretentive drug delivery systems containing zinc acetate and sodium bicarbonate.

    PubMed

    Baki, Gabriella; Bajdik, János; Pintye-Hódi, Klára

    2011-03-25

    The aim of this study was to develop and study floating controlled drug delivery systems consisting of a model drug (zinc acetate dihydrate), different forms of a matrix-forming polymer (Metolose 90 SH) and sodium bicarbonate as an effervescent component. The proportions of Metolose and bicarbonate were varied, and the effects of the different ratios on the properties of the resulting powders and tablets were determined. The water uptakes of different powder mixtures were initially evaluated. These tests indicated the interaction of the active and effervescent agent, this phenomenon leading to an unpredicted increase in the amount of liquid taken up. This interaction was evaluated as concerns the degradation of the hydrophilic matrix system. The disintegration of tablets with different compositions revealed that this interaction increases the time required for the disintegration of these systems. The study demonstrated that the interaction of the components induced significant changes in the parameters of this new sensitive delivery system. In the last steps, the buoyancy and dissolution properties of tablets that appeared appropriate for the formulation of a controlled drug delivery system were investigated.

  13. Diabetic silkworms for evaluation of therapeutically effective drugs against type II diabetes

    PubMed Central

    Matsumoto, Yasuhiko; Ishii, Masaki; Hayashi, Yohei; Miyazaki, Shinya; Sugita, Takuya; Sumiya, Eriko; Sekimizu, Kazuhisa

    2015-01-01

    We previously reported that sugar levels in the silkworm hemolymph, i.e., blood, increase immediately (within 1 h) after intake of a high-glucose diet, and that the administration of human insulin decreases elevated hemolymph sugar levels in silkworms. In this hyperglycemic silkworm model, however, administration of pioglitazone or metformin, drugs used clinically for the treatment of type II diabetes, have no effect. Therefore, here we established a silkworm model of type II diabetes for the evaluation of anti-diabetic drugs such as pioglitazone and metformin. Silkworms fed a high-glucose diet over a long time-period (18 h) exhibited a hyperlipidemic phenotype. In these hyperlipidemic silkworms, phosphorylation of JNK, a stress-responsive protein kinase, was enhanced in the fat body, an organ that functionally resembles the mammalian liver and adipose tissue. Fat bodies isolated from hyperlipidemic silkworms exhibited decreased sensitivity to human insulin. The hyperlipidemic silkworms have impaired glucose tolerance, characterized by high fasting hemolymph sugar levels and higher hemolymph sugar levels in a glucose tolerance test. Administration of pioglitazone or metformin improved the glucose tolerance of the hyperlipidemic silkworms. These findings suggest that the hyperlipidemic silkworms are useful for evaluating the hypoglycemic activities of candidate drugs against type II diabetes. PMID:26024298

  14. Diabetic silkworms for evaluation of therapeutically effective drugs against type II diabetes.

    PubMed

    Matsumoto, Yasuhiko; Ishii, Masaki; Hayashi, Yohei; Miyazaki, Shinya; Sugita, Takuya; Sumiya, Eriko; Sekimizu, Kazuhisa

    2015-05-29

    We previously reported that sugar levels in the silkworm hemolymph, i.e., blood, increase immediately (within 1 h) after intake of a high-glucose diet, and that the administration of human insulin decreases elevated hemolymph sugar levels in silkworms. In this hyperglycemic silkworm model, however, administration of pioglitazone or metformin, drugs used clinically for the treatment of type II diabetes, have no effect. Therefore, here we established a silkworm model of type II diabetes for the evaluation of anti-diabetic drugs such as pioglitazone and metformin. Silkworms fed a high-glucose diet over a long time-period (18 h) exhibited a hyperlipidemic phenotype. In these hyperlipidemic silkworms, phosphorylation of JNK, a stress-responsive protein kinase, was enhanced in the fat body, an organ that functionally resembles the mammalian liver and adipose tissue. Fat bodies isolated from hyperlipidemic silkworms exhibited decreased sensitivity to human insulin. The hyperlipidemic silkworms have impaired glucose tolerance, characterized by high fasting hemolymph sugar levels and higher hemolymph sugar levels in a glucose tolerance test. Administration of pioglitazone or metformin improved the glucose tolerance of the hyperlipidemic silkworms. These findings suggest that the hyperlipidemic silkworms are useful for evaluating the hypoglycemic activities of candidate drugs against type II diabetes.

  15. Comparative evaluation of polymersome versus micelle structures as vehicles for the controlled release of drugs

    NASA Astrophysics Data System (ADS)

    Alibolandi, Mona; Ramezani, Mohammad; Abnous, Khalil; Sadeghi, Fatemeh; Hadizadeh, Farzin

    2015-02-01

    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.

  16. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug... classification in lieu of the Academy's classification. (d) For new drugs and antibiotics, supplements to...

  17. 21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug... classification in lieu of the Academy's classification. (d) For new drugs and antibiotics, supplements to...

  18. Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective.

    PubMed

    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.

  19. Synthesis and Biological Evaluation of 2,4-Diaminopyrimidine-Based Antifolate Drugs against Bacillus anthracis

    PubMed Central

    Nammalwar, Baskar; Muddala, N. Prasad; Bourne, Christina R.; Henry, Mary; Bourne, Philip C.; Bunce, Richard A.; Barrow, Esther W.; Berlin, K. Darrell; Barrow, William W.

    2014-01-01

    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. PMID:24642909

  20. Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

    SciTech Connect

    Wang, Kejian; Weng, Zuquan; Sun, Liya; Sun, Jiazhi; Zhou, Shu-Feng; He, Lin

    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.

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... classification in lieu of the Academy's classification. (d) For new drugs and antibiotics, supplements to provide... an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug... the drug to be misbranded. (2) The Academy classification of a drug as other than “effective” for...

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

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... classification in lieu of the Academy's classification. (d) For new drugs and antibiotics, supplements to provide... an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug... the drug to be misbranded. (2) The Academy classification of a drug as other than “effective” for...

  3. Development and in vitro evaluation of a buccal drug delivery system based on preactivated thiolated pectin.

    PubMed

    Hauptstein, Sabine; Hintzen, Fabian; Müller, Christiane; Ohm, Moritz; Bernkop-Schnürch, Andreas

    2014-11-01

    The aim of this study was to evaluate the potential of preactivated thiolated pectin (Pec-Cys-MNA) for buccal drug delivery. Therefore, a gel formulation containing this novel polymer and the model drug lidocaine was prepared and investigated in vitro in terms of rheology, mucoadhesion, swelling behavior and drug release in comparison to formulations based on pectin (Pec) and thiolated pectin (Pec-Cys). Both pectin derivatives showed gel formation without addition of any other excipient due to self-crosslinking thiol groups. Under same conditions, pectin did not show gel formation. Viscosity of Pec-Cys-based formulation increased 92-fold and viscosity of Pec-Cys-MNA-based formulations by 4958-fold compared to pectin-based formulation. Gels did not dissolve in aqueous environment during several hours and were able to take up water. Mucoadhesion of pectin on buccal tissue could be improved significantly, value of total work of adhesion increased in the following rank order: Pec-Cys-MNA > Pec-Cys > Pec. The retention time of a model drug incorporated in gel formulations on buccal mucosa under continuous rinsing with phosphate-buffered saline was prolonged, after 1.5 h 3-fold higher amount of a model drug was to be found on tissue after application of Pec-Cys-MNA-based formulation compared to pectin-based and 2-fold compared to Pec-Cys-based formulation. The Pec-Cys-MNA-based gel showed a more sustained release of lidocaine than Pec-Cys-based gel, whereas pectin solution revealed an immediate release. According to these results, the self-crosslinking pectin-derivative is a promising tool for buccal application.

  4. Evaluation and appraisal of drug information services in a rural secondary level care hospital, Anantapur, AP

    PubMed Central

    Bhavsar, Rohit; Zachariah, Seeba; Thomas, Dixon; Kannan, Shanmugha M.

    2012-01-01

    Background: Drug Information Center (DIC) is an information center which provides drug information (DI) to healthcare professionals. The aim was to evaluate the performance of DIC for improving the quality and quantity of information services provided to the healthcare professionals. The service was provided free of cost to the customers. Materials and Methods: This descriptive study was conducted for the period of 6 months from February to August 2011 excluding May due to vacation. Customers were asked: how did they find the service provided to them? Was it good, satisfactory, or need improvement? There were written feedback forms to be filled by the customers, including customer satisfaction questions. The official publication of the DIC, RIPER PDIC Bulletin was screened for its types of articles/number of drug news published. The bulletin is circulated for free to the healthcare professionals electronically. Results and Discussion: A total of 232 queries were obtained during the study period of 6 months. Average number of queried received to the DIC was 39 per month. Most preferred mode of queries was personal access (89%). Majority of queries were received from nurses, i.e., 162 (70%) queries and 81% of all queries were drug oriented for improving knowledge. There were only 19% of the queries for individual patients; doctors asked most of those queries. Only 3% queries answered were rated as need improvement by the healthcare professionals. Rest were considered as either Good (56%) or satisfactory (49%). Range of drug news published in each bulletin was 3–4 and most of the other articles include expert opinion to improve practice or training. Conclusion: The DI services were satisfactorily used for academic interests. Nurses used the service for the highest compared to other health care professionals. Future studies should plan to establish the usefulness of DI to improve healthcare practice. PMID:23248563

  5. Pharmacoscintigraphic evaluation of potential of lipid nanocarriers for nose-to-brain delivery of antidepressant drug.

    PubMed

    Alam, M Intakhab; Baboota, Sanjula; Ahuja, Alka; Ali, Mushir; Ali, Javed; Sahni, Jasjeet K; Bhatnagar, Aseem

    2014-08-15

    Efficacy of antidepressants relies upon their continued presence at the site of action (brain) over a prolonged period of time. The BBB restricts the access of antidepressants to the brain on oral as well as intravenous administration. Direct delivery (by-passing the BBB) of antidepressant drugs can increase the CSF concentration with concomitant reduction in dose and side effects. Intranasal administration of nanostructured lipid carriers (NLC) containing antidepressant drug circumvent the BBB and maintain the prolonged release at the site of action. The aim of the present study was to evaluate the enhancement in brain uptake of NLC containing duloxetine (DLX) after intranasal administration. Duloxetine loaded NLC (DLX-NLC) was evaluated pharmacoscintigraphically for drug targeting potential (DTP), drug targeting efficiency (DTE) and biodistribution studies in different organs including brain. The radiolabeling efficiency of DLX and DLX-NLC was found to be 98.41 ± 0.96 and 98.87 ± 0.82 after 30 min, respectively. The biodistribution studies exhibited higher percentage of radioactivity/g for DLX-NLC formulations in brain as compared with the DLX. The higher DTP (86.80%) and DTE (757.74%) suggested that DLX-NLC formulation has a better brain targeting efficiency than DLX solution (DTP=65.12%; DTE=287.34%) when administered intranasally. Moreover, the intranasal administration exhibited about 8-times higher concentration of DLX in brain when compared with the intravenous administration of DLX solution. The intranasal NLC containing DLX can be employed as an effective method for the treatment of depression.

  6. Implementing a pharmacovigilance program to evaluate cutaneous adverse drug reactions in an antiretroviral access program

    PubMed Central

    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

  7. Resource Guide to the Evaluation of the Faculty Development Program in Alcohol and Other Drug Abuse. Part I: Overview of the Evaluation Model.

    ERIC Educational Resources Information Center

    Pacific Inst. for Research and Evaluation, Walnut Creek, CA.

    This is an overview of an evaluation model developed to be used with the Faculty Development Program in Alcohol and Other Drug Abuse clinical training program for professional school faculty in medicine, nursing and social work. The evaluation model is in two major parts, a national evaluation which examines program process and outcome across all…

  8. [Evaluation of potential drug interactions in primary health care prescriptions in Vitória da Conquista, Bahia (Brazil)].

    PubMed

    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 < 0,001). Prescriptions from primary care in Vitória da 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.

  9. Malaria (For Parents)

    MedlinePlus

    ... it is passed from person to person (from mother to child in "congenital malaria," or through blood ... risk for malaria. Your doctor can give your family anti-malarial drugs to prevent the disease, which ...

  10. Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy.

    PubMed

    Singh, R G; Rajak, M; Ghosh, B; Agrawal, A; Dubey, G P

    2013-07-01

    Worldwide, diabetic nephropathy is one of the leading causes of end-stage renal failure. This hospital-based single-center prospective open-label randomized case-control interventional study was performed to evaluate and compare the native drug Dioscorea bulbifera with fosinopril in the management of diabetic nephropathy. Patients with diabetic nephropathy with proteinuria >500 mg/day or albuminuria >300 mg/ day, S Cr ≤2.5 mg/dL and hypertension controlled with a single drug were included into the study and were divided into three groups according to the interventional drugs that they were given; group A (n = 46) on fosinopril (5-40 mg/day), group B (n = 45) on Dioscorea bulbifera (500 mg BD) and group C (n = 46) on neither of these drugs. All necessary laboratory investigations needed to assess the effect of both the drugs were carried out. Patients were followed-up for six months. The study included 137 patients (M:F 2.61:1) with an age range of 19-76 years. At the sixth-month follow-up, a significant decrease in the systolic blood pressure was noted in all three groups whereas the diastolic blood pressure decreased significantly only in group B. There was significantly better control of both systolic and diastolic blood pressures in group B than in the other groups. Although fasting blood sugar was poorly controlled in the initial visit in all three groups, there was a significant decrease at the sixth-month follow-up in all three groups. Moreover, the decrease was significantly more pronounced in group B than in the other two groups. Low-density lipoprotein decreased significantly only in group B. Proteinuria, serum transforming growth factor-β, interleukin-6 (IL-6) and C-reactive protein decreased in both group A and group B, more so in the latter, but the differences between the groups were not statistically significant. Importantly, proteinuria and serum IL-6 showed an increasing trend in group C. It can be concluded that Dioscorea bulbifera was more

  11. 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

    PubMed Central

    Long, Amanda J.; Annes, William F.; Witcher, Jennifer W.; Knadler, Mary Pat; Ayan-Oshodi, Mosun A.; Mitchell, Malcolm I.; Leese, Phillip; Hillgren, Kathleen M.

    2017-01-01

    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 Km 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 (IC50 = 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. PMID:27895114

  12. Evaluating drug delivery with salt formation: Drug disproportionation studied in situ by ATR-FTIR imaging and Raman mapping.

    PubMed

    Ewing, Andrew V; Wray, Patrick S; Clarke, Graham S; Kazarian, Sergei G

    2015-01-01

    Two different vibrational spectroscopic approaches, ATR-FTIR spectroscopic imaging and Raman mapping, were used to investigate the components within a tablet containing an ionised drug during dissolution experiments. Delivering certain drugs in their salt form is a method that can be used to improve the bioavailability and dissolution of the poorly aqueous soluble materials. However, these ionised species have a propensity to covert back to their thermodynamically favourable free acid or base forms. Dissolution experiments of the ionised drug in different aqueous media resulted in conversion to the more poorly soluble free acid form, which is detrimental for controlled drug release. This study investigates the chemical changes occurring to formulations containing a development ionised drug (37% by weight), in different aqueous pH environments. Firstly, dissolution in a neutral medium was studied, showing that there was clear release of ionised monosodium form of the drug from the tablet as it swelled in the aqueous medium. There was no presence of any drug in the monohydrate free acid form detected in these experiments. Dissolution in an acidic (0.1M HCl) solution showed disproportionation forming the free acid form. Disproportionation occurred rapidly upon contact with the acidic solution, initially resulting in a shell of the monohydrate free acid form around the tablet edges. This slowed ingress of the solution into the tablet before full conversion of the ionised form to the free acid form was characterised in the spectroscopic data.

  13. Photothermal evaluation of the influence of nicotine, antitumor drugs, and radiation on cellular absorbing structures

    NASA Astrophysics Data System (ADS)

    Zharov, Vladimir P.; Galitovsky, Valentin; Chowdhury, Parimal; Chambers, Timothy

    2004-07-01

    This short review presents findings from a recent evaluation of the diagnostic capabilities of a new experimental design of the advanced photothermal (PT) imaging system; specifically, its performance in studying the impact of nicotine, a combination of antitumor drugs, and radiation on the absorbing structures of various cells. We used this imaging system to test our hypothesis that low doses of chemicals or drugs lead to changes in cell metabolism, that these changes are accompanied by the shrinking of cellular absorbing zones (e.g. organelles), and that these reactions cause increased local absorption. Conversely, high (toxic) doses may lead to swelling of organelles or release of chromophores into the intracellular space, causing decreased local absorption. In this study, we compared PT images and PT responses of the pancreatic exocrine tumor cell line AR42J resulting from exposure to various concentrations of nicotine versus those of control cells. We found that responses were almost proportional to the drug concentration in concentrations ranging from 1 nM-100 μM, reached saturation at a maximum of approximately 100 μM-1 mM, and then fell rapidly at concentrations ranging from 1-50 mM. We also examined the influence of antitumor drugs (vinblastine and paclitaxel) on KB3 carcinoma cells, with drug concentrations ranging from 10-10 nM to 10 nM. In this instance, exposure initially led to slight cell activation, which was then followed by decreased cellular PT response. Drug administration led to corresponding changes in the amplitude and spatial intracellular localization of PT responses, including bubble formation, as an indicator of local absorption level. Additionally, it was shown that, depending on cell type, x-ray radiation may produce effects similar to those resulting from exposure to drugs. Independent verification with a combined PT-fluorescence assay and conventional staining kits (trypan blue, Annexin V-propidium iodide [PI]) revealed that this

  14. Evaluation of the drug solubility and rush ageing on drug release performance of various model drugs from the modified release polyethylene oxide matrix tablets.

    PubMed

    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.

  15. In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions.

    PubMed

    Bani-Jaber, Ahmad; Alshawabkeh, Iyad; Abdullah, Samaa; Hamdan, Imad; Ardakani, Adel; Habash, Maha

    2016-10-17

    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.

  16. Evaluation of contents-based image retrieval methods for a database of logos on drug tablets

    NASA Astrophysics Data System (ADS)

    Geradts, Zeno J.; Hardy, Huub; Poortman, Anneke; Bijhold, Jurrien

    2001-02-01

    In this research an evaluation has been made of the different ways of contents based image retrieval of logos of drug tablets. On a database of 432 illicitly produced tablets (mostly containing MDMA), we have compared different retrieval methods. Two of these methods were available from commercial packages, QBIC and Imatch, where the implementation of the contents based image retrieval methods are not exactly known. We compared the results for this database with the MPEG-7 shape comparison methods, which are the contour-shape, bounding box and region-based shape methods. In addition, we have tested the log polar method that is available from our own research.

  17. Training in Evaluation Skills for Drug Treatment and Drug Prevention Professionals in the Commonwealth Caribbean: How Do Non-Governmental and Statutory Services Compare?

    ERIC Educational Resources Information Center

    Klein, Axel; Day, Marcus

    2006-01-01

    In the countries of the Commonwealth Caribbean there has been a dramatic expansion in drug demand reduction (DDR) programmes over the past decade. Often drawing on models originating in the countries providing the funding in North America or Europe, these activities have often been inadequately monitored and rarely evaluated. The absence of…

  18. Evaluations of imidazolium ionic liquids as novel skin permeation enhancers for drug transdermal delivery.

    PubMed

    Zhang, Ding; Wang, Huai-Ji; Cui, Xiu-Ming; Wang, Cheng-Xiao

    2016-01-13

    In this work, imidazolium ionic liquids (imidazolium ILs) were employed as the novel chemical permeation enhancers (CPEs) and their performances and mechanisms of action were deeply investigated. Testosterone was used as a model drug to investigate the transdermal delivery enhancement of twenty imdidazolium ILs. The results suggested that the promotion activity connected to the structure and composition of the ILs. The quantitative structure-activity relationship (QSAR) model revealed a good linearity between the electronic properties of ILs and their enhancements. Furthermore, the transepidermal water loss (TEWL) and scanning laser confocal microscope (CLSM) examinations showed the strong improvement of ILs on skin barrier permeability, which were well correlated with the drug penetration profiles. The total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscope (AFM) evaluations of skins indicated that the ILs can disrupt the regular and compact arrangements of the corneocytes, change the surface properties of stratum corneum, and make the skin structure more permeable. Our work demonstrated the significant skin permeation promotion profiles of the imidazolium ILs, which are of great potential in transdermal drug delivery systems.

  19. In vivo evaluation of a self-nanoemulsifying drug delivery system for curcumin.

    PubMed

    Nazari-Vanani, R; Moezi, L; Heli, H

    2017-04-01

    Curcumin has attracted particular attention in recent years due to its great variety of beneficial biological and pharmacological activities. However, its efficacy has been limited due to its low bioavailability, and this limitation can be overcome by novel drug delivery systems. Self-nanoemulsifying drug delivery system (SNEDDS) is a novel route to improve oral bioavailability of lipophilic drugs. SNEDDS spontaneously forms fine oil-in-water nanoemulsion by mild agitation. An optimal formula for a SNEDDS comprised ethyl oleate:tween 80:PEG 600 (50:40:10% w/w) with 11.2-nm uniform droplets was developed for curcumin delivery. The SNEDDS was characterized and its loading properties for curcumin were orally evaluated in rat. The results showed a significant increment of 3.95 times in Cmax, and the curcumin bioavailability was enhanced by 194.2%, compared to the curcumin suspension in water. The development of the SNEDDS formulation had a great potential as a possible alternative for curcumin administration.

  20. Taxonomic evaluation of misidentification of crude herbal drugs marketed in Iran

    PubMed Central

    Joharchi, Mohammad Reza; Amiri, Mohammad Sadegh

    2012-01-01

    Objective: Medicinal plants organize an effective source of folk and modern medicine. Correct identification, authentication and quality control are essential to ensure safety, therapeutic potency, efficacy and reproducible quality of herbal medicines. The aim of this study is to use taxonomic method for authentication of traditional herbal drugs which are commonly sold in herbal shops in Iran. In this regard, twenty-seven cases of herbal drugs suspected to be adulterated were investigated. Material and Methods: Crude raw material of herbal drugs was prepared from the various markets in Iran and was identified at the Ferdowsi University of Mashhad Herbarium (FUMH). Results: Taxonomic evaluation revealed that 78 species belonging to 21 families which are traded in Iranian market should be considered as authentic, adulterated and substituted samples. Conclusion: It was concluded that nowadays, many of the medicinal plants available in the market have ambiguous identification along with adulteration and contamination. The present study provides awareness amongst the traders, researchers, clinicians and manufacturing units about the ambiguity of authenticity in the traded herbal raw materials. PMID:25050238

  1. Concurrent evaluation of microscopic observation of drug susceptibility assay for pulmonary and extrapulmonary tuberculosis

    PubMed Central

    Zadbuke, Sonali Sudhir; Set, Reena; Khan, Nishat; Shastri, Jayanthi

    2017-01-01

    BACKGROUND: Methods for detection and drug susceptibility of tuberculosis (TB) with solid media are inexpensive but slow and laborious. Rapid methods to diagnose TB and multidrug-resistant TB (MDR-TB) are a global priority for TB control. OBJECTIVES: A study was performed to compare the sensitivity of detection of mycobacterial growth and time of culture positivity by microscopic observation of drug susceptibility (MODS) assay with that of Lowenstein–Jensen (LJ) culture in pulmonary and extrapulmonary TB and to evaluate the concordance of the susceptibilities to isoniazid (INH) and rifampicin (RIF) by MODS and proportion method on LJ. MATERIALS AND METHODS: A prospective, laboratory-based study was conducted on a total of 300 samples from suspected cases of pulmonary and extrapulmonary TB. Samples were inoculated on LJ medium as per the standard guidelines and MODS assay was performed. RESULTS: Sensitivity of MODS assay was 80% and 83.3% and specificity was 92.9% and 83.3% for pulmonary and extrapulmonary samples, respectively. Difference between mean time to detection of Mycobacterium TB (MTB) by LJ medium and MODS was statistically significant, with MODS being faster. drug susceptibility testing (DST) by MODS when compared to economic variant of proportion method was 87.87% for RIF, 90.9% for INH, and 96.96% for MDR-TB detection. CONCLUSION: MODS assay provides rapid, safe, and sensitive detection of TB faster than the existing gold standard. It is extremely promising in effectively diagnosing MDR-TB. PMID:28367022

  2. A critical evaluation of the relevant parameters for drug redispersion from adhesive mixtures during inhalation.

    PubMed

    de Boer, A H; Dickhoff, B H J; Hagedoorn, P; Gjaltema, D; Goede, J; Lambregts, D; Frijlink, H W

    2005-04-27

    In this paper, the parameters that are relevant to the drug redispersion from adhesive mixtures during inhalation are discussed and evaluated. The results obtained with air classifier technology give strong evidence for a dominating influence of carrier surface properties on the fraction of drug detached during inhalation at a low carrier payload (< or =1%, w/w), versus a dominating effect of carrier bulk properties at higher payloads. Furthermore, the results indicate that there is a fundamental difference between so-called active carrier sites and large surface discontinuities. The difference refers to the saturation concentrations, the rates of saturation and their effects on drug detachment during inhalation. The degree of saturation of the active sites appears to be proportional with the square root of the carrier surface payload (after 10 min mixing time in a Turbula mixer at 90 rpm). The storage volume of the discontinuities seems largely independent of the carrier diameter for particles derived from the same batch of crystalline lactose. Saturation of these discontinuities is completed at a much lower carrier surface payload than saturation of the active sites. Relatively large discontinuities are beneficial to de-agglomeration principles that make use of inertial separation forces during inhalation, as they provide shelter from inertial and frictional press-on forces during mixing which increase the strength of the interparticulate bonds in the powder mixture. For de-agglomeration principles generating frictional, drag or lift forces, carrier surface depressions and projections are disadvantageous however, as they also provide shelter from these removal forces.

  3. Evaluation of two immunoassay procedures for drug testing in hair samples.

    PubMed

    Musshoff, F; Kirschbaum, K M; Graumann, K; Herzfeld, C; Sachs, H; Madea, B

    2012-02-10

    A preliminary initial enzyme-linked immunosorbent assay (LUCIO-Direct ELISA kit) and a preliminary DRI enzyme immunoassay were evaluated for drug detection in head hair with respect to lowered cutoff values recommended in Germany for the control of abstinence in cases of re-granting of drivers' licences. Following drug classes were included: cannabinoids, opiates, cocaine like substances, amphetamine, methamphetamine (and methylenedioxyamphetamines), methadone, and benzodiazepines. 759 analyses were performed using LUCIO-Direct ELISA kits and 936 analyses using DRI enzyme immunoassay tests. Sample size for each drug group and immunoassay test reached from 74 to 178. The LUCIO-Direct ELISA kit revealed a sensitivity of 91% for amphetamine up to 98% for methadone (methamphetamine 92%, cocaine 94%, opiates 94%, benzodiazepines 96%) and values of specificity of 72% for methadone up to 89% for amphetamine and benzodiazepines. The test was not useful for a preliminary screening for tetrahydrocannabinol (sensitivity of 65%) in consideration of a suggested cutoff of 0.02 ng/mg. The DRI enzyme immunoassay test was only useful for morphine and cocaine testing at low recommended new cutoff values (0.1 ng/mg) revealing sensitivities of 94% and 99%, respectively.

  4. Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution.

    PubMed

    Clewe, Oskar; Karlsson, Mats O; Simonsson, Ulrika S H

    2015-12-01

    Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

  5. A noticeable difference? Productivity costs related to paid and unpaid work in economic evaluations on expensive drugs.

    PubMed

    Krol, Marieke; Papenburg, Jocé; Tan, Siok Swan; Brouwer, Werner; Hakkaart, Leona

    2016-05-01

    Productivity costs can strongly impact cost-effectiveness outcomes. This study investigated the impact in the context of expensive hospital drugs. This study aimed to: (1) investigate the effect of productivity costs on cost-effectiveness outcomes, (2) determine whether economic evaluations of expensive drugs commonly include productivity costs related to paid and unpaid work, and (3) explore potential reasons for excluding productivity costs from the economic evaluation. We conducted a systematic literature review to identify economic evaluations of 33 expensive drugs. We analysed whether evaluations included productivity costs and whether inclusion or exclusion was related to the study population's age, health and national health economic guidelines. The impact on cost-effectiveness outcomes was assessed in studies that included productivity costs. Of 249 identified economic evaluations of expensive drugs, 22 (9 %) included productivity costs related to paid work. One study included unpaid productivity. Mostly, productivity cost exclusion could not be explained by the study population's age and health status, but national guidelines appeared influential. Productivity costs proved often highly influential. This study indicates that productivity costs in economic evaluations of expensive hospital drugs are commonly and inconsistently ignored in economic evaluations. This warrants caution in interpreting and comparing the results of these evaluations.

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

    PubMed

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

    2016-03-10

    Malaria remains one of the most common and deadly infectious diseases worldwide. The severity of this global public health challenge is reflected by the approximately 198 million people, who were reportedly infected in 2013 and by the more than 584,000 related deaths in that same year. The rising emergence of drug resistance towards the once effective artemisinin combination therapies (ACTs) has become a serious concern and warrants more robust drug development strategies, with the objective of eradicating malaria infections. The intricate biology and life cycle of Plasmodium parasites complicate the understanding of the disease in such a way that would enhance the development of more effective chemotherapies that would achieve radical clinical cure and that would prevent disease relapse. Phenotypic cell based assays have for long been a valuable approach and involve the screening and analysis of diverse compounds with regards to their activities towards whole Plasmodium parasites in vitro. To achieve the Millennium Development Goal (MDG) of malaria eradication by 2020, new generation drugs that are active against all parasite stages (erythrocytic (blood), exo-erythrocytic (liver stages and gametocytes)) are needed. Significant advances are being made in assay development to overcome some of the practical challenges of assessing drug efficacy, particularly in the liver and transmission stage Plasmodium models. This review discusses primary screening models and the fundamental progress being made in whole cell based efficacy screens of anti-malarial activity. Ongoing challenges and some opportunities for improvements in assay development that would assist in the discovery of effective, safe and affordable drugs for malaria treatments are also discussed.

  7. Exhaled breath for drugs of abuse testing - evaluation in criminal justice settings.

    PubMed

    Beck, Olof

    2014-01-01

    Exhaled breath is being developed as a possible specimen for drug testing based on the collection of aerosol particles originating from the lung fluid. The present study was aimed to evaluate the applicability of exhaled breath for drugs of abuse testing in criminal justice settings. Particles in exhaled breath were collected with a new device in parallel with routine urine testing in two Swedish prisons, comprising both genders. Urine screening was performed according to established routines either by dipstick or by immunochemical methods at the Forensic Chemistry Laboratory and confirmations were with mass spectrometry methods. A total of 247 parallel samples were studied. Analysis of exhaled breath samples was done with a sensitive mass spectrometric method and identifications were made according to forensic standards. In addition tested subjects and personnel were asked to fill in a questionnaire concerning their views about drug testing. In 212 cases both the urine and breath testing were negative, and in 22 cases both urine and breath were positive. Out of 6 cases where breath was negative and urine positive 4 concerned THC. Out of 7 cases where, breath was positive and urine negative 6 concerned amphetamine. Detected substances in breath comprised: amphetamine, methamphetamine, THC, methylphenidate, buprenorphine, 6-acetylmorphine, cocaine, benzoylecgonine, diazepam and tramadol. Both the prison inmates and staff members reported breath testing to be preferable due to practical considerations. The results of this study documented that drug testing using exhaled breath provided as many positives as urine testing despite an expected shorter detection window, and that the breath sampling procedure was well accepted and provided practical benefits reported both by the prison inmates and testing personnel.

  8. Adverse Drug Event Causality Analysis (ADECA): A Process for Evaluating Evidence and Assigning Drugs to Risk Categories for Sudden Death.

    PubMed

    Woosley, Raymond L; Romero, Klaus; Heise, Craig W; Gallo, Tyler; Tate, Jared; Woosley, Raymond David; Ward, Sophie

    2017-03-08

    Growing evidence indicates that many drugs have the ability to cause a potentially lethal cardiac arrhythmia, torsades de pointes (TdP). This necessitates the development of a compilation of drugs that have this potential toxicity. Such a list is helpful in identifying the etiology of TdP in patients taking multiple drugs and assists decision making by those caring for patients at high risk of TdP. The Arizona Center for Education and Research on Therapeutics (AZCERT) has developed a process to standardize the identification of drugs and place them in risk categories for their clinical ability to cause TdP and QT prolongation. AZCERT's Adverse Drug Event Causality Analysis (ADECA) utilizes 16 types of data drawn from four sources to compile an open-source knowledge base, QTdrugs, which is maintained on the CredibleMeds.org website. Because the evidence for most drugs is incomplete, the ADECA process is used to place drugs into one of three categories that represent different levels of certainty: known TdP risk, possible TdP risk, and conditional TdP risk. Each category has strict evidentiary requirements for clinical evidence of TdP and/or QT prolongation. These are described in this paper. Because evidence can evolve over time, the ADECA process includes the continuous gathering and analysis of newly emerging evidence to revise the lists. The QTdrugs lists have proven to be a valued, readily available, commercial influence-free resource for healthcare providers, patients, researchers, and authors of consensus guidelines for the safe use of medicines.

  9. A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity

    PubMed Central

    Bale, Shyam Sundhar; Sridharan, Gautham Vivek; Golberg, Inna; Prodanov, Ljupcho; McCarty, William J.; Usta, Osman Berk; Jindal, Rohit; Yarmush, Martin L.

    2015-01-01

    To evaluate drug and metabolite efficacy on a target organ, it is essential to include metabolic function of hepatocytes, and to evaluate metabolite influence on both hepatocytes and the target of interest. Herein, we have developed a two-chamber microfabricated device separated by a membrane enabling communication between hepatocytes and cancer cells. The microscale environment created enables cell co-culture in a low media-to-cell ratio leading to higher metabolite formation and rapid accumulation, which is lost in traditional plate cultures or other interconnected models due to higher culture volumes. We demonstrate the efficacy of this system by metabolism of tegafur by hepatocytes resulting in cancer cell toxicity. PMID:26925437

  10. Synthesis, cytotoxicity and mechanistic evaluation of 4-oxoquinoline-3-carboxamide derivatives: finding new potential anticancer drugs.

    PubMed

    Forezi, Luana da S M; Tolentino, Nathalia M C; de Souza, Alessandra M T; Castro, Helena C; Montenegro, Raquel C; Dantas, Rafael F; Oliveira, Maria E I M; Silva, Floriano P; Barreto, Leilane H; Burbano, Rommel M R; Abrahim-Vieira, Bárbara; de Oliveira, Riethe; Ferreira, Vitor F; Cunha, Anna C; Boechat, Fernanda da C S; de Souza, Maria Cecília B V

    2014-05-22

    As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.

  11. Drugs in the Workplace: Research and Evaluation Data. Volume II. Research Monograph 100.

    ERIC Educational Resources Information Center

    Gust, Steven W., Ed.; And Others

    This monograph presents 14 articles on the topics of the nature and extent of drug use by the workforce; drug use and job performance indicators; and drug free workplace program research. These articles are included: (1) Research on Drugs and the Workplace: Introduction and Summary (Steven Gust, Dennis Crouch, J. Michael Walsh); (2) Drug Use…

  12. Evaluation of intrathecal drug delivery system for intractable pain in advanced malignancies

    PubMed Central

    Zheng, Shuyue; He, Liangliang; Yang, Xiaohui; Li, Xiuhua; Yang, Zhanmin

    2017-01-01

    Abstract Pain is prevalent in advanced malignancies; however, some patients cannot get adequate pain relief by conservative routes of analgesic administration or experience serious side effects related to high dose of opioids. For those who have exhausted multimodal conservative analgesic, intrathecal drug delivery is an alternative intervention for truly effective pain management. The objective of this study was to evaluate the clinical efficacy and safety of intrathecal drug delivery system (IDDS) for the treatment of intractable pain in advanced cancer patients. A prospective cohort study was performed between July 2015 and October 2016. Fifty-three patients undergoing intractable cancer-related pain or intolerable drug-related adverse effects were recruited and received IDDS therapy with a patient-controlled intrathecal analgesia pump. The assessment was conducted during admission, in titration period, and followed up monthly to death by scheduled refill visits. Pain numeric rating scale scores, comprehensive toxicity scores, quality of life scores, systemic opioid use (basal and breakthrough dose), intrathecal morphine use (basal and patient-controlled intrathecal analgesia dose), and complications were recorded to evaluate the curative effect and safety. Between baseline and all subsequent follow-ups, statistically significant decreases in pain numeric rating scale scores and comprehensive toxicity scores were verified. A statistical improvement in quality of life scores was found after starting IDDS therapy. Both basal and breakthrough doses of systemic opioid showed a significant decrease during the follow-up period. And there was a modest escalation in the intrathecal morphine dose throughout the duration of study. No infective, device-related, and catheter-related complications were observed. The findings showed that IDDS therapy allowed for rapid and highly effective pain relief with less toxicity in comparison to conservative medications. Patients with

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

    PubMed

    Munksgaard, Rasmus; Demant, Jakob; Branwen, Gwern

    2016-09-01

    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 to attribute to anything other than methodological issues. The analysis and conclusions drawn from studies using these methods are promising and insightful. However, based on the replication of Dolliver's study, we suggest that researchers using these methodologies consider and that datasets be made available for other researchers, and that methodology and dataset metrics (e.g. number of downloaded pages, error logs) are described thoroughly in the context of web-o-metrics and web crawling.

  14. Cytotoxicity and biocompatibility evaluation of a poly(magnesium acrylate) hydrogel synthesized for drug delivery.

    PubMed

    Cheddadi, Maha; López-Cabarcos, Enrique; Slowing, Karla; Barcia, Emilia; Fernández-Carballido, Ana

    2011-07-15

    We report the synthesis and characterization as well as cytotoxicity and biocompatibility studies of a poly(magnesium acrylate) hydrogel (PAMgA) developed for drug delivery applications. Two hydrogels with different mesh sizes, large and short, were synthesized (L-C PAMgA and S-C PAMgA). The hydrogels were characterized through swelling, FT-IR and DSC. Cytotoxicity in vitro was evaluated on cell line NIH-3T3 fibroblasts via direct contact and two indirect contact methods (MTT and flow citometry). Both PAMgA hydrogels exhibited low cytotoxicity with survival rates higher than 90%. To select their administration route, biocompatibility was evaluated after intraperitoneal, subcutaneous, and oral administration to mice of both hydrogels at different dose ranges. Swelling percentages obtained were 33.3 ± 4.2% and 166.7 ± 8.3% for L-C PAMgA and S-C PAMgA respectively, showing a great difference in both hydrogels. Among the administration routes assayed, the hydrogels were well tolerated after oral administration of a wide dose range (10-500 mg/kg), thereby indicating that both PAMgA hydrogels are excellent candidates for oral administration due to their in vitro biocompatibility and oral non-toxicity. These results together with the fact that their synthesis is simple and inexpensive make them good candidates for the design of oral drug delivery devices.

  15. [Evaluation of therapeutic effect of new Russian drug semax in optic nerve disease].

    PubMed

    Polunin, G S; Nurieva, S M; Baiandin, D L; Sheremet, N L; Andreeva, L A

    2000-01-01

    Semax is a synthetic analog of adrenocorticotropic hormone 4-10 with a pronounced nootropic effect. It was used in the treatment of vascular, toxic allergic, and inflammatory diseases of the optic nerve and partial atrophy of the optic nerve in parallel with basic neurotrophic and antiinflammatory therapy. For evaluating the drug efficiency, the patients were divided into 3 groups, administered the drug via different routes. In group 1 semax was administered intransally as nasal drops, in group 2 by endonasal electrophoresis, and group 3 was control. Addition of semax to therapeutic complex in patients with diseases of the optic nerve had a favorable impact on the intensity and rate of recovery and improved the visual functions. Semax effectively protected nervous tissue from aftereffects of injury, particularly during the acute stage of optic nerve disease: it stimulated positive changes in the clinical picture, which were evaluated by improvement of visual acuity, extension of the total visual field, increase in the electric sensitivity and conductivity of the optic nerve, and improvement of color vision.

  16. Development and evaluation of a novel product to remove surface contamination of hazardous drugs.

    PubMed

    Cox, Joshua; Speed, Vonni; O'Neal, Sara; Hasselwander, Terry; Sherwood, Candice; Eckel, Stephen F; Zamboni, William C

    2017-03-01

    Background Even while following best practices, surface exposures of hazardous drugs (HDs) are high and numerous. Thus, it is important to develop new products to reduce the surface contamination of HDs. Hazardous Drug Clean (HDClean™) was developed to decontaminate and remove HDs from various types of surfaces and overcome the problems associated with other cleaning products. Methods HDClean was evaluated to remove mock surface exposures of HDs (docetaxel, paclitaxel, ifosfamide, cyclophosphamide, 5-FU, and cisplatin) from various types of surfaces. In two separate cancer centers, studies were performed to evaluate HDClean in reducing surface contamination of HDs in the pharmacy departments where no closed system transfer device (CSTD) was used. In a third cancer center, studies were performed comparing the effectiveness of a CSTD + Surface Safe compared with CSTD + HDClean to remove HDs. Results HDClean was able to completely remove mock exposures of a wide range of HDs from various surfaces (4 and 8 sq ft areas). Daily use of HDClean was equal to or more effective in reducing surface contamination of HDs in two pharmacies compared with a CSTD. HDClean was significantly more effective in removing HDs, especially cisplatin, compared with Surface Safe and does not have the problems associated with decontamination solutions that contain sodium hypochlorite. Conclusion These studies support HDClean as an effective decontaminating product, that HDClean is more effective than Surface Safe in removing HDs and is equal to or more effective than CSTD in controlling HD surface exposures.

  17. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products.

    PubMed

    Raney, Sam G; Franz, Thomas J; Lehman, Paul A; Lionberger, Robert; Chen, Mei-Ling

    2015-11-01

    The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products.

  18. In vitro Models to Evaluate Drug-Induced Hypersensitivity: Potential Test Based on Activation of Dendritic Cells

    PubMed Central

    Galbiati, Valentina; Papale, Angela; Kummer, Elena; Corsini, Emanuela

    2016-01-01

    Hypersensitivity drug reactions (HDRs) are the adverse effect of pharmaceuticals that clinically resemble allergy. HDRs account for approximately 1/6 of drug-induced adverse effects, and include immune-mediated (“allergic”) and non-immune-mediated (“pseudo allergic”) reactions. In recent years, the severe and unpredicted drug adverse events clearly indicate that the immune system can be a critical target of drugs. Enhanced prediction in preclinical safety evaluation is, therefore, crucial. Nowadays, there are no validated in vitro or in vivo methods to screen the sensitizing potential of drugs in the pre-clinical phase. The problem of non-predictability of immunologically-based hypersensitivity reactions is related to the lack of appropriate experimental models rather than to the lack of -understanding of the adverse phenomenon. We recently established experimental conditions and markers to correctly identify drug associated with in vivo hypersensitivity reactions using THP-1 cells and IL-8 production, CD86 and CD54 expression. The proposed in vitro method benefits from a rationalistic approach with the idea that allergenic drugs share with chemical allergens common mechanisms of cell activation. This assay can be easily incorporated into drug development for hazard identification of drugs, which may have the potential to cause in vivo hypersensitivity reactions. The purpose of this review is to assess the state of the art of in vitro models to assess the allergenic potential of drugs based on the activation of dendritic cells. PMID:27462271

  19. Evaluation of various processes for simultaneous complexation and granulation to incorporate drug-cyclodextrin complexes into solid dosage forms.

    PubMed

    Gyanani, Vijay; Siddalingappa, Basavaraj; Betageri, Guru V

    2015-01-01

    Insoluble drugs often formulated with various excipients to enhance the dissolution. Cyclodextrins (CDs) are widely used excipients to improve dissolution profile of poorly soluble drugs. Drug-CD complexation process is complex and often requires multiple processes to produce solid dosage form. Hence, this study explored commonly used granulation processes for simultaneous complexation and granulation. Poorly soluble drugs ibuprofen and glyburide were selected as experimental drugs. Co-evaporation of drug:CD mixture from a solvent followed by wet granulation with water was considered as standard process for comparison. Spray granulation and fluid bed processing (FBP) using drug:CD solution in ethanol were evaluated as an alternative processes. The dissolution data of glyburide tablets indicated that tablets produced by spray granulation, FBP and co-evaporation-granulation have almost identical dissolution profile in water and 0.1% SLS (>70% in water and >60% in SLS versus 30 and 34%, respectively for plain tablet, in 120 min). Similarly, ibuprofen:CD tablets produced by co-evaporation-granulation and FBP displayed similar dissolution profile in 0.01 M HCl (pH 2.0) and buffer pH 5.5 (>90 and 100% versus 44 and 80% respectively for plain tablets, 120 min). Results of this study demonstrated that spray granulation is simple and cost effective process for low dose poorly soluble drugs to incorporate drug:CD complex into solid dosage form, whereas FBP is suitable for poorly soluble drugs with moderate dose.

  20. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    SciTech Connect

    Marks, Louise; Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew; Kirk, Sarah; Valentin, Jean-Pierre

    2012-09-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt{sub max} and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability.

  1. Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

    PubMed

    Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

    2017-01-13

    Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.

  2. The principle of safety evaluation in medicinal drug - how can toxicology contribute to drug discovery and development as a multidisciplinary science?

    PubMed

    Horii, Ikuo

    2016-01-01

    Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as "biological responses to foreign substances." This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of "on-target" or "off-target", and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of "how can multidisciplinary toxicology contribute to innovative drug discovery and development?" And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision

  3. Maximizing Health or Sufficient Capability in Economic Evaluation? A Methodological Experiment of Treatment for Drug Addiction.

    PubMed

    Goranitis, Ilias; Coast, Joanna; Day, Ed; Copello, Alex; Freemantle, Nick; Frew, Emma

    2016-11-17

    Conventional practice within the United Kingdom and beyond is to conduct economic evaluations with "health" as evaluative space and "health maximization" as the decision-making rule. However, there is increasing recognition that this evaluative framework may not always be appropriate, and this is particularly the case within public health and social care contexts. This article presents a methodological case study designed to explore the impact of changing the evaluative space within an economic evaluation from health to capability well-being and the decision-making rule from health maximization to the maximization of sufficient capability. Capability well-being is an evaluative space grounded on Amartya Sen's capability approach and assesses well-being based on individuals' ability to do and be the things they value in life. Sufficient capability is an egalitarian approach to decision making that aims to ensure everyone in society achieves a normatively sufficient level of capability well-being. The case study is treatment for drug addiction, and the cost-effectiveness of 2 psychological interventions relative to usual care is assessed using data from a pilot trial. Analyses are undertaken from a health care and a government perspective. For the purpose of the study, quality-adjusted life years (measured using the EQ-5D-5L) and years of full capability equivalent and years of sufficient capability equivalent (both measured using the ICECAP-A [ICEpop CAPability measure for Adults]) are estimated. The study concludes that different evaluative spaces and decision-making rules have the potential to offer opposing treatment recommendations. The implications for policy makers are discussed.

  4. Evaluations of an in-house drug resistance method for HIV-1 drug resistance using ViroSeq™ 2.0 genotyping system as a gold standard.

    PubMed

    Chaturbhuj, Devidas N; Deshmukh, Pravin S; Hingankar, Nitin K; Siddhaarth, K; Deshpande, Sohan N; Sen, Sourav; Kabra, Sandhya; Paranjape, Ramesh S; Tripathy, Srikanth P

    2013-04-01

    An in-house method was evaluated for its efficiency to detect the HIV-1 drug resistance mutations. This method was compared with the ViroSeq™ Genotyping System 2.0 (Celera Diagnostics, US) a gold standard. Sixty-five stored plasma samples, previously tested for HIV-1 drug resistance using the ViroSeq™ method were used to evaluate the in-house method. Out of the sixty five plasma samples, sixty were HIV-1 positive clinical samples; four samples from the Virology Quality Assessment (VQA) program and one positive control from the ViroSeq™ kit were used in this study. The sequences generated by the ViroSeq™ and an in-house method showed 99.5±0.5% and 99.7±0.4% (mean±SD) nucleotide and amino acid identity, respectively. Out of 214 Stanford HIVdb listed HIV-1 drug resistance mutations in the protease and reverse transcriptase regions, concordance was observed in 203 (94.9%), partial discordance in 11 (5.1%) and complete discordance was absent. The in-house primers are broadly sensitive in genotyping multiple HIV-1 group M subtypes. The amplification sensitivity of the in-house method was 1000 copies/ml. The evaluation of the in-house method provides results comparable with that of ViroSeq™ method thus, making the in-house method suitable for HIV-1 drug resistance testing in the developing countries.

  5. The evaluation of biodegradable four star PEO-PLA copolymer as a drug delivery vector

    NASA Astrophysics Data System (ADS)

    Salaam, Latisha Evette

    Current drug delivery vectors for sustained release include both naturally occurring and artificially synthesized polymers. Several linear copolymer systems have been explored for use as drug delivery systems because they form micelles and microspheres as a result of having hydrophobic and hydrophilic polymer portions. The pharmaceutical agent is released due to degradation of the polymer and/or by swelling of the polymer. This release is dependant upon the material containing the pharmaceutical agent; thus material design is a major parameter in establishing a drug delivery vector. Material design allows tailored physical and chemical characteristics, which are key to establishing release. The overall goal of this research is to obtain and evaluate an unstudied branched Polyethylene glycol based polyether ester as a drug delivery vector through assessing and characterizing the micellar aggregation state, neat material thermal characteristics and morphology, micellar material degradation, effect of degradation on the micelle structure, and computational estimation of molecular aggregate force. This system may present enhanced physical properties for containing and delivering hydrophobic drug molecules due to its covalently linked branches. Three constructs of four star polyethylene oxide polylactide copolymer were examined. The samples differed in molecular weight and chain length of the polylactide subunit and in stereo form. Characterization of micelles revealed that solubility decreased with increasing polylactide chain length and molecular aggregation in aqueous solution and that the critical micelle concentration was lower for the star system than for previously reported systems. Transmission electron microscopy and second virial calculations revealed polydispersity and batch to batch variation. Differential Scanning Calorimetry thermograms show two distinct transition peaks for the neat material samples. Thermogravimetric Analysis sample thermograms exhibited

  6. Evaluation of Serum Adiponectin Concentrations Among Drug Abusers on Methadone Maintenance Treatment

    PubMed Central

    Montazerifar, Farzaneh; Karajibani, Mansour; Lashkaripour, Kobra; Yousefi, Maryam

    2013-01-01

    Background: Adiponectin, an adipocyte-derived protein, modulates a number of metabolic processes. Methadone maintenance treatment (MMT) changes the level of hormones produced by adipose tissue in addicts. However, current data remains contradictory. Objectives: The aim of this study was to evaluate the effect of MMT on serum adiponectin levels in drug addicts. Materials and Methods: Twenty-five drug abusers with a mean age of 37.4 ± 8.7 years were referred to the Baharan Hospital, Zahedan, and 22 healthy age-matched control subjects with a mean age of 35 ± 9.5 years were enrolled in the study. Addicts were treated with methadone at (40 to 120 mg/d) for six months. Measurement of anthropometric parameters, serum adiponectin, and biochemical parameter levels, were assessed in the addicts, before and after six months of MMT, but only once in the healthy controls. Results: The mean basal serum adiponectin level was not significantly lower in the drug abuser group compared to the healthy subjects (P > 0.05). After six months of MMT, the mean serum adiponectin level of the drug addicts was not significantly different from their mean baseline level or that of the healthy subjects (P > 0.05). However, the mean baseline serum adiponectin level was significantly lower in overweight/obese addicts when compared to underweight patients and healthy individuals (P < 0.001). After six months of MMT, the mean level of serum adiponectin increased significantly in the underweight subjects compared to the normal weight and overweight/obese subjects (P < 0.0001) and the control group (P < 0.001). Adiponectin concentration was correlated inversely with body mass index and positively correlated with waist circumference and serum high-density lipoprotein levels. Conclusions: This study showed that MMT did not markedly alter the concentration of serum adiponectin in drug abusers. However, in regard to the variations in the serum lipid profiles and anthropometric parameters, the findings

  7. Ophthalmic drug-loaded N,O-carboxymethyl chitosan hydrogels: synthesis, in vitro and in vivo evaluation

    PubMed Central

    Yang, Li-qun; Lan, Yu-qing; Guo, Hui; Cheng, Liang-zheng; Fan, Ji-zhou; Cai, Xiang; Zhang, Li-ming; Chen, Ru-fu; Zhou, Huai-sheng

    2010-01-01

    Aim: To investigate the ability of drug-loaded N,O-carboxymethyl chitosan (CMCS) hydrogels to modulate wound healing after glaucoma filtration surgery. Methods: The drug-loaded CMCS hydrogels were in situ synthesized using genipin as the crosslinker in the presence of 5-fluorouracil (5FU) or bevacizumab. Their structures were characterized by FTIR, ultraviolet-visible (UV-vis) spectroscopy and scanning electron microscopy (SEM). In-vitro drug release experiments and in vivo evaluation in rabbits were performed. Results: The results of FTIR, UV-vis spectroscopy and SEM analyses indicated that 5FU was encapsulated into the CMCS hydrogels that were crosslinked by genipin. The in vitro drug release experiments showed that nearly 100% of 5FU was released from the drug-loaded hydrogels within 8 h, but less than 20% bevacizumab was released after 53 h. The in vivo evaluation in rabbits indicated that the drug-loaded CMCS hydrogels were nontoxic to the cornea and were gradually biodegraded in the eyes. Furthermore, the drug-loaded CMCS hydrogels effectively inhibited conjunctival scarring after glaucoma filtration surgery and controlled postoperative intraocular pressure (IOP). Conclusion: The drug-loaded CMCS hydrogels provide a great opportunity to increase the therapeutic efficacy of glaucoma filtration surgery. PMID:21042284

  8. Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion

    PubMed Central

    Weersink, Rianne A; Bouma, Margriet; Burger, David M; Drenth, Joost P H; Hunfeld, Nicole G M; Kranenborg, Minke; Monster-Simons, Margje H; van Putten, Sandra A W; Metselaar, Herold J; Taxis, Katja; Borgsteede, Sander D

    2016-01-01

    Introduction Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis. Methods and analysis For each drug, a six-step evaluation process will be followed. (1) Available evidence on the pharmacokinetics and safety of a drug in patients with liver cirrhosis will be collected from the Summary of Product Characteristics (SmPC) and a systematic literature review will be performed. (2) Data regarding two outcomes, namely pharmacokinetics and safety, will be extracted and presented in a standardised assessment report. (3) A safety classification and dosage suggestion will be proposed for each drug. (4) An expert panel will discuss the validity and clinical relevance of this suggested advice. (5) Advices will be implemented in all relevant Clinical Decision Support Systems in the Netherlands and published on a website for patients and healthcare professionals. (6) The continuity of the advices will be guaranteed by a yearly check of new literature and comments on the advices. This protocol will be applied in the evaluation of a selection of drugs: (A) drugs used to treat (complications of) liver cirrhosis, and (B) drugs frequently prescribed to the general population. Ethics and dissemination Since this study does not directly involve human participants, it does not require ethical clearance. Besides implementation on a website and in clinical decision support systems, we aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings. PMID:27733414

  9. The inhibitory effect of Zingiber corallinum Hance essential oil on drug-resistant bacteria and evaluation of its acute toxicity

    PubMed Central

    Yang, Ce; Zhou, Lin-Lin; Wang, Hai-Yan; Huang, Su-Na; Liu, Qing; Hu, Shi-Lin; Li, Ting-Rong; Chen, Yan-Bing; Jiang, Jian-Xin

    2011-01-01

    Summary Background The excessive and irregular use of antibiotics could result in the generation and diffusion of drug-resistant bacteria. The aim of this study was to investigate the inhibitory effect of Zingiber corallinum Hance essential oil (ZCHO) on drug-resistant bacteria, especially on drug-resistant Acinetobacter baumannii. Material/Methods Susceptibility testing was used to evaluate the effect of ZCHO on growth inhibition of drug-resistant bacteria by paper disk method. Mice orally administered with ZCHO were used to observe acute toxicity and to determine median lethal dose (LD50) of ZCHO. Broth dilution method was used to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ZCHO on drug-resistant Acinetobacter baumannii. Results ZCHO exhibited an obvious inhibitory effect not only on gram-negative drug-resistant bacteria including Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Acinetobacter baumannii, but also on gram-positive drug-resistant bacteria including Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus. The ZCHO containing 79% terpinen-4-ol revealed better bacteriostatic effect than ZCHO with 34% terpinen-4-ol. The LD50 of ZCHO was 1790.427 mg/kg. The MIC and MBC of ZCHO on drug-resistant Acinetobacter baumannii were 1457.81 mg/L. Conclusions ZCHO has obvious bacteriostasis and bactericidal effects, especially against drug-resistant Acinetobacter baumannii. Therefore, ZCHO is a promising natural bioactive component with antibacterial effect and satisfactory safety due to its low toxicity. PMID:21525802

  10. Bispectral Index in Evaluating Effects of Sedation Depth on Drug-Induced Sleep Endoscopy

    PubMed Central

    Lo, Yu-Lun; Ni, Yung-Lun; Wang, Tsai-Yu; Lin, Ting-Yu; Li, Hsueh-Yu; White, David P.; Lin, Jr-Rung; Kuo, Han-Pin

    2015-01-01

    Objective: To evaluate the effect of sedation depth on drug-induced sleep endoscopy (DISE). Methods: Ninety patients with obstructive sleep apnea (OSA) and 18 snorers underwent polysomnography and DISE under bispectral index (BIS)-guided propofol infusion at two different sedation levels: BIS 65–75 (light sedation) and 50–60 (deep sedation). Results: For the patients with OSA, the percentages of velopharynx, oropharynx, hypopharynx, and larynx obstructions under light sedation were 77.8%, 63.3%, 30%, and 33.3%, respectively. Sedation depth was associated with the severity of velopharynx and oropharynx obstruction, oropharynx obstruction pattern, tongue base obstruction, epiglottis anteroposterior prolapse and folding, and arytenoid prolapse. In comparison, OSA severity was associated with the severity of velopharynx obstruction, severity of oropharynx obstruction, and arytenoid prolapse (odds ratio (95% confidence interval); 14.3 (4.7–43.4), 11.7 (4.2–32.9), and 13.2 (2.8–62.3), respectively). A good agreement was noted between similar DISE findings at different times and different observers (kappa value 0.6 to 1, respectively). A high percentage of arytenoid prolapse (46.7% among the patients with OSA under light sedation) was noted. Conclusions: Greater sedative depth increased upper airway collapsibility under DISE assessment. DISE under BIS-guided propofol infusion, and especially a level of 65–75, offers an objective and reproducible method to evaluate upper airway collapsibility. Some findings were induced by drug sedation and need careful interpretation. Specific arytenoid prolapse patterns were noted for which further investigations are warranted. Clinical Trials Registration: http://www.clinicaltrials.gov, identifier: NCT01100554 Commentary: A commentary on this article appears in this issue on page 965. Citation: Lo YL, Ni YL, Wang TY, Lin TY, Li HY, White DP, Lin JR, Kuo HP. Bispectral index in evaluating effects of sedation depth on drug

  11. Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers

    PubMed Central

    Wu, Kai; Xu, Jianfeng; Fong, Regan; Yao, Xiaozhou; Xu, Yanmei; Guiney, William; Gray, Frank; Lockhart, Andrew

    2016-01-01

    Abstract. Objective: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). Methods: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 – 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. Results: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. Conclusions: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. PMID:27719741

  12. Evaluation of an Injectable Thermosensitive Hydrogel As Drug Delivery Implant for Ocular Glaucoma Surgery

    PubMed Central

    Zhao, Feng; Zheng, Qiongjuan; Li, Xiaoning; Luo, Jing; Liu, Ji; Quan, Daping; Ge, Jian

    2014-01-01

    In this study, a biodegradable thermo-sensitive hydrogel from poly(trimethylene carbonate)15-F127-poly(trimethylene carbonate)15 (PTMC15-F127-PTMC15) was designed and evaluated as an injectable implant during ocular glaucoma filtration surgery in vivo and in vitro. Mitomycin C (MMC) was loaded into this hydrogel for controlled released to prolong the efficacy and to reduce the long-term toxicity. The properties of the hydrogel were confirmed using 1H NMR and gel permeation chromatography (GPC). Compared to the Pluronic F127 hydrogel, the PTMC15-F127-PTMC15 hydrogel showed a good solution-gel transition temperature at 37°C, a lower work concentration of 5% w/v and a longer mass loss time of more than 2 weeks. The in vitro study showed that the drug could be released from PTMC15-F127-PTMC15 (5% w/v) hydrogel for up to 16 days with only 57% of drug released in the first day. Moreover, the cell toxicity, which was tested via LDH and ANNEXIN V/PI, decreased within 72 h in human tenon's fibroblast cells (HTFs). The in vivo behavior in a rabbit glaucoma filtration surgery model indicated that this hydrogel loaded with 0.1 mg/ml MMC led to a better functional bleb with a prolonged mean bleb survival time (25.5±2.9 days). The scar tissue formation, new collagen deposition and myofibroblast generation appeared to be reduced upon histological and immunohistochemistry examinations, with no obvious side effects and inflammatory reactions. The in vitro and in vivo results demonstrated that this novel hydrogel is a safe and effective drug delivery candidate in ocular glaucoma surgery. PMID:24950176

  13. Development, Optimization, and Evaluation of Carvedilol-Loaded Solid Lipid Nanoparticles for Intranasal Drug Delivery.

    PubMed

    Aboud, Heba M; El Komy, Mohammed H; Ali, Adel A; El Menshawe, Shahira F; Abd Elbary, Ahmed

    2016-12-01

    Carvedilol, a beta-adrenergic blocker, suffers from poor systemic availability (25%) due to first-pass metabolism. The aim of this work was to improve carvedilol bioavailability through developing carvedilol-loaded solid lipid nanoparticles (SLNs) for nasal administration. SLNs were prepared by emulsion/solvent evaporation method. A 2(3) factorial design was employed with lipid type (Compritol or Precirol), surfactant (1 or 2% w/v poloxamer 188), and co-surfactant (0.25 or 0.5% w/v lecithin) concentrations as independent variables, while entrapment efficiency (EE%), particle size, and amount of carvedilol permeated/unit area in 24 h (Q 24) were the dependent variables. Regression analysis was performed to identify the optimum formulation conditions. The in vivo behavior was evaluated in rabbits comparing the bioavailability of carvedilol after intravenous, nasal, and oral administration. The results revealed high drug EE% ranging from 68 to 87.62%. Carvedilol-loaded SLNs showed a spherical shape with an enriched core drug loading pattern having a particle size in the range of 66 to 352 nm. The developed SLNs exhibited significant high amounts of carvedilol permeated through the nasal mucosa as confirmed by confocal laser scanning microscopy. The in vivo pharmacokinetic study revealed that the absolute bioavailability of the optimized intranasal SLNs (50.63%) was significantly higher than oral carvedilol formulation (24.11%). Hence, we conclude that our developed SLNs represent a promising carrier for the nasal delivery of carvedilol.

  14. In Vitro Evaluation of the Effects of Eurycoma longifolia Extract on CYP-Mediated Drug Metabolism.

    PubMed

    Han, Young Min; Kim, In Sook; Rehman, Shaheed Ur; Choe, Kevin; Yoo, Hye Hyun

    2015-01-01

    Eurycoma longifolia (Simaroubaceae) is a popular folk medicine that has traditionally been used in Southeast Asia as an antimalarial, aphrodisiac, antidiabetic, and antimicrobial and in antipyretic remedies. This study evaluates the effects of Eurycoma longifolia extract on cytochrome P450 (CYP) enzyme-mediated drug metabolism to predict the potential for herb-drug interactions. Methanolic extract of E. longifolia root was tested at concentrations of 1, 3, 10, 30, 100, 300, and 1000 µg/mL in human liver microsomes or individual recombinant CYP isozymes. The CYP inhibitory activity was measured using the cocktail probe assay based on liquid chromatography-tandem mass spectrometry. E. longifolia showed weak, concentration-dependent inhibition of CYP1A2, CYP2A6, and CYP2C19. The inhibitory effects on these CYP isozymes were further tested using individual recombinant CYP isozymes, showing IC50 values of 324.9, 797.1, and 562.9 μg/mL, respectively. In conclusion, E. longifolia slightly inhibited the metabolic activities of CYP1A2, CYP2A6, and CYP2C19 but this issue requires careful attention in taking herbal medicines or dietary supplements containing E. longifolia extracts.

  15. In Vitro Evaluation of the Effects of Eurycoma longifolia Extract on CYP-Mediated Drug Metabolism

    PubMed Central

    Han, Young Min; Kim, In Sook; Rehman, Shaheed Ur; Choe, Kevin; Yoo, Hye Hyun

    2015-01-01

    Eurycoma longifolia (Simaroubaceae) is a popular folk medicine that has traditionally been used in Southeast Asia as an antimalarial, aphrodisiac, antidiabetic, and antimicrobial and in antipyretic remedies. This study evaluates the effects of Eurycoma longifolia extract on cytochrome P450 (CYP) enzyme-mediated drug metabolism to predict the potential for herb-drug interactions. Methanolic extract of E. longifolia root was tested at concentrations of 1, 3, 10, 30, 100, 300, and 1000 µg/mL in human liver microsomes or individual recombinant CYP isozymes. The CYP inhibitory activity was measured using the cocktail probe assay based on liquid chromatography-tandem mass spectrometry. E. longifolia showed weak, concentration-dependent inhibition of CYP1A2, CYP2A6, and CYP2C19. The inhibitory effects on these CYP isozymes were further tested using individual recombinant CYP isozymes, showing IC50 values of 324.9, 797.1, and 562.9 μg/mL, respectively. In conclusion, E. longifolia slightly inhibited the metabolic activities of CYP1A2, CYP2A6, and CYP2C19 but this issue requires careful attention in taking herbal medicines or dietary supplements containing E. longifolia extracts. PMID:26240600

  16. Polymeric nanocarriers for magnetic targeted drug delivery: preparation, characterization, and in vitro and in vivo evaluation.

    PubMed

    Licciardi, Mariano; Scialabba, Cinzia; Fiorica, Calogero; Cavallaro, Gennara; Cassata, Giovanni; Giammona, Gaetano

    2013-12-02

    In this paper the preparation of magnetic nanocarriers (MNCs), containing superparamagnetic domains, is reported, useful as potential magnetically targeted drug delivery systems. The preparation of MNCs was performed by using the PHEA-IB-p(BMA) graft copolymer as coating material through the homogenization-solvent evaporation method. Magnetic and nonmagnetic nanocarriers containing flutamide (FLU-MNCs) were prepared. The prepared nanocarriers have been exhaustively characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and magnetic measurements. Biological evaluation was performed by in vitro cytotoxicity and cell uptake tests and in vivo biodistribution studies. Magnetic nanocarriers showed dimensions of about 300 nm with a narrow size distribution, an amount of loaded FLU of 20% (w/w), and a superparamagnetic behavior. Cell culture experiments performed on prostate cancer cell line LNCaP demonstrated the cytotoxic effect of FLU-MNCs. In vivo biodistribution studies carried out by the application of an external magnetic field in rats demonstrated the effect of the external magnet on modifying the biodistribution of FLU-MNCs. FLU-MNCs resulted efficiently internalized by tumor cells and susceptible to magnetic targeting by application of an external magnetic field. The proposed nanocarriers can represent a very promising approach to obtain an efficient magnetically targeted anticancer drug delivery system.

  17. Xenon-133 determination of muscle blood flow: Use in evaluating cardioactive drugs

    SciTech Connect

    Wexler, J.P.; Davis, L.; Mancini, D.; Chadwick, B.; Le Jemtel, T.

    1985-05-01

    Cardioactive drugs may effect both the central and peripheral circulatory systems. The effects on the central and peripheral circulatory systems of chronic Captorpril therapy in 7 pts with severe congestive heart failure (CHF) were evaluated simultaneously. Skeletal muscle blood flow (SMBF) determined using 133-Xe washout and a Cd/Te detector, oxygen consumption (VO/sub 2/), and radial artery and femoral vein O/sub 2/ concentration difference (A-V) were determined at rest and peak upright bicycle exercise before (BT) and after (AT) 6-12 weeks of Captopril therapy. In CI pts there was a significant increase in VO/sub 2/ and SMBF AT vs BT. In contrast, in CNC pts there was no change in VO/sub 2/ and a significant decrease in SMBF AT vs BT. In pts with severe CHF who are CI, there is an apparent fall in peripheral vascular resistance (PVR). In contrast, in CNC pts there is an increase in PVR. This study demonstrates that SMBF determines using 133-Xe is an important method for determining the effects of cardioactive drugs.

  18. Adopting a practical statistical approach for evaluating assay agreement in drug discovery.

    PubMed

    Sun, Dongyu; Whitty, Adrian; Papadatos, James; Newman, Miki; Donnelly, Jason; Bowes, Scott; Josiah, Serene

    2005-08-01

    The authors assess the equivalence of 2 assays and put forward a general approach for assay agreement analysis that can be applied during drug discovery. Data sets generated by different assays are routinely compared to each other during the process of drug discovery. For a given target, the assays used for high-throughput screening and structure-activity relationship studies will most likely differ in their assay reagents, assay conditions, and/or detection technology, which makes the interpretation of data between assays difficult, particularly as most assays are used to measure quantitative changes in compound potency against the target. To better quantify the relationship of data sets from different assays for the same target, the authors evaluated the agreement between results generated by 2 different assays that measure the activity of compounds against the same protein, ALK5. The authors show that the agreement between data sets can be quantified using correlation and Bland-Altman plots, and the precision of the assays can be used to define the expectations of agreement between 2 assays. They propose a scheme for addressing issues of assay data equivalence, which can be applied to address questions of how data sets compare during the lead identification and lead optimization processes in which assays are frequently added and changed.

  19. Quantum Dot-Loaded Liposomes to Evaluate the Behavior of Drug Carriers after Oral Administration.

    PubMed

    Tahara, Kohei; Fujimoto, Shiho; Fujii, Fumihiko; Tozuka, Yuichi; Jin, Takashi; Takeuchi, Hirofumi

    2013-01-01

    We have developed submicron-sized liposomes modified with a mucoadhesive polymer to enhance peptide drug absorption after oral administration. Liposomal behavior in the gastrointestinal tract is a critical factor for effective peptide drug delivery. The purpose of this study was to prepare quantum dot- (QD-) loaded submicron-sized liposomes and examine liposomal behavior in the body after oral administration using in vivo fluorescence imaging. Two types of CdSe/CdZnS QDs with different surface properties were used: hydrophobic (unmodified) QDs and hydrophilic QDs with glutathione (GSH) surface modifications. QD- and GSH-QD-loaded liposomes were prepared by a thin film hydration method. Transmission electron microscopy revealed that QDs were embedded in the liposomal lipid bilayer. Conversely, GSH-QDs were present in the inner aqueous phase. Some of the GSH-QDs were electrostatically associated with the lipid membrane of stearylamine-bearing cationic liposomes. QD-loaded liposomes were detected in Caco-2 cells after exposure to the liposomes, and these liposomes were not toxic to the Caco-2 cells. Furthermore, we evaluated the in vivo bioadhesion and intestinal penetration of orally administered QD-loaded liposomes by observing the intestinal segment using confocal laser scanning microscopy.

  20. Quantum Dot-Loaded Liposomes to Evaluate the Behavior of Drug Carriers after Oral Administration

    PubMed Central

    Tahara, Kohei; Fujimoto, Shiho; Fujii, Fumihiko; Tozuka, Yuichi; Jin, Takashi; Takeuchi, Hirofumi

    2013-01-01

    We have developed submicron-sized liposomes modified with a mucoadhesive polymer to enhance peptide drug absorption after oral administration. Liposomal behavior in the gastrointestinal tract is a critical factor for effective peptide drug delivery. The purpose of this study was to prepare quantum dot- (QD-) loaded submicron-sized liposomes and examine liposomal behavior in the body after oral administration using in vivo fluorescence imaging. Two types of CdSe/CdZnS QDs with different surface properties were used: hydrophobic (unmodified) QDs and hydrophilic QDs with glutathione (GSH) surface modifications. QD- and GSH-QD-loaded liposomes were prepared by a thin film hydration method. Transmission electron microscopy revealed that QDs were embedded in the liposomal lipid bilayer. Conversely, GSH-QDs were present in the inner aqueous phase. Some of the GSH-QDs were electrostatically associated with the lipid membrane of stearylamine-bearing cationic liposomes. QD-loaded liposomes were detected in Caco-2 cells after exposure to the liposomes, and these liposomes were not toxic to the Caco-2 cells. Furthermore, we evaluated the in vivo bioadhesion and intestinal penetration of orally administered QD-loaded liposomes by observing the intestinal segment using confocal laser scanning microscopy. PMID:26555997

  1. Near-infrared spectroscopy technique to evaluate the effects of drugs in treating traumatic brain edema

    NASA Astrophysics Data System (ADS)

    Xie, J.; Qian, Z.; Yang, T.; Li, W.; Hu, G.

    2011-01-01

    The aim of this study was to evaluate the effects of several drugs in treating traumatic brain edema (TBE) following traumatic brain injury (TBI) using near-infrared spectroscopy (NIRs) technology. Rats with TBE models were given hypertonic saline (HS), mannitol and mannitol+HS respectively for different groups. Light scattering properties of rat's local cortex was measured by NIRs within the wavelength range from 700 to 850 nm. TBE models were built in rats' left brains. The scattering properties of the right and left target corresponding to the position of normal and TBE tissue were measured and recorded in vivo and real-time by a bifurcated needle probe. The brain water contents (BWC) were measured by the wet and dry weight method after injury and treatment hours 1, 6, 24, 72 and 120. A marked linear relationship was observed between reduced scattering coefficient (μs') and BWC. By recording μs' of rats' brains, the entire progressions of effects of several drugs were observed. The result may suggest that the NIRs techniques have a potential for assessing effects in vivo and real-time on treatment of the brain injury.

  2. Formulation and evaluation of gastroretentive microballoons containing baclofen for a floating oral controlled drug delivery system.

    PubMed

    Dube, T S; Ranpise, N S; Ranade, A N

    2014-01-01

    The objective of the present study was to fabricate and evaluate a multiparticulate oral gastroretentive dosage form of baclofen characterized by a central large cavity (hollow core) promoting unmitigated floatation with practical applications to alleviate the signs and symptoms of spasticity and muscular rigidity. Solvent diffusion and evaporation procedure were applied to prepare floating microspheres with a central large cavity using various combinations of ethylcellulose (release retardant) and HPMC K4M (release modifier) dissolved in a mixture of dichloromethane and methanol (2:1). The obtained microspheres (700-1000 µm) exhibit excellent floating ability (86 ± 2.00%) and release characteristics with entrapment efficiency of 95.2 ± 0.32%. Microspheres fabricated with ethylcellulose to HPMC K4M in the ratio 8.5:1.5 released 98.67% of the entrapped drug in 12 h. Muscle relaxation caused by baclofen microspheres impairs the rotarod performance for more than 12 h. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate- labeled microspheres was no less than 10 h. The buoyant baclofen microspheres provide a promising gastroretentive drug delivery system to deliver baclofen in spastic patients with a sustained release rate.

  3. Systematic review for evaluation of tolerability of nonsteroidal antiinflammatory drugs in osteoarthritis patients in Japan.

    PubMed

    Uemura, Shinichi; Ochi, Takahiro; Sugano, Kentaro; Makuch, Robert W

    2003-01-01

    To evaluate the gastrointestinal tolerability of nonsteroidal antiinflammatory drugs (NSAIDs) in osteoarthritis patients in Japan, a systematic review of Japanese randomized controlled trials was performed. This study consisted of double-blind, randomized, controlled clinical trials with 4-week NSAID treatment of osteoarthritis patients in Japan. The analysis included 4725 patients from 25 trials. On average the cumulative incidences of patients who had experienced any adverse reaction and any adverse digestive reaction were 14.3% [95% confidence interval (CI) 13.3%-15.3%] and 10.4% (95% CI 9.4%-11.4%), respectively. The cumulative incidence for the upper gastrointestinal (GI) symptoms such as abdominal pain, nausea/vomiting, and dyspepsia was estimated to be approximately 10.9%. When the risk of upper GI symptoms was compared between males and females, the summary odds ratio was 1.71 (95% CI 1.11-2.65). Comparing the risk of upper GI symptoms between patients 59 years of age and younger and those 60+ years old, the summary odds ratio was 1.07 (95% CI 0.75-1.52). Despite the incidence of adverse reactions varying across the drugs being used, there was an obvious increased risk of GI symptoms.

  4. Changing environments and alternative perspectives in evaluating the cost-effectiveness of new antipsychotic drugs.

    PubMed

    Rosenheck, Robert; Doyle, Jefferson; Leslie, Douglas; Fontana, Alan

    2003-01-01

    This article examines the ways in which changes in the treatment environment and in measurement perspectives can affect the evaluation of cost-effectiveness of new medications. In three studies we reexamined data from a clinical trial of haloperidol and clozapine conducted from 1993 to 1996. The results of the studies are as follows: Study 1 found that clozapine treatment was associated with significantly reduced inpatient costs, and increased outpatient costs, suggesting that as systems use less inpatient care and more outpatient care, more effective medications may increase, rather than decrease, costs in sicker patients. Study 2 found that while provider assessments and standard measures favored clozapine over haloperidol, patient responses showed little evidence of a clinical advantage for clozapine and a less favorable side-effect profile. Study 3 found that while annual drug costs in the published trial were estimated to be dollars 4,545 for a full year of clozapine treatment, atypical antipsychotic costs in 2000 were estimated to range from dollars 1,254 to dollars 3,016 in the Department of Veterans Affairs system, and from dollars 2,221 to dollars 8,147 in the private sector. In conclusion, cost-effectiveness, as evaluated in studies like CATIE, will increasingly need to be tied to service system contingencies, environments, and evaluation perspectives.

  5. Towards the development of an in vitro model of atherosclerotic peripheral vessels for evaluating drug-coated endovascular technologies.

    PubMed

    Cunnane, Eoghan M; Walsh, Michael T

    2016-09-01

    Here, we review the in vitro models used to evaluate drug-coated endovascular technologies. The models are assessed in the context of representing the drug transport/uptake and mechanical properties of atherosclerotic peripheral vessels. Studies to date have incorporated a vessel-simulating hydrogel compartment to examine drug elution from endovascular devices. However, comparisons between in vitro models and atherosclerotic tissue are difficult because ex vivo data are limited in their applicability to diseased peripheral vessels. Furthermore, appropriate ex vivo mechanical properties are not incorporated into these models. Therefore, there is a need to characterise the drug transport/uptake properties of appropriate atherosclerotic tissue and incorporate existing ex vivo mechanical data into current in vitro models to more accurately represent drug behaviour in atherosclerotic peripheral vessels.

  6. Batch-to-batch quality consistency evaluation of botanical drug products using multivariate statistical analysis of the chromatographic fingerprint.

    PubMed

    Xiong, Haoshu; Yu, Lawrence X; Qu, Haibin

    2013-06-01

    Botanical drug products have batch-to-batch quality variability due to botanical raw materials and the current manufacturing process. The rational evaluation and control of product quality consistency are essential to ensure the efficacy and safety. Chromatographic fingerprinting is an important and widely used tool to characterize the chemical composition of botanical drug products. Multivariate statistical analysis has showed its efficacy and applicability in the quality evaluation of many kinds of industrial products. In this paper, the combined use of multivariate statistical analysis and chromatographic fingerprinting is presented here to evaluate batch-to-batch quality consistency of botanical drug products. A typical botanical drug product in China, Shenmai injection, was selected as the example to demonstrate the feasibility of this approach. The high-performance liquid chromatographic fingerprint data of historical batches were collected from a traditional Chinese medicine manufacturing factory. Characteristic peaks were weighted by their variability among production batches. A principal component analysis model was established after outliers were modified or removed. Multivariate (Hotelling T(2) and DModX) control charts were finally successfully applied to evaluate the quality consistency. The results suggest useful applications for a combination of multivariate statistical analysis with chromatographic fingerprinting in batch-to-batch quality consistency evaluation for the manufacture of botanical drug products.

  7. In vitro evaluation of S-(+)-ibuprofen as drug candidate for intra-articular drug delivery system.

    PubMed

    Bédouet, Laurent; Pascale, Florentina; Bonneau, Michel; Laurent, Alexandre

    2015-01-01

    Intra-articular drug delivery systems (DDSs) are envisaged as interesting alternative to locally release non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to reduce pain in patients with osteoarthritis. The present study examines the efficacy of S-(+)-ibuprofen on cartilage degradation as drug candidate for DDS loading. Humeral cartilage and joint capsule explants were collected from healthy sheep shoulder joints and they were cultured in mono- or in co-culture for 13 days with LPS in combination with S-(+)-ibuprofen at 50 µM and 1 mM. S-(+)-ibuprofen (50 µM) blocked prostaglandins production in LPS-activated explants but did not reduce cartilage degradation. By contrast, 1 mM S-(+)-ibuprofen treatment of cartilage explants reduced nitric oxide synthesis by 51% (p = 0.0072), proteoglycans degradation by 35% (p = 0.0114) and expression of serum amyloid protein - the main protein induced upon LPS challenge - by 44% (p < 0.0001). On contrary, in presence of synovial membrane, the protective effects of S-(+)-ibuprofen on cartilage damages were significantly diminished. At 1mM, S-(+)-ibuprofen reduced the cell lysis during culture of cartilage and joint capsule either in mono- or in co-culture. This study performed on sheep explants shows that 1 mM S-(+)-ibuprofen inhibited cartilage degradation via a mechanism independent of cyclooxygenase inhibition. Reduction of prostaglandins synthesis at 50 µM in all treatment groups and reduction of cartilage degradation observed at 1 mM suggest that S-(+)-ibuprofen could be considered as a promising drug candidate for the loading of intra-articular DDS.

  8. Mucosa-plate for direct evaluation of mucoadhesion of drug carriers.

    PubMed

    Tachaprutinun, Amornset; Pan-In, Porntip; Wanichwecharungruang, Supason

    2013-01-30

    The method to prepare mucosa-plates, glass slides covalently coated with mucin, is demonstrated. The use of the plate to evaluate mucoadhesion of nanocarriers made from different four polymeric materials, N-succinylchitosan (NS-chitosan), alginate (ALG), ethylcellulose (EC), and a blend of EC and methylcellulose (EC/MC), was demonstrated. While different mucoadhesion of the four carriers could be detected using mucosa-plate, the conventional viscosity measurement could not differentiate their mucin-binding ability. ALG and NS-chitosan nanospheres showed the best attachment to the mucosa-plate compared to the EC/MC and EC spheres. Capsaicin, a model hydrophobic drug, was loaded into the carriers and the ability of the different polymeric carriers to retain capsaicin at the stomach tissue was compared using an ex vivo fresh porcine stomach assay. Ability to retain capsaicin at the stomach tissue correlated well with binding affinity toward the mucosa-plate and the loading capacity of the carriers.

  9. Fractal evaluation of drug amorphicity from optical and scanning electron microscope images

    NASA Astrophysics Data System (ADS)

    Gavriloaia, Bogdan-Mihai G.; Vizireanu, Radu C.; Neamtu, Catalin I.; Gavriloaia, Gheorghe V.

    2013-09-01

    Amorphous materials are metastable, more reactive than the crystalline ones, and have to be evaluated before pharmaceutical compound formulation. Amorphicity is interpreted as a spatial chaos, and patterns of molecular aggregates of dexamethasone, D, were investigated in this paper by using fractal dimension, FD. Images having three magnifications of D were taken from an optical microscope, OM, and with eight magnifications, from a scanning electron microscope, SEM, were analyzed. The average FD for pattern irregularities of OM images was 1.538, and about 1.692 for SEM images. The FDs of the two kinds of images are less sensitive of threshold level. 3D images were shown to illustrate dependence of FD of threshold and magnification level. As a result, optical image of single scale is enough to characterize the drug amorphicity. As a result, the OM image at a single scale is enough to characterize the amorphicity of D.

  10. Evaluating a policing strategy intended to disrupt an illicit street-level drug market.

    PubMed

    Corsaro, Nicholas; Brunson, Rod K; McGarrell, Edmund F

    2010-12-01

    The authors examined a strategic policing initiative that was implemented in a high crime Nashville, Tennessee neighborhood by utilizing a mixed-methodological evaluation approach in order to provide (a) a descriptive process assessment of program fidelity; (b) an interrupted time-series analysis relying upon generalized linear models; (c) in-depth resident interviews. Results revealed that the initiative corresponded with a statistically significant reduction in drug and narcotics incidents as well as perceived changes in neighborhood disorder within the target community. There was less-clear evidence, however, of a significant impact on other outcomes examined. The implications that an intensive crime prevention strategy corresponded with a reduction in specific forms of neighborhood crime illustrates the complex considerations that law enforcement officials face when deciding to implement this type of crime prevention initiative.

  11. Preclinical evaluation of thermoreversible triamcinolone acetonide hydrogels for drug delivery to the inner ear.

    PubMed

    Engleder, Elisabeth; Honeder, Clemens; Klobasa, Julia; Wirth, Michael; Arnoldner, Christoph; Gabor, Franz

    2014-08-25

    Intratympanic glucocorticoid therapy aims to reduce the side effects associated with systemic long-time therapy of inner ear diseases or traumata after cochlear implantation. For that purpose, thermoreversible hydrogels being fluid at room temperature but solid at body temperature are known to be appropriate drug delivery systems. In this work, the two key parameters sol-gel transition time and temperature of Poloxamer 407 (POX 407) based hydrogels containing oto-compatible micronized triamcinolone acetonide (TAAc) were evaluated by rheological experiments varying the concentrations of the different compounds. A 20% POX 407 hydrogel in PBS containing 30% TAAc emerged as the most appropriate formulation. Oscillation-rotation-oscillation studies at two temperature levels were found to be an useful in-vitro test system for the hydrogel which revealed sufficient storage stability at 4 °C, injectability of the sol, solidification within 20s at body temperature and persistent stiffness indicating prolonged adhesion at the round window membrane. According to the in-vitro release studies using the Transwell™ system, absorption of the poor water soluble TAAc is partly due to the low amount of dissolved drug but predominantly due to micellar transport resulting in a cumulative release of 262.6±13.4 μg TAAc within one week followed by a sustained release of 193.1±8.3 μg TAAc within the next three weeks. Thus, the formation of POX 407 micelles is the basis not only for gel formation but also absorptivity of TAAc. All in all, fine tuned rheological experiments and absorption studies emerged as useful tools for preclinical evaluation of intratympanally administered hydrogels.

  12. Intracranial drug-delivery scaffolds: Biocompatibility evaluation of sucrose acetate isobutyrate gels

    SciTech Connect

    Lee, James; Jallo, George I.; Penno, Margaret B.; Gabrielson, Kathleen L.; Young, G. David; Johnson, Randolph M.; Gillis, Edward M.; Rampersaud, Charles; Carson, Benjamin S.; Guarnieri, Michael . E-mail: mguarnie@jhmi.edu

    2006-08-15

    Introduction: Sucrose acetate isobutyrate (SAIB) is a water insoluble, biodegradable gel used for controlled-release oral and subcutaneous drug delivery. We investigated SAIB compatibility in the rat central nervous system (CNS) by implanting solutions of SAIB in adult and in neonatal brains. Methods: 10-15 {mu}L solutions of SAIB gels in 0-30% ethanol were injected into the cerebral cortex of adult Fischer 344 rats. Control animals were implanted with a 10 mg biodegradable poly anhydride copolymer of poly [bis (p-carboxyphenoxy) propane] anhydride and sebacic acid (PCPP:SA). Adult rats were evaluated for signs of pain and distress, including changes in posture, facial signs, and grooming behavior. 1-2 {mu}L solutions of SAIB gels in 15% ethanol were injected into brains of 12-24 h-old rats. Neonatal rats were evaluated for survival. Adult and neonatal brains were examined by histopathology 3-48 days after implant. Results: Gel implants produced elliptical compression of cortical tissue, cell loss, and inflammation. Cell loss appeared to be confined to the implantation wound and associated neuronal fields. In adult rats, neurophil compression, inflammation, and cell loss appeared similar with the 10-mg PCPP:SA implants and the 10-mg SAIB implants. There was no clinical evidence of pain or distress from SAIB implants. 1-2 {mu}L implants of SAIB-15% ethanol had no effect on survival of neonatal animals. Conclusion: Brain implants of SAIB induce a mild to moderate inflammatory response and associated neuronal cell damage. The implants appeared to be biocompatible in adult and neonatal animals. These results suggest that further studies of SAIB as an injectable drug-delivery scaffold for CNS therapeutic agents are warranted.

  13. Transmission Assessment Surveys (TAS) to Define Endpoints for Lymphatic Filariasis Mass Drug Administration: A Multicenter Evaluation

    PubMed Central

    Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo; Bougma, Windtaré R.; Dorkenoo, Améyo M.; El-Setouhy, Maged; Fischer, Peter U.; Gass, Katherine; Gonzalez de Peña, Manuel; Mercado-Hernandez, Leda; Kyelem, Dominique; Lammie, Patrick J.; Flueckiger, Rebecca M.; Mwingira, Upendo J.; Noordin, Rahmah; Offei Owusu, Irene; Ottesen, Eric A.; Pavluck, Alexandre; Pilotte, Nils; Rao, Ramakrishna U.; Samarasekera, Dilhani; Schmaedick, Mark A.; Settinayake, Sunil; Simonsen, Paul E.; Supali, Taniawati; Taleo, Fasihah; Torres, Melissa; Weil, Gary J.; Won, Kimberly Y.

    2013-01-01

    Background Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. Methodology The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6–7 year olds or 1st–2nd graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. Principal Findings/Conclusions In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance

  14. Preclinical evaluation of thermoreversible triamcinolone acetonide hydrogels for drug delivery to the inner ear

    PubMed Central

    Engleder, Elisabeth; Honeder, Clemens; Klobasa, Julia; Wirth, Michael; Arnoldner, Christoph; Gabor, Franz

    2014-01-01

    Intratympanic glucocorticoid therapy aims to reduce the side effects associated with systemic long-time therapy of inner ear diseases or traumata after cochlear implantation. For that purpose, thermoreversible hydrogels being fluid at room temperature but solid at body temperature are known to be appropriate drug delivery systems. In this work, the two key parameters sol–gel transition time and temperature of Poloxamer 407 (POX 407) based hydrogels containing oto-compatible micronized triamcinolone acetonide (TAAc) were evaluated by rheological experiments varying the concentrations of the different compounds. A 20% POX 407 hydrogel in PBS containing 30% TAAc emerged as the most appropriate formulation. Oscillation–rotation–oscillation studies at two temperature levels were found to be an useful in-vitro test system for the hydrogel which revealed sufficient storage stability at 4 °C, injectability of the sol, solidification within 20 s at body temperature and persistent stiffness indicating prolonged adhesion at the round window membrane. According to the in-vitro release studies using the Transwell™ system, absorption of the poor water soluble TAAc is partly due to the low amount of dissolved drug but predominantly due to micellar transport resulting in a cumulative release of 262.6 ± 13.4 μg TAAc within one week followed by a sustained release of 193.1 ± 8.3 μg TAAc within the next three weeks. Thus, the formation of POX 407 micelles is the basis not only for gel formation but also absorptivity of TAAc. All in all, fine tuned rheological experiments and absorption studies emerged as useful tools for preclinical evaluation of intratympanally administered hydrogels. PMID:24907595

  15. [Key Points for Design and Evaluation of Clinical Studies in Treating Children's Attention Deficit Hyperactivity Disorder by Chinese Medical New Drugs].

    PubMed

    Shen, Wen; Ma, Rong; Hu, Si-yuan

    2015-05-01

    Based on collecting data at home and abroad, we combined clinical practice of scientific researches. We also summarized key points for design and evaluation of clinical studies in treating children's attention deficit hyperactivity disorder by Chinese medical new drugs from objective and design, selection of diagnostic criteria, recruitment and dropping-out of subjects, effectiveness evaluation, safety evaluation, drug combination, and quality control, and so on. We hope to provide reference for design and evaluation of clinical studies by Chinese medical new drugs.

  16. Synthesis and evaluation of amphiphilic peptides as nanostructures and drug delivery tools

    NASA Astrophysics Data System (ADS)

    Sayeh, Naser Ali

    us to explore requirements for generating peptides with optimized drug encapsulation and to establish correlations between the structure of peptides with their drug entrapment properties. Thus, the general objective of this dissertation was to design and evaluate additional cyclic or amphiphilic peptides as nanostructures, compare their efficiency in delivery of small molecules with the previously reported cyclic peptides containing tryptophan and arginine residues. This dissertation consists of three chapters. Chapter 1. MANUSCRIPT (published in Current Organic Chemistry 2014). The objective of this work was to design amphiphilic linear and cyclic peptides containing hydrophobic tryptophan W residues that were linked through a triazole ring to positively charged arginine R and lysine (K) residues. The peptides were synthesized through click chemistry between hydrophobic peptides containing alkyne and positively charged peptides containing azide groups. Characterization of their structures like solubility, CD, TEM, cytotoxicity were investigated. The conjugates were showed minimal cytotoxicity at two cell lines. The secondary structures of both peptides were similar to a distorted α-helix as shown by CD spectroscopy. TEM imaging also showed that linear-linear (WG(triazole-KR-NH2))3 and cyclic-linear [WG(triazole-KR-NH2)]3 peptides formed nano-sized structures. Chapter 2. MANUSCRIPT I (Submitted to Journal of Molecular Modeling). In this work, we investigated the structural and dynamical aspects of cyclic-linear peptide ([WG(triazole-KR-NH2)] 3 and linear-linear peptide (WG(triazole-KR-NH2))3) formed nanostructures compared to a drug delivery system with [WR]4. While [WR]4 was found to be an efficient molecular transporter for small molecule drugs, such as lamivudine and dasatinib, cyclic-linear peptide ([WG(triazole-KR-NH2)]3 was inefficient. Molecular modeling was used to explain the differential behavior of these peptides. We showed how the morphology of these

  17. Evaluation of New Drugs for Treatment of Prostate Cancer Patients Using Gene Signatures and the Connectivity Map Database

    DTIC Science & Technology

    2012-06-01

    0.745 arachidonyltrifluoromethane -0.741 Prestwick-1083 -0.741 decamethonium bromide -0.739 praziquantel -0.739 bisoprolol -0.737 5666823 -0.727...amrinone, bacitracin, azapropazone, praziquantel , sulindac sulfide. Task 2. Test the highest scoring drugs from the Connectivity Map analysis in...topiramate, praziquantel , sulindac sulfide) out of 11 evaluated drugs strongly induced apoptosis relative to the solvent DMSO when used at the

  18. Design and evaluation of effervescent floating tablets based on hydroxyethyl cellulose and sodium alginate using pentoxifylline as a model drug

    PubMed Central

    Rahim, Safwan Abdel; Carter, Paul A; Elkordy, Amal Ali

    2015-01-01

    The aim of this work was to design and evaluate effervescent floating gastro-retentive drug delivery matrix tablets with sustained-release behavior using a binary mixture of hydroxyethyl cellulose and sodium alginate. Pentoxifylline was used as a highly water-soluble, short half-life model drug with a high density. The floating capacity, swelling, and drug release behaviors of drug-loaded matrix tablets were evaluated in 0.1 N HCl (pH 1.2) at 37°C±0.5°C. Release data were analyzed by fitting the power law model of Korsmeyer–Peppas. The effect of different formulation variables was investigated, such as wet granulation, sodium bicarbonate gas-forming agent level, and tablet hardness properties. Statistical analysis was applied by paired sample t-test and one-way analysis of variance depending on the type of data to determine significant effect of different parameters. All prepared tablets through wet granulation showed acceptable physicochemical properties and their drug release profiles followed non-Fickian diffusion. They could float on the surface of dissolution medium and sustain drug release over 24 hours. Tablets prepared with 20% w/w sodium bicarbonate at 50–54 N hardness were promising with respect to their floating lag time, floating duration, swelling ability, and sustained drug release profile. PMID:25848220

  19. Evaluation of physicochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit.

    PubMed

    Gikic, M; Di Paolo, E R; Pannatier, A; Cotting, J

    2000-06-01

    Patients in paediatric intensive care units (PICU) often receive numerous medications by the parenteral route. Frequently two or more drugs are delivered simultaneously through the same line and the risk of physicochemical incompatibilities is thus important. The objectives of this study were 1) to identify prospectively the combinations of injectable drugs administered in the PICU of our university hospital and 2) to analyze them according to information found in the literature. The data were collected by a pharmacist over a 30-day period and classified in three categories: compatible, incompatible and undocumented. Nineteen patients were included in the study with a median age of 3.2 years. The mean number (+/- SD) of injectable drugs per patient and per day was 6.5 (+/- 2.8), for a total of 26 drugs and 7 solutes. 64 combinations of drugs were observed with 2 (31.3%), 3 (45.3%), 4 (10.9%) or 5 (12.5%) drugs. 81 drug-drug and 94 drug-solute combinations were recorded. Among these, 151 (86.3%) were compatible, 6 (3.4%) incompatible and 18 (10.3%) undocumented. The incompatibilities included furosemide (Lasix), a drug in alkaline solution and Vamina-Glucose, a total parenteral nutrition solution. No clinical consequences resulting from drug incompatibilities were shown in this study. We suggest that in vitro compatibility tests on standard drug combinations, as well as a training program for nurses on drug incompatibility problems would sensitively increase the security of parenteral drug administration.

  20. Application of RPMI 2650 as a cell model to evaluate solid formulations for intranasal delivery of drugs.

    PubMed

    Gonçalves, Vanessa S S; Matias, Ana A; Poejo, Joana; Serra, Ana T; Duarte, Catarina M M

    2016-12-30

    During the development of intranasal drug delivery systems for local/systemic effect or brain targeting, it is necessary to assess its cytotoxicity and drug transport through nasal epithelium. In order to avoid animal experiments or the use of excised tissues, in vitro cell models, such as RPMI 2650 cells, are being preferred during recent years. Nevertheless, the deposition of solid formulations into nasal cell layers with further transepithelial transport rate of drugs has been poorly studied or reported. Thus, the purpose of this work is to further investigate RPMI 2650 cell line as an effective alternative to animal tissues for solid drug-loaded formulations cytotoxicity and drug permeation studies in order to become an option as a tool for drug discovery. Furthermore, we wanted to determine the extent to which the administration of drugs in particulate forms would differ in relation to the permeability of the same compounds applied as solutions. RPMI 2650 cells were cultured in submersed or at air-liquid interface conditions and characterized regarding transepithelial electrical resistance (TEER) and production of mucus. Pure ketoprofen (used as model compound) and five formulations loaded with same drug, namely solid lipid particles (Gelucire 43/01™), structured lipid particles (Gelucire 43/01™:Glyceryl monooleate) and aerogel microparticles (Alginate, Alginate:Pectin, Alginate:Carrageenan), were evaluated with RPMI 2650 model in terms of cytotoxicity and permeability of drug (applied as solution, dispersion or powder+buffer). RPMI 2650 cells were capable to grow in monolayer and multilayer, showing the same permeability as excised human nasal mucosa for sodium fluorescein (paracellular marker), with analogous TEER values and production of mucus, as referred by other authors. None of the powders showed cytotoxicity when applied to RPMI 2650 cells. Regarding permeation of drug through cell layers, not only the form of application of powders but also their

  1. [Thinking about evaluation of proprietary Chinese medicines containing toxic herbs during switch process of non-prescription drugs].

    PubMed

    Xia, Dongsheng; Cheng, Gang; Li, Xinling; Zhou, Jieming; Xiao, Aili; Zhang, Chengxu; Du, Xiaoxi

    2010-12-01

    To enhance the scientific and fair evaluation about proprietary Chinese medicines containing toxic herbs during the switch process of non-prescription drugs, and to ensure those medicines to be used safely by the public in their self-medication. Combined with current research status of toxic herbs, the experience and knowledge accumulated in the practical work of selection and switch of OTC Chinese medicines for years, thinking about the feasible standards about evaluation and management of proprietary Chinese medicines containing toxic herbs at this stage. Initially established ideas and methods about evaluation of proprietary Chinese medicines containing toxic herbs during the switch process of non-prescription drugs. Basically solved the main problem currently faced by toxic herbs during the OTC switch process of proprietary Chinese medicines, effectively promoted the work on OTC switch, and had the important significance in making consumers use non-prescription drugs conveniently and safely.

  2. [Evaluation of the Association of Hand-Foot Syndrome with Anticancer Drugs Using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) Databases].

    PubMed

    Sasaoka, Sayaka; Matsui, Toshinobu; Abe, Junko; Umetsu, Ryogo; Kato, Yamato; Ueda, Natsumi; Hane, Yuuki; Motooka, Yumi; Hatahira, Haruna; Kinosada, Yasutomi; Nakamura, Mitsuhiro

    2016-01-01

    The Japanese Ministry of Health, Labor, and Welfare lists hand-foot syndrome as a serious adverse drug event. Therefore, we evaluated its association with anticancer drug therapy using case reports in the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). In addition, we calculated the reporting odds ratio (ROR) of anticancer drugs potentially associated with hand-foot syndrome, and applied the Weibull shape parameter to time-to-event data from JADER. We found that JADER contained 338224 reports from April 2004 to November 2014, while FAERS contained 5821354 reports from January 2004 to June 2014. In JADER, the RORs [95% confidence interval (CI)] of hand-foot syndrome for capecitabine, tegafur-gimeracil-oteracil, fluorouracil, sorafenib, and regorafenib were 63.60 (95%CI, 56.19-71.99), 1.30 (95%CI, 0.89-1.89), 0.48 (95%CI, 0.30-0.77), 26.10 (95%CI, 22.86-29.80), and 133.27 (95%CI, 112.85-157.39), respectively. Adverse event symptoms of hand-foot syndrome were observed with most anticancer drugs, which carry warnings of the propensity to cause these effects in their drug information literature. The time-to-event analysis using the Weibull shape parameter revealed differences in the time-dependency of the adverse events of each drug. Therefore, anticancer drugs should be used carefully in clinical practice, and patients may require careful monitoring for symptoms of hand-foot syndrome.

  3. New Antimalarial Hits from Dacryodes edulis (Burseraceae) - Part I: Isolation, In Vitro Activity, In Silico “drug-likeness” and Pharmacokinetic Profiles

    PubMed Central

    Zofou, Denis; Tematio, Esther Laure; Ntie-Kang, Fidele; Tene, Mathieu; Ngemenya, Moses N.; Tane, Pierre; Titanji, Vincent P. K.

    2013-01-01

    The aims of the present study were to identify the compounds responsible for the anti-malarial activity of Dacryoedes edulis (Burseraceae) and to investigate their suitability as leads for the treatment of drug resistant malaria. Five compounds were isolated from ethyl acetate and hexane extracts of D. edulis stem bark and tested against 3D7 (chloroquine-susceptible) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum, using the parasite lactate dehydrogenase method. Cytotoxicity studies were carried out on LLC-MK2 monkey kidney epithelial cell-line. In silico analysis was conducted by calculating molecular descriptors using the MOE software running on a Linux workstation. The “drug-likeness” of the isolated compounds was assessed using Lipinski criteria, from computed molecular properties of the geometry optimized structures. Computed descriptors often used to predict absorption, distribution, metabolism, elimination and toxicity (ADMET) were used to assess the pharmacokinetic profiles of the isolated compounds. Antiplasmodial activity was demonstrated for the first time in five major natural products previously identified in D. edulis, but not tested against malaria parasites. The most active compound identified was termed DES4. It had IC50 values of 0.37 and 0.55 µg/mL, against 3D7 and Dd2 respectively. In addition, this compound was shown to act in synergy with quinine, satisfied all criteria of “Drug-likeness” and showed considerable probability of providing an antimalarial lead. The remaining four compounds also showed antiplasmodial activity, but were less effective than DES4. None of the tested compounds was cytotoxicity against LLC-MK2 cells, suggesting their selective activities on malaria parasites. Based on the high in vitro activity, low toxicity and predicted “Drug-likeness” DES4 merits further investigation as a possible drug lead for the treatment of malaria. PMID:24282507

  4. Evaluation of Lipid-based Drug Delivery System (Phytosolve) on Oral Bioavailability of Dibudipine

    PubMed Central

    Keyhanfar, Fariborz; Khani, Samira; Bohlooli, Shahab

    2014-01-01

    The objective of present study was to evaluate pharmacokinetic parameters of dibudipine Phytosolve after oral administration in rats. The solubility test was carried out to select suitable oily solvent for dibudipine. Phytosolve formulation was prepared with a medium chain triglyceride (MCT) oil (20%), soybean phospholipids (5%) and a 70% fructose solution (75%). The effect of polyol content on the mean globule size of Phytosolve formulation was studied. The optimized formulation was evaluated for robustness toward dilution, transparency, droplet size, zeta potential and transmission electron microscopic analysis. The Phytosolve of dibudipine with an average droplet size of 142.3 ± 4.3 nm and surface charge -18.36 ± 0.37 mv was administered orally to rats. The average relative bioavalabilities of dibudipine in the plasma with Phytosolve were 170.4% and 211.2% as compared to the oily solution and aqueous suspension respectively. So this formulation could be offered as a useful technique to improve the oral delivery of the poorly water soluble drugs such as dibudipine. PMID:25587302

  5. Orally disintegrating tablet of novel salt of antiepileptic drug: formulation strategy and evaluation.

    PubMed

    Rahman, Ziyaur; Siddiqui, Akhtar; Khan, Mansoor A

    2013-11-01

    The aim of present research was to design and evaluate orally disintegrating tablet (ODT) of novel lamotrigine-cyclamate salt. Box-Behnken response surface methodology was selected to design the optimized formulation. The independent factors selected were tablet hardness (X1), disintegrant (X2) and lubricant (X3) levels, and responses chosen were disintegration time (DT, Y1), friability (Y2), T50 (Y3), and T90 (Y4). The tablets were also characterized for drug uniformity by near infrared chemical imaging (NIR-CI) and taste masking evaluation by electronic tongue. All the selected independent variables were statistically (p<0.05) effect the Y1 while Y2, Y3, and Y4 affected only by X2. The optimized ODT was found to meet the regulatory requirement of DT and friability specification. The NIR-CI images indicated uniform distribution of active and inactive ingredients within the tablets. The electronic tongue results were analyzed by principle component analysis (PCA). It indicated that novel salt of lamotrigine and its ODT formulation have a taste similar to cyclamic acid which is indicated by close proximity on PCA score plot, lower Euclidean distance, and high discrimination index values. Furthermore, these parameters were very close to ODT placebo formulation. On the other hand, lamotrigine, its ODT, and placebo formulation were far from each other. In summary, lamotrigine salt provides another avenue for pediatric friendly formulation for children and will enhance patience compliance.

  6. Evaluation of thermal and non-thermal effects of UHF RFID exposure on biological drugs.

    PubMed

    Calcagnini, Giovanni; Censi, Federica; Maffia, Michele; Mainetti, Luca; Mattei, Eugenio; Patrono, Luigi; Urso, Emanuela

    2012-11-01

    The Radio Frequency Identification (RFID) technology promises to improve several processes in the healthcare scenario, especially those related to traceability of people and things. Unfortunately, there are still some barriers limiting the large-scale deployment of these innovative technologies in the healthcare field. Among these, the evaluation of potential thermal and non-thermal effects due to the exposure of biopharmaceutical products to electromagnetic fields is very challenging, but still slightly investigated. This paper aims to setup a controlled RF exposure environment, in order to reproduce a worst-case exposure of pharmaceutical products to the electromagnetic fields generated by the UHF RFID devices placed along the supply chain. Radiated powers several times higher than recommended by current normative limits were applied (10 W and 20 W). The electric field strength at the exposed sample location, used in tests, was as high as 100 V/m. Non-thermal effects were evaluated by chromatography techniques and in vitro assays. The results obtained for a particular case study, the ActrapidTM human insulin preparation, showed temperature increases lower than 0.5 °C and no significant changes in the structure and performance of the considered drug.

  7. Structured evaluation of rodent behavioral tests used in drug discovery research

    PubMed Central

    Hånell, Anders; Marklund, Niklas

    2014-01-01

    A large variety of rodent behavioral tests are currently being used to evaluate traits such as sensory-motor function, social interactions, anxiety-like and depressive-like behavior, substance dependence and various forms of cognitive function. Most behavioral tests have an inherent complexity, and their use requires consideration of several aspects such as the source of motivation in the test, the interaction between experimenter and animal, sources of variability, the sensory modality required by the animal to solve the task as well as costs and required work effort. Of particular importance is a test’s validity because of its influence on the chance of successful translation of preclinical results to clinical settings. High validity may, however, have to be balanced against practical constraints and there are no behavioral tests with optimal characteristics. The design and development of new behavioral tests is therefore an ongoing effort and there are now well over one hundred tests described in the contemporary literature. Some of them are well established following extensive use, while others are novel and still unproven. The task of choosing a behavioral test for a particular project may therefore be daunting and the aim of the present review is to provide a structured way to evaluate rodent behavioral tests aimed at drug discovery research. PMID:25100962

  8. Personalized Cardiovascular Medicine Today: A Food and Drug Administration/Center for Drug Evaluation and Research Perspective.

    PubMed

    Blaus, Alison; Madabushi, Rajanikanth; Pacanowski, Michael; Rose, Martin; Schuck, Robert N; Stockbridge, Norman; Temple, Robert; Unger, Ellis F

    2015-10-13

    Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective.

  9. Predicting drugs and proteins in parasite infections with topological indices of complex networks: theoretical backgrounds, applications, and legal issues.

    PubMed

    González-Díaz, Humberto; Romaris, Fernanda; Duardo-Sanchez, Aliuska; Pérez-Montoto, Lázaro G; Prado-Prado, Francisco; Patlewicz, Grace; Ubeira, Florencio M

    2010-01-01

    Quantitative Structure-Activity Relationship (QSAR) models have been used in Pharmaceutical design and Medicinal Chemistry for the discovery of anti-parasite drugs. QSAR models predict biological activity using as input different types of structural parameters of molecules. Topological Indices (TIs) are a very interesting class of these parameters. We can derive TIs from graph representations based on only nodes (atoms) and edges (chemical bonds). TIs are not time-consuming in terms of computational resources because they depend only on atom-atom connectivity information. This information expressed in the molecular graphs can be tabulated in the form of adjacency matrices easy to manipulate with computers. Consequently, TIs allow the rapid collection, annotation, retrieval, comparison and mining of molecular structures within large databases. The interest in TIs has exploded because we can use them to describe also macromolecular and macroscopic systems represented by complex networks of interactions (links) between the different parts of a system (nodes) such as: drug-target, protein-protein, metabolic, host-parasite, brain cortex, parasite disease spreading, Internet, or social networks. In this work, we review and comment on the following topics related to the use of TIs in anti-parasite drugs and target discovery. The first topic reviewed was: Topological Indices and QSAR for antiparasitic drugs. This topic included: Theoretical Background, QSAR for anti-malaria drugs, QSAR for anti-Toxoplasma drugs. The second topic was: TOMO-COMD approach to QSAR of antiparasitic drugs. We included in this topic: TOMO-COMD theoretical background and TOMO-COMD models for antihelmintic activity, Trichomonas, anti-malarials, anti-trypanosome compounds. The third section was inserted to discuss Topological Indices in the context of Complex Networks. The last section is devoted to the MARCH-INSIDE approach to QSAR of antiparasitic drugs and targets. This begins with a theoretical

  10. Evaluation of anti-inflammatory drug-conjugated silicon quantum dots: their cytotoxicity and biological effect.

    PubMed

    Hanada, Sanshiro; Fujioka, Kouki; Futamura, Yasuhiro; Manabe, Noriyoshi; Hoshino, Akiyoshi; Yamamoto, Kenji

    2013-01-10

    Silicon quantum dots (Si-QDs) have great potential for biomedical applications, including their use as biological fluorescent markers and carriers for drug delivery systems. Biologically inert Si-QDs are less toxic than conventional cadmium-based QDs, and can modify the surface of the Si-QD with covalent bond. We synthesized water-soluble alminoprofen-conjugated Si-QDs (Ap-Si). Alminoprofen is a non-steroid anti-inflammatory drug (NSAID) used as an analgesic for rheumatism. Our results showed that the "silicon drug" is less toxic than the control Si-QD and the original drug. These phenomena indicate that the condensed surface integration of ligand/receptor-type drugs might reduce the adverse interaction between the cells and drug molecules. In addition, the medicinal effect of the Si-QDs (i.e., the inhibition of COX-2 enzyme) was maintained compared to that of the original drug. The same drug effect is related to the integration ratio of original drugs, which might control the binding interaction between COX-2 and the silicon drug. We conclude that drug conjugation with biocompatible Si-QDs is a potential method for functional pharmaceutical drug development.

  11. Social Control Theory: Evaluating a Model for the Study of Adolescent Alcohol and Drug Use.

    ERIC Educational Resources Information Center

    Thompson, Elaine Adams; And Others

    1982-01-01

    Found that social control indicators (attachment to conventional institutions, commitment to conventional goals, involvement in conventional activities, and belief in conventional norms) predicted adolescent alcohol and drug use. However, peer relationships with drug users was the most significant predictor of drug involvement. (Author/MJL)

  12. Evaluating the risk of patient re-identification from adverse drug event reports

    PubMed Central

    2013-01-01

    Background Our objective was to develop a model for measuring re-identification risk that more closely mimics the behaviour of an adversary by accounting for repeated attempts at matching and verification of matches, and apply it to evaluate the risk of re-identification for Canada’s post-marketing adverse drug event database (ADE).Re-identification is only demonstrably plausible for deaths in ADE. A matching experiment between ADE records and virtual obituaries constructed from Statistics Canada vital statistics was simulated. A new re-identification risk is considered, it assumes that after gathering all the potential matches for a patient record (all records in the obituaries that are potential matches for an ADE record), an adversary tries to verify these potential matches. Two adversary scenarios were considered: (a) a mildly motivated adversary who will stop after one verification attempt, and (b) a highly motivated adversary who will attempt to verify all the potential matches and is only limited by practical or financial considerations. Methods The mean percentage of records in ADE that had a high probability of being re-identified was computed. Results Under scenario (a), the risk of re-identification from disclosing the province, age at death, gender, and exact date of the report is quite high, but the removal of province brings down the risk significantly. By only generalizing the date of reporting to month and year and including all other variables, the risk is always low. All ADE records have a high risk of re-identification under scenario (b), but the plausibility of that scenario is limited because of the financial and practical deterrent even for highly motivated adversaries. Conclusions It is possible to disclose Canada’s adverse drug event database while ensuring that plausible re-identification risks are acceptably low. Our new re-identification risk model is suitable for such risk assessments. PMID:24094134

  13. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.

    PubMed

    Dolton, Michael J; Ray, John E; Marriott, Deborah; McLachlan, Andrew J

    2012-06-01

    Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

  14. Evaluating the Capability of Information Technology to Prevent Adverse Drug Events: A Computer Simulation Approach

    PubMed Central

    Anderson, James G.; Jay, Stephen J.; Anderson, Marilyn; Hunt, Thaddeus J.

    2002-01-01

    Background: The annual cost of morbidity and mortality due to medication errors in the U.S. has been estimated at $76.6 billion. Information technology implemented systematically has the potential to significantly reduce medication errors that result in adverse drug events (ADEs). Objective: To develop a computer simulation model that can be used to evaluate the effectiveness of information technology applications designed to detect and prevent medication errors that result in adverse drug effects. Methods: A computer simulation model was constructed representing the medication delivery system in a hospital. STELLA, a continuous simulation software package, was used to construct the model. Parameters of the model were estimated from a study of prescription errors on two hospital medical/surgical units and used in the baseline simulation. Five prevention strategies were simulated based on information obtained from the literature. Results: The model simulates the four stages of the medication delivery system: prescribing, transcribing, dispensing, and administering drugs. We simulated interventions that have been demonstrated in prior studies to decrease error rates. The results suggest that an integrated medication delivery system can save up to 1,226 days of excess hospitalization and $1.4 million in associated costs annually in a large hospital. The results of the analyses regarding the effects of the interventions on the additional hospital costs associated with ADEs are somewhat sensitive to the distribution of errors in the hospital, more sensitive to the costs of an ADE, and most sensitive to the proportion of medication errors resulting in ADEs. Conclusions: The results suggest that clinical information systems are potentially a cost-effective means of preventing ADEs in hospitals and demonstrate the importance of viewing medication errors from a systems perspective. Prevention efforts that focus on a single stage of the process had limited impact on the

  15. Cell-based fluorescence assay for evaluation of new-drugs potential for phospholipidosis in an early stage of drug development.

    PubMed

    Fujimura, Hisako; Dekura, Eriha; Kurabe, Michie; Shimazu, Noriko; Koitabashi, Mieko; Toriumi, Wataru

    2007-08-01

    To evaluate new-drugs potential for phospholipidosis (PL), we developed a cell-based fluorescence assay using a fluorescent-labeled phospholipid analogue (NBD-PE). CHL/IU cells derived from newborn hamster lung were exposed to positive reference compounds (amiodarone, imipramine, chloroquine, propranolol, chlorpromazine and amantadine) in the presence of NBD-PE, and the level of PL, as indicated by accumulation of fluorescent inclusions in the cytoplasm, was evaluated using fluorescence microscopy and fluorometry. All positive reference compounds induced accumulation of fluorescent inclusions in a concentration-dependent manner with an increase in fluorescence intensity. Fluorescence microscopically, the positive dose of test compound was determined as the concentration with a grade equivalent to or above that of 3.13 microM of amiodarone. Based on this criterion, 8 of 20 test compounds including PL-positive or -negative compounds were judged positive that were concurrent with the pathological results from rat toxicity studies. Furthermore, a positive criterion for fluorometry was decided as equivalent to or above 25% of maximum intensity induced by 1.56-25.0 microM amiodarone. In comparison of fluorometry methods with fluorescence microscopy method, 19 of 20 compounds were judged same. From these findings, we concluded that the assay developed in this study is a rapid and reliable method to predict new-drugs potential for PL at an early stage of drug development.

  16. Performance evaluation of on-site oral fluid drug screening devices in normal police procedure in Germany.

    PubMed

    Musshoff, Frank; Hokamp, Eva Große; Bott, Ulrich; Madea, Burkhard

    2014-05-01

    There is a need for quick and reliable methods for rapid screening of drug-influenced drivers on the roadside by police. Because the window of detection in oral fluid is more similar to blood than to urine, this matrix should therefore be appropriate for screening procedures. The performance of the Rapid STAT(®) (Mavand Solution GmbH, Mössingen, Germany), DrugWipe5/5+(®) (Securetec Detektions-Systeme AG, Brunnthal, Germany) and Dräger DrugTest(®) 5000 (Draeger Safety AG & Co. KGaA, Luebeck, Germany) on-site oral fluid devices was evaluated with random oral fluid specimens from car drivers in North Rhine-Westphalia (Germany). Additionally, some drivers were checked using an on-site urine device (DrugScreen(®), NAL von Minden, Regensburg, Germany). During a 11-month period, 1.212 drivers were tested. Both OF and urine on-site tests were compared to serum results. The following sensitivities were obtained by the oral fluid devices: THC 71% (DrugWipe(®)), 87% (Dräger), 91% (RapidSTAT); opiates 95% (Dräger), 100% (DrugWipe(®), RapidSTAT(®)); amphetamine 84% (DrugTest(®) 5000), 90% (RapidSTAT(®)), 100% (DrugTest(®) 5000); methamphetamine 50% (DrugTest(®) 5000), 100% (RapidSTAT(®)); cocaine 76% (DrugTest(®) 5000), 100% (DrugWipe(®), RapidSTAT(®)); methadone 33-63%, and benzodiazepines 0-33% (both with a low number of positives). THC specificity was especially low (29% [DrugWipe(®)] and 47% [DrugTest(®) 5000]) due to low cut-off concentrations. These data were similar to those obtained from the literature (e.g., DRUID project). The urine screening device showed a good sensitivity (THC 93%, opiate 94%, amphetamine 94%, methamphetamine 75% (low number of positives), cocaine 100%) and also an acceptable specificity (39%, 86%, 63%, 77%, 47%, respectively). Although oral fluid may be a useful matrix for on-site testing of drugged drivers, it is evident that oral fluid devices still show a lack of sensitivity (methamphetamine, benzodiazepines) and

  17. Evaluation of knowledge of Health care professionals on warfarin interactions with drug and herb medicinal in Central Saudi Arabia

    PubMed Central

    Al-Arifi, Mohamed N.; Wajid, Syed; Al-Manie, Nawaf K.; Al-Saker, Faisal M.; Babelgaith, Salmeen D.; Asiri, Yousif A.; Sales, Ibrahim

    2016-01-01

    Objectives: To evaluate health care professionals’ knowledge on warfarin interactions with drugs and herbs. Methods: A self-administered questionnaire was developed to assess health care professionals’ knowledge on warfarin interactions with drug and herb. Respondents were asked to classify 15 drugs that may effect on warfarin action as “enhance”, “inhibit “, “no effect”. The study sample involved health care professionals (physicians, pharmacists and nurses) from king Salman hospital, Saudi Arabia. Results: About 92.2% of health care professionals identified warfarin interactions with aspirin, 4.4% for warfarin and fluoxetine. Warfarin and cardiac agents (atenolol) was correctly identified by 11.1% of respondents. In warfarin –herb interactions section, the majority of respondents (66.7%) identified the interaction between green tea and warfarin. Approximately one-third of respondents (n=33) correctly classified warfarin interactions with cardamom. No significant difference was found between the health care professionals (p=0.49) for warfarin-drug interactions knowledge score and p= 0.52 for warfarin- herb interactions knowledge score. Conclusion: This study suggests that health care professionals’ knowledge of warfarin- drug-herb interactions was inadequate. Therefore, health care professionals should receive more education programs about drug-drug/herb interactions to provide appropriate patient counseling and optimal therapeutic outcomes. PMID:27022381

  18. Evaluation by quantitative image analysis of anticancer drug activity on multicellular spheroids grown in 3D matrices

    PubMed Central

    Gomes, Aurélie; Russo, Adrien; Vidal, Guillaume; Demange, Elise; Pannetier, Pauline; Souguir, Zied; Lagarde, Jean-Michel; Ducommun, Bernard; Lobjois, Valérie

    2016-01-01

    Pharmacological evaluation of anticancer drugs using 3D in vitro models provides invaluable information for predicting in vivo activity. Artificial matrices are currently available that scale up and increase the power of such 3D models. The aim of the present study was to propose an efficient and robust imaging and analysis pipeline to assess with quantitative parameters the efficacy of a particular cytotoxic drug. HCT116 colorectal adenocarcinoma tumor cell multispheres were grown in a 3D physiological hyaluronic acid matrix. 3D microscopy was performed with structured illumination, whereas image processing and feature extraction were performed with custom analysis tools. This procedure makes it possible to automatically detect spheres in a large volume of matrix in 96-well plates. It was used to evaluate drug efficacy in HCT116 spheres treated with different concentrations of topotecan, a DNA topoisomerase inhibitor. Following automatic detection and quantification, changes in cluster size distribution with a topotecan concentration-dependent increase of small clusters according to drug cytotoxicity were observed. Quantitative image analysis is thus an effective means to evaluate and quantify the cytotoxic and cytostatic activities of anticancer drugs on 3D multicellular models grown in a physiological matrix. PMID:28105152

  19. Prediction and Early Evaluation of Anticancer Therapy Response: From Imaging of Drug Efflux Pumps to Targeted Therapy Response.

    PubMed

    Meng, Qingqing; Li, Zheng; Li, Shaoshun

    2016-01-01

    Multidrug resistance (MDR) describes the resistance of tumor cells to chemotherapy and has been ascribed to the overexpression of drug efflux pumps. Molecular imaging of drug efflux pumps is helpful to identify the patients who may be resistant to the chemotherapy and thus will avoid the unnecessary treatment and increase the therapeutic effectiveness. Imaging probes targeting drug efflux pumps can non-invasively evaluate the Pgp function and play an important role in identification of MDR, prediction of response, and monitoring MDR modulation. On the other hand, new anticancer agents based on molecular targets such as epidermal growth factor receptor (EGFR) and angiogenic factor receptor may potentially be combined with chemotherapeutic drugs to overcome the MDR. Imaging of molecular targets visualize treatment response of patients at molecular level vividly and help to select right patients for certain targeted anticancer therapy. Among all the imaging modalities, nuclear imaging including positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging has the greatest promise for rapid translation to the clinic and can realize quantitative visualization of biochemical processes in vivo. In this review, we will summarize the nuclear imaging probes utilized for predicting and evaluating the early anticancer therapy response.99mTc labeled agents and PET based radiopharmaceuticals like 18F-Paclitaxel, 11C-Verapamil for drug efflux pumps imaging will be discussed here. Moreover, molecular imaging probes used for targeted therapy response evaluation like 18F-Tamoxifen,89Zr-Trastuzumab will also be introduced in this review.

  20. Data-mining for sulfur and fluorine: an evaluation of pharmaceuticals to reveal opportunities for drug design and discovery.

    PubMed

    Ilardi, Elizabeth A; Vitaku, Edon; Njardarson, Jon T

    2014-04-10

    Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends associated with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronologically and classified according to an association with a particular clinical indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qualitative conclusions in this article aim to promote innovative insights into drug development.

  1. Formulation and Evaluation of Galantamine Gel as Drug Reservoir in Transdermal Patch Delivery System

    PubMed Central

    Fong Yen, Woo; Basri, Mahiran; Ahmad, Mansor; Ismail, Maznah

    2015-01-01

    Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer's disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system. PMID:25853145

  2. Gene regulatory network inference: evaluation and application to ovarian cancer allows the prioritization of drug targets

    PubMed Central

    2012-01-01

    of proteins encoded by the 10 highest-confidence target genes, and by 15 genes with differential regulation in normal and cancer conditions, reveals 75% to be potential drug targets. Conclusions Our study represents a concrete application of gene regulatory network inference to ovarian cancer, demonstrating the complete cycle of computational systems biology research, from genome-scale data analysis via network inference, evaluation of methods, to the generation of novel testable hypotheses, their prioritization for experimental validation, and discovery of potential drug targets. PMID:22548828

  3. Evaluation of new anti-infective drugs for the treatment of infectious arthritis in adults. Infectious Diseases Society of America and the Food and Drug Administration.

    PubMed

    Norden, C; Nelson, J D; Mader, J T; Calandra, G B

    1992-11-01

    This guideline describes clinical trials of new anti-infective drugs for the treatment of septic arthritis due to bacteria other than Neisseria gonorrhoeae in adults. Septic arthritis is associated with fever and with physical findings at the affected joint. Diagnosis is established by culture of synovial fluid. Treatment includes the administration of antimicrobial drugs and drainage of the joint by needle aspiration or surgery. Multicenter, randomized comparative clinical trials that are single-, double-, or evaluator-blinded should be performed. However, an open trial of a new antimicrobial agent with historical controls is acceptable. Patients should receive treatment for at least 2-3 weeks. After 5 days of antimicrobial therapy, synovial fluid should be sterile and clinical signs and symptoms should have diminished. Patients should be followed for 2-4 weeks after completion of therapy.

  4. 78 FR 5817 - Detecting and Evaluating Drug-Induced Liver Injury; What's Normal, What's Not, and What Should We...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-28

    ... Normal, What's Not, and What Should We Do About It?; Public Conference; Request for Comments AGENCY: Food... Evaluating Drug-Induced Liver Injury; What's Normal, What's Not, and What Should We Do About It?'' This... prevented the approval of others. It ] discusses methods of detecting DILI by periodic tests of serum...

  5. An Initial Evaluation of the North Carolina Alcohol and Drug Education Traffic Schools. Volume I: Technical Report.

    ERIC Educational Resources Information Center

    Popkin, Carol L.; And Others

    This report contains the results of an evaluation of the North Carolina Alcohol Drug Education Traffic Schools (ADETS), established for the primary purpose of treating first offenders convicted of driving under the influence (DUI), and careless and reckless driving after drinking. Following the executive summary and introduction, the second…

  6. 78 FR 17744 - Social Security Ruling, SSR 13-2p; Titles II and XVI: Evaluating Cases Involving Drug Addiction...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-22

    ... From the Federal Register Online via the Government Publishing Office SOCIAL SECURITY ADMINISTRATION Social Security Ruling, SSR 13-2p; Titles II and XVI: Evaluating Cases Involving Drug Addiction and Alcoholism (DAA); Correction AGENCY: Social Security Administration. ACTION: Notice of...

  7. Reducing Alcohol and Other Drug-Related Harm in Young People: Evaluation of a Youth Engagement Program

    ERIC Educational Resources Information Center

    McKenzie, Stephen; Droste, Nic; Hickford, Salli; Miller, Peter

    2011-01-01

    Deakin University's RuralLife alcohol and other drug (AOD) research initiative was commissioned by St John of God Hospital and Barwon Youth to evaluate their Youth Engagement Program (YEP), which is an AOD harm-reduction program intended to engage young people with AOD problems in a region that has a higher-than-state-average proportion of young…

  8. A New Method for Evaluating Actual Drug Release Kinetics of Nanoparticles inside Dialysis Devices via Numerical Deconvolution.

    PubMed

    Zhou, Yousheng; He, Chunsheng; Chen, Kuan; Ni, Jieren; Cai, Yu; Guo, Xiaodi; Wu, Xiao Yu

    2016-12-10

    Nanoparticle formulations have found increasing applications in modern therapies. To achieve desired treatment efficacy and safety profiles, drug release kinetics of nanoparticles must be controlled tightly. However, actual drug release kinetics of nanoparticles cannot be readily measured due to technique difficulties, although various methods have been attempted. Among existing experimental approaches, dialysis method is the most widely applied one due to its simplicity and avoidance of separating released drug from the nanoparticles. Yet this method only measures the released drug in the medium outside a dialysis device (the receiver), instead of actual drug release from the nanoparticles inside the dialysis device (the donor). Thus we proposed a new method using numerical deconvolution to evaluate actual drug release kinetics of nanoparticles inside the donor based on experimental release profiles of nanoparticles and free drug solution in the receptor determined by existing dialysis tests. Two computer programs were developed based on two different numerical methods, namely least square criteria with prescribed Weibull function or orthogonal polynomials as input function. The former was used for all analyses in this work while the latter for verifying the reliability of the predictions. Experimental data of drug release from various nanoparticle formulations obtained from different dialysis settings and membrane pore sizes were used to substantiate this approach. The results demonstrated that this method is applicable to a broad range of nanoparticle and microparticle formulations requiring no additional experiments. It is independent of particle formulations, drug release mechanisms, and testing conditions. This new method may also be used, in combination with existing dialysis devices, to develop a standardized method for quality control, in vitro-in vivo correlation, and for development of nanoparticles and other types of dispersion formulations.

  9. Comparative evaluation of the cytotoxic and apoptotic potential of Poecilocerus pictus and Calotropis gigantea.

    PubMed

    Mathen, Caroline; Peter, Shiney Mary; Hardikar, Bhagyashree P

    2011-01-01

    Calotropis gigantea, the giant milkweed, is traditionally used for the treatment of cancer and in Ayurvedic medicine as an anti-helminthic, anti-pyretic, and anti-malarial agent. Poecilocerus pictus, an orthopteran insect, feeds on C. gigantea and both are known to possess cardiac glycosides. The increasing reports on the specific cytotoxicity of cardiac glycosides on human tumor cell lines led us to attempt characterization and comparative evaluation of cardenolides in both the insect and plant extracts for their anti-tumor and apoptotic potential.Chemical characterization using high-performance thin layer chromatography, ultraviolet and infrared spectra analysis confirmed the presence of cardiac glycosides, but differences in the components of the insect extract were indicative of biotransformation. The cytotoxicity studies revealed a more potent trend for the insect extract compared with the plant extract on A549 and COLO205 cells. There was a considerably lesser measure of toxicity on WI38 cells and peripheral blood lymphocytes, whereas B16F1 remained unaffected by both extracts. DNA ploidy analysis on COLO205 indicated that both extracts induced dose-dependent apoptosis. Therefore, both the insect and the plant extracts differentiate between human cancer cells and normal cells and exhibit species specificity. Further investigations are necessary to establish these extracts as promising lead candidates for anti-neoplastic activity.

  10. Evaluation of symptomatic slow-acting drugs in osteoarthritis using the GRADE system

    PubMed Central

    Bruyère, Olivier; Burlet, Nansa; Delmas, Pierre D; Rizzoli, René; Cooper, Cyrus; Reginster, Jean-Yves

    2008-01-01

    Background Symptomatic slow-acting drugs (SYSADOA) have been largely studied over the last decade. The objective of this study is to prepare a document providing recommendations for the use of SYSADOA in osteoarthritis (OA). Methods The following interventions were taken into consideration: avocado/soybean unsaponifiables, chondroitin sulfate, diacereine, glucosamine sulfate, hyaluronic acid, oral calcitonin, risedronate, strontium ranelate. Recommendations were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus downsides and subsequent judgment about the strength of recommendations. Results Chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid have demonstrated pain reduction and physical function improvement with very low toxicity, with moderate to high quality evidence. Even if pre-clinical data and some preliminary in vivo studies have suggested that oral calcitonin and strontium ranelate could be of potential interest in OA, additional well-designed studies are needed. Conclusion In the benefit/risk ratio, the use of chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid could be of potential interest for the symptomatic management of OA. PMID:19087296

  11. Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Alsup, Jason W.; Lai, Yurong; Hu, Yiding; Heyde, Bruce R.; Tung, David

    2009-03-01

    Asthma and chronic obstructive pulmonary disease (COPD) are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT), intranasal (IN), or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD) was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN) dosing, and was able to achieve dose dependent lung deposition.

  12. Evaluation of parenteral drugs for anesthesia in the blue crab (Callinectes sapidus).

    PubMed

    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 (<3 min). Pentobarbital had prolonged inductions (2 min) and often caused violent excitement and poor anesthesia. Propofol induced light anesthesia accompanied by distress and limb autotomy. Inductions with ketamine, xylazine, tiletamine-zolazepam, and ketamine-xylazine were usually fast (<60 sec). Their anesthetic effects were generally very short (5-10 min) but predictable, smooth, and with good muscle relaxation. The latter two protocols induced a deep plane of anesthesia more consistently but also more significant bradycardia. Intracardiac ketamine injection was fatal in four of five crabs. In conclusion, the anesthetic protocols were considered unsuitable for prolonged anesthesia. However, if very short-term anesthesia is desired, then tiletamine-zolazepam or ketamine-xylazine is recommended. Further studies are indicated to identify a safe anesthetic protocol of longer duration in C. sapidus as well as in other crab species.

  13. Drug-induced sleep endoscopy changes snoring management plan very significantly compared to standard clinical evaluation.

    PubMed

    Pilaete, Karen; De Medts, Joris; Delsupehe, Kathelijne Godelieve

    2014-05-01

    Drug-induced sleep endoscopy (DISE) is a new tool in the work-up of patients with sleep-disordered breathing (SDB). We assessed the impact of DISE on the treatment plan of snoring patients. This is a single institution prospective longitudinal clinical trial. The setting is a private teaching hospital. A consecutive series of 100 snoring patients prospectively underwent a standardised questionnaire, clinical examination, rhinomanometry, allergy skin prick testing, DISE and polysomnography. Management plan before and after DISE evaluation was compared. In 61 patients (excluding 16 patients sent for continuous positive airway pressure, three patients refused sleep endoscopy and 20 were lost to follow-up), we compared the treatment plans. DISE showed single level airway collapse in 13 and multilevel collapse in 48 patients. The site of flutter did not add additional information as compared to the pattern and the location of the collapse. After DISE, the initial management plan changed in 41% of patients irrespective of the type of initial management plan. The only somewhat accurate initial treatment plan was uvulopalatopharyngoplasty (unchanged in 11/13 patients). Excluding moderate to severe obstructive sleep apnea patients DISE is an indispensable tool in treatment decision in all SDB patients. We suggest to simplify the protocol for DISE reporting.

  14. Structural mapping of the ClpB ATPases of Plasmodium falciparum: Targeting protein folding and secretion for antimalarial drug design

    PubMed Central

    AhYoung, Andrew P; Koehl, Antoine; Cascio, Duilio; Egea, Pascal F

    2015-01-01

    Caseinolytic chaperones and proteases (Clp) belong to the AAA+ protein superfamily and are part of the protein quality control machinery in cells. The eukaryotic parasite Plasmodium falciparum, the causative agent of malaria, has evolved an elaborate network of Clp proteins including two distinct ClpB ATPases. ClpB1 and ClpB2 are involved in different aspects of parasitic proteostasis. ClpB1 is present in the apicoplast, a parasite-specific and plastid-like organelle hosting various metabolic pathways necessary for parasite growth. ClpB2 localizes to the parasitophorous vacuole membrane where it drives protein export as core subunit of a parasite-derived protein secretion complex, the Plasmodium Translocon of Exported proteins (PTEX); this process is central to parasite virulence and survival in the human host. The functional associations of these two chaperones with parasite-specific metabolism and protein secretion make them prime drug targets. ClpB proteins function as unfoldases and disaggregases and share a common architecture consisting of four domains—a variable N-terminal domain that binds different protein substrates, followed by two highly conserved catalytic ATPase domains, and a C-terminal domain. Here, we report and compare the first crystal structures of the N terminal domains of ClpB1 and ClpB2 from Plasmodium and analyze their molecular surfaces. Solution scattering analysis of the N domain of ClpB2 shows that the average solution conformation is similar to the crystalline structure. These structures represent the first step towards the characterization of these two malarial chaperones and the reconstitution of the entire PTEX to aid structure-based design of novel anti-malarial drugs. PMID:26130467

  15. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

    NASA Astrophysics Data System (ADS)

    Dao, KinhLuan Lenny D.

    Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

  16. Drug use assessment and risk evaluation in pregnancy--the PEGASUS-project.

    PubMed

    Irl, C; Kipferler, P; Hasford, J

    1997-10-01

    Since the thalidomide tragedy it is well accepted that drugs can have adverse effects on the unborn child. Although numerous studies show that drug use during pregnancy is widespread, there still is a serious lack of comprehensive and valid data on the risks of drug use during pregnancy. One objective of the PEGASUS-project, which focuses on Munich, is to enlarge the knowledge on embryo- and fetotoxic properties of drugs by prospectively recording information on drug exposure during pregnancy and analysing these data with regard to untoward fetal outcome. First results of PEGASUS confirm that drug utilization during pregnancy is rather common-85% of women use at least one preparation. The most frequent groups are haematologicals, minerals, iodide, and vitamins. Randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects. However, only very few women in the PEGASUS-project recorded folic acid intake during the critical period or in sufficient dosage.

  17. Docking into knowledge-based potential fields: a comparative evaluation of DrugScore.

    PubMed

    Sotriffer, Christoph A; Gohlke, Holger; Klebe, Gerhard

    2002-05-09

    A new application of DrugScore is reported in which the knowledge-based pair potentials serve as objective function in docking optimizations. The Lamarckian genetic algorithm of AutoDock is used to search for favorable ligand binding modes guided by DrugScore grids as representations of the protein binding site. The approach is found to be successful in many cases where DrugScore-based re-ranking of already docked ligand conformations does not yield satisfactory results. Compared to the AutoDock scoring function, DrugScore yields slightly superior results in flexible docking.

  18. Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy

    PubMed Central

    Wong, Victor C.; Fong, Linda E.; Adams, Nicholas M.; Xue, Qiong; Dey, Siddharth S.; Miller-Jensen, Kathryn

    2014-01-01

    Human immunodeficiency virus 1 (HIV) latency remains a significant obstacle to curing infected patients. One promising therapeutic strategy is to purge the latent cellular reservoir by activating latent HIV with latency-reversing agents (LRAs). In some cases, co-drugging with multiple LRAs is necessary to activate latent infections, but few studies have established quantitative criteria for determining when co-drugging is required. Here we systematically quantified drug interactions between histone deacetylase inhibitors and transcriptional activators of HIV and found that the need for co-drugging is determined by the proximity of latent infections to the chromatin-regulated viral gene activation threshold at the viral promoter. Our results suggest two classes of latent viral integrations: those far from the activation threshold that benefit from co-drugging, and those close to the threshold that are efficiently activated by a single drug. Using a primary T cell model of latency, we further demonstrated that the requirement for co-drugging was donor dependent, suggesting that the host may set the level of repression of latent infections. Finally, we showed that single drug or co-drugging doses could be optimized, via repeat stimulations, to minimize unwanted side effects while maintaining robust viral activation. Our results motivate further study of patient-specific latency-reversing strategies. PMID:26191086

  19. Vinylpyrrolidone-co-(meth)acrylic acid inserts for ocular drug delivery: synthesis and evaluation.

    PubMed

    Barbu, Eugen; Sarvaiya, Indrajeetsinh; Green, Keith L; Nevell, Thomas G; Tsibouklis, John

    2005-09-15

    Copolymeric hydrogels constituting of vinylpyrrolidone and methacrylic or acrylic acid repeat units have been prepared and investigated for their ability to act as controlled release vehicles in ophthalmic drug delivery. The materials were synthesized by radical-induced polymerization in the presence of N,N'-methylenebisacrylamide crosslinker, and the influences of network composition and drug solubility upon the swelling properties, adhesion behavior, and drug release characteristics were studied. In vitro release experiments showed that some of these materials could be useful vehicles for the delivery of drugs such as pilocarpine or chloramphenicol, while in vivo studies, using the rabbit model, confirmed their high potential for the controlled ocular delivery of pilocarpine hydrochloride.

  20. In vitro and in vivo evaluation of ketotifen fumarate-loaded silicone hydrogel contact lenses for ocular drug delivery.

    PubMed

    Xu, Jinku; Li, Xinsong; Sun, Fuqian

    2011-02-01

    The purpose of this work was to evaluate the usefulness of silicone hydrogel contact lenses loaded with ketotifen fumarate for ocular drug delivery. First, silicone contact lenses were prepared by photopolymerization of bitelechelic methacrylated polydimethylsiloxanes macromonomer, 3-methacryloxypropyltris(trimethylsiloxy)silane, and N,N-dimethylacrylamide using ethylene glycol dimethacrylate as a cross-linker and Darocur 1173 as an initiator followed by surface plasma treatment. Then, the silicone hydrogel matrices of the contact lenses were characterized by equilibrium swelling ratio (ESR), tensile tests, ion permeability, and surface contact angle. Finally, the contact lenses were loaded with ketotifen fumarate by pre-soaking in drug solution to evaluate drug loading capacity, in vitro and in vivo release behavior of the silicone contact lenses. The results showed that ESR and ion permeability increase, and the surface contact angle and tensile strength decreased with the increase of DMA component in the silicone hydrogel. The drug loading and in vitro releases were dependent on the hydrogel composition of hydrophilic/hydrophobic phase of the contact lenses. In rabbit eyes, the pre-soaked contact lenses sustained ketotifen fumarate release for more than 24 h, which leads to a more stable drug concentration and a longer mean retention time in tear fluid than that of eye drops of 0.05%.

  1. Evaluation of drug effects on Toxoplasma gondii nuclear and plastid DNA replication using real-time PCR.

    PubMed

    Zhao, Qing; Zhang, Ming; Hong, Lingxian; Zhou, Kefu; Lin, Yuguang

    2010-04-01

    Toxoplasma gondii Nicolle and Manceaux, 1908 is a unicellular protozoan that can infect a broad spectrum of organisms including humans. In addition to a nuclear genome, it also carries a circular DNA within a plastid-like organelle (apicoplast) and a linear genome within its mitochondria. The plastid organelle has been shown to be the target of various anti-parasitic drugs or antibiotics. To evaluate the effects of agents on the DNA replication of T. gondii, we tested six drugs (ciprofloxacin, acetylspiramycin, clindamycin, azithromycin, artemether, and sulfadiazine) on the parasite cultured in Hela cells. After drug treatment for 48 h, the parasite growth and DNA replication were evaluated and quantitated using TaqMan real-time quantitative PCR with oligonucleotide primers synthesized based on a gene from the apicoplast genome (ycf24, Genbank accession no. U87145) and a gene from the nuclear genome (uprt, Genbank accession no. U10246). Our results showed that ciprofloxacin was the most effective in inhibiting the replication of the plastid DNA after 48 h drug treatment, with a reduction of 22% in the copy number of the plastid DNA. Artemether was the most effective drug in suppressing the proliferation of tachyzoites. This study also demonstrates that real-time quantitative PCR is a simple and useful technique for monitoring parasite growth and DNA replication.

  2. Development of drug-in-adhesive transdermal patch for α-asarone and in vivo pharmacokinetics and efficacy evaluation.

    PubMed

    Hu, Ying; Wu, Yao-Yao; Xia, Xiao-Jing; Wu, Zheng; Liang, Wen-Quan; Gao, Jian-Qing

    2011-01-01

    A transdermal drug delivery system has been reported that can increase the bioavailability, reduce the administration duration, and maintain the concentration of drug in blood. In the present study, drug-in-adhesive transdermal patches of α-asarone using Eudragit E100 as pressure-sensitive adhesives and oleic acid plus isopropyl myristate as penetration co-enhancers were developed. In vitro permeation, in vivo pharmacokinetics in rabbits, and efficacy in asthmatic rats were evaluated. The results showed that co-enhancers could induce a synergistic effect on α-asarone permeability. In vivo study suggested that the patch can keep a relatively certain blood level of drug within 10-30 h in rabbits. Furthermore, the patch with the size of 4 cm² containing drug 3 mg/cm² showed a noticeable treating effect on asthmatic rats which is equivalent to the effect of dexamethasone, while avoiding the side-effect induced by the corticorsteroid. This suggests that the drug-in-adhesive transdermal patch is a promising delivery system containing α-asarone to be used for asthma treatment.

  3. Green fabricated reduced graphene oxide: evaluation of its application as nano-carrier for pH-sensitive drug delivery.

    PubMed

    Ma, Naxin; Zhang, Baohua; Liu, Jing; Zhang, Pei; Li, Zhonghao; Luan, Yuxia

    2015-12-30

    A green and mild approach for the preparation of reduced graphene oxide (rGO) was proposed by using riboflavin-5'-phosphate sodium salt dihydrate as a reducing reagent and stabilizer without any other reagent. The fabricated nano-rGO was systematically evaluated for its application as nano-carrier for pH-sensitive drug delivery. The hemolytic toxicity test indicated the as-prepared nano-rGO had negligible hemolytic activity, which demonstrating its safety in drug delivery system. Doxorubicin hydrochloride (DOX) as a model drug was successfully attached onto the surface of nano-rGO via strong π-π stacking interaction. Compared with common carriers, the obtained DOX-loaded nano-rGO nanohybrid exhibited characteristics of high drug loading content, good stability, pH-sensitive and sustainable release of drugs. Cytotoxicity assay results suggested such nanohybrid exhibited effective cytotoxicity to MCF-7 and A549 cells by nonspecific endocytosis mechanism. Therefore, the present green fabricated rGO could be a good candidate as an ideal nano-carrier for drug delivery and controlled release.

  4. A research framework for pharmacovigilance in health social media: Identification and evaluation of patient adverse drug event reports.

    PubMed

    Liu, Xiao; Chen, Hsinchun

    2015-12-01

    Social media offer insights of patients' medical problems such as drug side effects and treatment failures. Patient reports of adverse drug events from social media have great potential to improve current practice of pharmacovigilance. However, extracting patient adverse drug event reports from social media continues to be an important challenge for health informatics research. In this study, we develop a research framework with advanced natural language processing techniques for integrated and high-performance patient reported adverse drug event extraction. The framework consists of medical entity extraction for recognizing patient discussions of drug and events, adverse drug event extraction with shortest dependency path kernel based statistical learning method and semantic filtering with information from medical knowledge bases, and report source classification to tease out noise. To evaluate the proposed framework, a series of experiments were conducted on a test bed encompassing about postings from major diabetes and heart disease forums in the United States. The results reveal that each component of the framework significantly contributes to its overall effectiveness. Our framework significantly outperforms prior work.

  5. A cell-free enzymatic activity assay for the evaluation of HIV-1 drug resistance to protease inhibitors

    PubMed Central

    Matsunaga, Satoko; Masaoka, Takashi; Sawasaki, Tatsuya; Morishita, Ryo; Iwatani, Yasumasa; Tatsumi, Masashi; Endo, Yaeta; Yamamoto, Naoki; Sugiura, Wataru; Ryo, Akihide

    2015-01-01

    Due to their high frequency of genomic mutations, human retroviruses often develop resistance to antiretroviral drugs. The emergence of drug-resistant human immunodeficiency virus type 1 (HIV-1) is a significant obstacle to the effective long-term treatment of HIV infection. The development of a rapid and versatile drug-susceptibility assay would enable acquisition of phenotypic information and facilitate determination of the appropriate choice of antiretroviral agents. In this study, we developed a novel in vitro method, termed the Cell-free drug susceptibility assay (CFDSA), for monitoring phenotypic information regarding the drug resistance of HIV-1 protease (PR). The CFDSA utilizes a wheat germ cell-free protein production system to synthesize enzymatically active HIV-1 PRs directly from PCR products amplified from HIV-1 molecular clones or clinical isolates in a rapid one-step procedure. Enzymatic activity of PRs can be readily measured by AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay Screen) in the presence or absence of clinically used protease inhibitors (PIs). CFDSA measurement of drug resistance was based on the fold resistance to the half-maximal inhibitory concentration (IC50) of various PIs. The CFDSA could serve as a non-infectious, rapid, accessible, and reliable alternative to infectious cell-based phenotypic assays for evaluation of PI-resistant HIV-1. PMID:26583013

  6. Evaluating the impact of hemp food consumption on workplace drug tests.

    PubMed

    Leson, G; Pless, P; Grotenhermen, F; Kalant, H; ElSohly, M A

    2001-01-01

    Foods containing seeds or oil of the hemp plant (Cannabis sativa L.) are increasingly found in retail stores in the U.S. The presence of delta9-tetrahydrocannabinol (THC) in these foods has raised concern over their impact on the results of workplace drug tests for marijuana. Previous studies have shown that eating hemp foods can cause screening and confirmed positive results in urine specimens. This study evaluated the impact of extended daily ingestion of THC via hemp oil on urine levels of its metabolite 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THC-COOH) for four distinct daily THC doses. Doses were representative of THC levels now commonly found in hemp seed products and a range of conceivable daily consumption rates. Fifteen THC-naïve adults ingested, over four successive 10-day periods, single daily THC doses ranging from 0.09 to 0.6 mg. Subjects self-administered THC in 15-mL aliquots (20 mL for the 0.6-mg dose) of four different blends of hemp and canola oils. Urine specimens were collected prior to the first ingestion of oil, on days 9 and 10 of each of the four study periods, and 1 and 3 days after the last ingestion. All specimens were screened for cannabinoids by radioimmunoassay (Immunalysis Direct RIA Kit), confirmed for THC-COOH by gas chromatography-mass spectrometry (